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Background: This analysis evaluated the incidence of all-cause colectomies (total or partial) among patients with moderate-to-severe active ulcerative colitis (UC) in the golimumab (GLM) Program of Ulcerative Colitis Utilizing an Investigational Treatment (PURSUIT)-maintenance (-M) and long-term extension (-LTE) studies. Methods: Eligible PURSUIT-M trial participants completed a 6-week GLM induction trial without requiring colectomy. Responders to GLM induction were randomized 1:1:1 to GLM 50 mg, GLM 100 mg, or placebo (PBO) maintenance for up to 1 year, administered every 4 weeks (q4w). Nonresponders to GLM or PBO induction received GLM 100 mg; responders to PBO induction received PBO (each administered q4w for up to 1 year). Participants who completed PURSUIT-M were eligible to continue their treatment in the 3-year PURSUIT-LTE study. Results: A total of 60 (4.9%) colectomies were reported among the 1228 patients who enrolled in the 1-year PURSUIT-M study, which included 672 participants who continued into the 3-year PURSUIT-LTE LTE study (of which 666 were treated). The colectomy rate during the 3-year extension was lower than that observed during the maintenance phase of the study (9/666 [1.4%] compared to 51/1228 [4.2%]). The majority (43/60 [71.7%]) of the reported colectomies occurred in patients who had not responded to induction therapy and who tended to have had more severe disease characteristics at baseline. Conclusions: This retrospective evaluation of colectomy data from the PURSUIT-M and -LTE studies in patients with moderate-to-severe active UC demonstrated a low (<5%) occurrence of colectomy with long-term (up to 4 years) GLM treatment. PURSUIT-M (NCT00488631; EudraCT, 2006-003399-37).
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INTRODUCTION: Golimumab, a monoclonal antibody against tumor necrosis factor-α (TNF-α), is used widely for treatment of rheumatic diseases. Long-term persistence is an important factor influencing therapeutic benefit and is a surrogate measure of efficacy. We compared five-year golimumab treatment persistence across studies, indications, and lines of therapy using pooled data from pivotal golimumab Phase III clinical trials. METHODS: This post-hoc analysis evaluated use of golimumab administered subcutaneously (50 or 100 mg every four weeks) for up to five years in 2228 adult participants with rheumatoid arthritis (RA; GO-BEFORE, GO-AFTER, and GO-FORWARD studies), psoriatic arthritis (PsA; GO-REVEAL study), or ankylosing spondylitis (AS; GO-RAISE study). Retention rate differences were evaluated by study, indication, and line of therapy using log-rank tests, and probability of treatment persistence was estimated by Kaplan-Meier analysis. RESULTS: Golimumab retention rates at Year 5 were consistently high when used as 1st-line therapy (69.8%) and did not differ significantly across the three indications tested (p = 0.5106) or across 1st-line studies (p = 0.2327). Retention at Year 5 was better in participants using golimumab as 1st-line than in those using it as 2nd-line (41.6%) therapy. Participants on 2nd-line golimumab therapy had a longer disease duration (median 9.2 years versus 3.7 years) than those on 1st-line golimumab therapy. CONCLUSIONS: These data support the value of long-term golimumab therapy in patients with chronic, immune-mediated rheumatic diseases when used as 1st-line (RA, PsA, AS) or 2nd-line (RA) therapy. Key Points ⢠Golimumab is a human monoclonal antibody directed against tumor necrosis factor-α (TNF-α) and is approved widely for the treatment of rheumatic autoimmune diseases. ⢠We compared the probability of treatment persistence, or the time of continuous drug use, for golimumab across five Phase III studies spanning multiple rheumatic indications over five years. ⢠Treatment persistence was favorable and did not differ significantly for participants with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, but persistence was greater when golimumab was used as 1st-line than as 2nd-line biologic therapy.
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Antirreumáticos , Artritis Psoriásica , Artritis Reumatoide , Espondilitis Anquilosante , Adulto , Humanos , Espondilitis Anquilosante/tratamiento farmacológico , Artritis Psoriásica/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/uso terapéutico , Antirreumáticos/efectos adversos , Resultado del Tratamiento , Anticuerpos MonoclonalesRESUMEN
BACKGROUND: In PURSUIT, golimumab (GLM) was efficacious in patients with moderate-to-severe ulcerative colitis (UC). We assessed whether remote monitoring of combined patient-reported Mayo stool frequency and rectal bleeding scores is an effective real-world outcome measure for assessing maintenance of GLM-induced clinical response. METHODS: This was a 54-week prospective, observational cohort study conducted at 43 European outpatient clinics in adults with moderate-to-severe UC who were biologic naïve or had received a maximum of one other biological therapy. Patients were treated according to European GLM UC label/local practice. Clinical response (based on partial or full Mayo score) was assessed at week 6, 10, or 14 of induction, depending on local practice. Investigators remotely monitored scores every 4 weeks. The primary endpoint was the proportion of induction responders in patient-reported continuous clinical response (pCCR) at week 54, defined as absence of UC flare based on combined patient-reported Mayo stool frequency and rectal bleeding scores every 4 weeks and full or partial Mayo score. A key secondary endpoint was the proportion of induction responders in clinical remission at week 54. RESULTS: Among 109 patients, 37 (34.0%) received at least two GLM induction doses and completed induction in clinical response (induction responders). At week 54, 15/37 (40.5%) induction responders were in pCCR, and 21/37 (56.8%) were in clinical remission. CONCLUSION: In daily clinical practice, regular remote monitoring of combined patient-reported Mayo stool frequency and rectal bleeding scores appears to be a meaningful real-world outcome measure for monitoring maintenance of GLM-induced clinical response in UC.
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Colitis Ulcerosa , Adulto , Anticuerpos Monoclonales , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/tratamiento farmacológico , Hemorragia Gastrointestinal , Humanos , Medición de Resultados Informados por el Paciente , Estudios Prospectivos , Inducción de Remisión , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Vorapaxar is a first-in-class antagonist of the protease-activated receptor-1, the primary thrombin receptor on human platelets, which mediates the downstream effects of thrombin in hemostasis and thrombosis. Prasugrel is a platelet inhibitor that acts as a P2Y12 receptor antagonist through an active metabolite, R-138727. This study investigated the interaction of these 2 platelet antagonists when coadministered. This was a randomized, open-label, multiple-dose study in 54 healthy volunteers consisting of a fixed-sequence crossover and a parallel group design. In sequence 1, 36 subjects received prasugrel 60 mg on day 1 and then prasugrel 10 mg once daily on days 2 to 7, followed by vorapaxar 40 mg and prasugrel 10 mg on day 8 and then vorapaxar 2.5 mg and prasugrel 10 mg orally once daily on days 9 to 28. In sequence 2, 18 subjects received vorapaxar 40 mg on day 1 and then vorapaxar 2.5 mg once daily on days 2 to 21. The geometric mean ratios (90% confidence intervals) for AUCτ and Cmax of coadministration/monotherapy for vorapaxar (0.93 ng·h/mL[0.85-1.02 ng·h/mL] and 0.95 ng/mL [0.86-1.05 ng/mL]) and R-138727 (0.91 ng·h/mL [0.85- 0.99 ng·h/mL] and 1.02 ng/mL [0.89-1.17 ng/mL]) were within prespecified bounds, demonstrating the absence of a pharmacokinetic interaction between vorapaxar and prasugrel. There was no specific safety or tolerability risk associated with multiple-dose coadministration of vorapaxar and prasugrel. In conclusion, in this study in healthy volunteers, there was no pharmacokinetic drug-drug interaction between vorapaxar and prasugrel. Multiple-dose coadministration of the 2 drugs was generally well tolerated.
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Lactonas/farmacocinética , Inhibidores de Agregación Plaquetaria/farmacocinética , Clorhidrato de Prasugrel/farmacocinética , Piridinas/farmacocinética , Adulto , Estudios Cruzados , Esquema de Medicación , Interacciones Farmacológicas , Femenino , Voluntarios Sanos , Humanos , Lactonas/administración & dosificación , Lactonas/efectos adversos , Lactonas/sangre , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/sangre , Clorhidrato de Prasugrel/administración & dosificación , Clorhidrato de Prasugrel/efectos adversos , Clorhidrato de Prasugrel/sangre , Piridinas/administración & dosificación , Piridinas/efectos adversos , Piridinas/sangre , Adulto JovenRESUMEN
BACKGROUND: Nitric oxide donors are widely used to treat cardiovascular disease, but their major limitation is the development of tolerance, a multifactorial process to which the in vivo release of nitric oxide is thought to contribute. Here we describe the preclinical and clinical results of a translational drug development effort to create a next-generation nitric oxide donor with improved pharmacokinetic properties and a unique mechanism of nitric oxide release through CYP3A4 metabolism that was designed to circumvent the development of tolerance. METHODS AND RESULTS: Single- and multiple-dose studies in telemetered dogs showed that MK-8150 induced robust blood-pressure lowering that was sustained over 14 days. The molecule was safe and well tolerated in humans, and single doses reduced systolic blood pressure by 5 to 20 mm Hg in hypertensive patients. Multiple-dose studies in hypertensive patients showed that the blood-pressure-lowering effect diminished after 10 days, and 28-day studies showed that the hemodynamic effects were completely lost by day 28, even when the dose of MK-8150 was increased during the dosing period. CONCLUSIONS: The novel nitric oxide donor MK-8150 induced significant blood-pressure lowering in dogs and humans for up to 14 days. However, despite a unique mechanism of nitric oxide release mediated by CYP3A4 metabolism, tolerance developed over 28 days, suggesting that tolerance to nitric oxide donors is multifactorial and cannot be overcome solely through altered in vivo release of nitric oxide. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01590810 and NCT01656408.
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Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Donantes de Óxido Nítrico/farmacología , Triazenos/farmacología , Adolescente , Adulto , Anciano , Animales , GMP Cíclico/metabolismo , Perros , Humanos , Técnicas In Vitro , Túbulos Renales Proximales/citología , Masculino , Persona de Mediana Edad , Donantes de Óxido Nítrico/uso terapéutico , Triazenos/uso terapéutico , Adulto JovenRESUMEN
PURPOSE: We examined first (incident) reports of selected adverse experiences associated with medical therapy in men with lower urinary tract symptoms secondary to benign prostatic hyperplasia. MATERIALS AND METHODS: We studied the 6 most common adverse experiences, including nonsexual function related experiences (dizziness, orthostatic hypotension and weakness) and sexual function related experiences (impotence, decreased libido and abnormal ejaculation) reported in the MTOPS (Medical Therapy of Prostatic Symptoms) Study. A total of 3,047 men were randomized to placebo, doxazosin, finasteride or combination therapy and followed for a mean duration of 4.5 years. We compared the incidence rates of adverse experiences at year 1 to the rates thereafter. RESULTS: For each assigned treatment group, the incidence rates were significantly higher for all 6 adverse experiences examined at year 1 compared with the rates thereafter. Men assigned to combination therapy experienced the highest rates at year 1 with rates 3.4-fold to 10.6-fold higher than rates after year 1. The incidence rates for orthostatic hypotension and dizziness were significantly higher in the doxazosin and combination therapy groups compared with the placebo group at year 1. The incidence rates of the 3 examined sexual function related adverse experiences were significantly higher in the finasteride and combination therapy groups than in the placebo group at year 1. CONCLUSIONS: Rates of the first report of sexual function related and other adverse experiences associated with doxazosin, finasteride and combination therapy were greatest during year 1 of treatment. These patterns should be considered by patients and physicians when treatment for lower urinary tract function is initiated with these drugs.
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Inhibidores de 5-alfa-Reductasa/efectos adversos , Antagonistas de Receptores Adrenérgicos alfa 1/efectos adversos , Doxazosina/efectos adversos , Finasterida/efectos adversos , Hiperplasia Prostática/tratamiento farmacológico , Inhibidores de 5-alfa-Reductasa/uso terapéutico , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapéutico , Doxazosina/uso terapéutico , Quimioterapia Combinada , Finasterida/uso terapéutico , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Próstata/fisiopatología , Factores de TiempoRESUMEN
BACKGROUND: There has been a longstanding question as to whether testosterone therapy could precipitate or worsen urinary symptoms in aging men. We investigated the effects of 1-year oral testosterone undecanoate (TU) therapy on urinary symptoms in aging, hypogonadal men. METHODS: A total of 322 men ≥50 years with symptomatic testosterone deficiency participated in a 1-year, randomized, multicenter, double-blind trial. Patients received placebo or oral TU 80 mg/day, 160 mg/day, or 240 mg/day. RESULTS AND LIMITATIONS: Compared with placebo, treatment with oral TU at doses of 80 mg/day and 160 mg/day resulted in no significant change in IPSS urinary symptoms or quality of life (QoL) scores. Treatment with oral TU 240 mg/day led to a statistically significant, but clinically insignificant, improvement in IPSS total score and a significant improvement in IPSS QoL score. None of the TU doses tested had a significant effect on PSA or PV. CONCLUSIONS: Long-term oral TU therapy had no deleterious effects on IPSS total score and did not change PV and PSA in aging, hypogonadal men. Oral TU therapy at a dose of 240 mg/day may even improve IPSS QoL score.
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Andrógenos/administración & dosificación , Hipogonadismo/tratamiento farmacológico , Síntomas del Sistema Urinario Inferior/tratamiento farmacológico , Testosterona/análogos & derivados , Administración Oral , Anciano , Envejecimiento , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Humanos , Hipogonadismo/fisiopatología , Síntomas del Sistema Urinario Inferior/etiología , Masculino , Persona de Mediana Edad , Hiperplasia Prostática/complicaciones , Testosterona/administración & dosificación , Testosterona/sangreRESUMEN
PURPOSE: We examined the prevalence of low testosterone (LT) and its relationship with body mass index (BMI) in men with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH), who were enrolled in a clinical trial of drug therapy, the Medical Therapy of Prostatic Symptoms (MTOPS) Study. MATERIALS AND METHODS: MTOPS enrolled 3047 men, and of these, 1896 had total testosterone (TT) measured at baseline. LT was defined as a single measurement of TT of <300 ng/dL. RESULTS: The overall prevalence of LT was 25.7%. Prevalence increased with increasing BMI; 14.7% among men who were normal weight (BMI <25 kg/m(2)) and 24.2% and 39.3% among overweight (BMI 25 to <30 kg/m(2)), and obese (baseline BMI ≥30 kg/m(2)) men, respectively. CONCLUSIONS: LT was observed in about one in four MTOPS study participants with baseline TT measurements. The prevalence of LT increased markedly with increasing BMI. Our findings suggest a high prevalence of LT in obese men with LUTS/BPH. Physicians should be alert to the possibility of symptoms of hypogonadism in this population.
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Hipogonadismo , Síntomas del Sistema Urinario Inferior/complicaciones , Obesidad , Hiperplasia Prostática/complicaciones , Testosterona/sangre , Anciano , Índice de Masa Corporal , Humanos , Hipogonadismo/sangre , Hipogonadismo/epidemiología , Hipogonadismo/etiología , Masculino , Persona de Mediana Edad , Obesidad/sangre , Obesidad/complicaciones , Obesidad/diagnóstico , Obesidad/epidemiología , Prevalencia , Factores de Riesgo , Estadística como AsuntoRESUMEN
OBJECTIVE: The American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) diabetes algorithm recommends a stratified approach to initial therapy to achieve a glycated hemoglobin (HbA1c) goal of ≤6.5% in patients with type 2 diabetes mellitus (T2DM) who have inadequate glycemic control. Data from a double-blind study in drug-naïve T2DM patients comparing initial monotherapy with metformin (MET) with initial dual therapy with a fixed-dose combination of sitagliptin and MET (SITA/MET FDC) was used to determine AACE/ACE HbA1c goal attainment in these treatment groups. METHODS: A total of 1,250 patients (mean baseline HbA1c = 9.9%) were randomized 1:1 to SITA/MET FDC 50/500 mg twice daily (b.i.d.) or MET 500 mg b.i.d. for 18 weeks. SITA/MET FDC and MET were uptitrated over 4 weeks to 50/1,000 mg b.i.d. and 1,000 mg b.i.d., respectively. RESULTS: At week 18, a higher percentage of patients receiving SITA/MET FDC had HbA1c levels ≤6.5% and <7% than those receiving MET alone within each of the 3 AACE/ACE HbA1c categories (6.5-7.5%, >7.5-9.0%, and >9.0%). Of patients with a baseline HbA1c >7.5-9.0% who initiated SITA/MET FDC, 48.6% achieved an HbA1c ≤6.5% at week 18 compared with 23.1% of patients who initiated MET monotherapy (P<.001). In patients with a baseline HbA1c >9.0%, 24.0% on SITA/MET FDC achieved an HbA1c ≤6.5% compared with 12.8% on MET alone (P<.001). CONCLUSION: In T2DM patients with a baseline HbA1c >7.5-9.0%, substantially more achieved the HbA1c goal of ≤6.5% with initial dual therapy (SITA/MET FDC) than with initial monotherapy (MET), which is in agreement with the AACE/ACE diabetes algorithm.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Pirazinas/uso terapéutico , Triazoles/uso terapéutico , Adolescente , Adulto , Anciano , Diabetes Mellitus Tipo 2/sangre , Quimioterapia Combinada , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemiantes/administración & dosificación , Masculino , Metformina/administración & dosificación , Persona de Mediana Edad , Pirazinas/administración & dosificación , Fosfato de Sitagliptina , Triazoles/administración & dosificación , Adulto JovenRESUMEN
OBJECTIVE: We investigated the effects of oral testosterone undecanoate (TU) on bone mineral density (BMD), lean body mass (LBM) and body fat mass (BFM) in aging men with symptomatic testosterone deficiency (TD). METHODS: Three hundred twenty-two men ≥50 years with TD symptoms and calculated free testosterone <0.26 nmol/L participated in a multicenter, double-blind, placebo-controlled trial. Patients were randomized to placebo, oral TU 80 mg/d, oral TU 160 mg/d, or oral TU 240 mg/d, administered as divided doses with normal meals. BMD of the hip and lumbar spine were evaluated by dual energy X-ray absorptiometry (DEXA), and body composition (LBM and BFM) by whole body DEXA. RESULTS: Oral TU significantly increased BMD at Month 12 at the lumbar spine (240 mg/d), total hip (240 mg/d), and trochanter and intertrochanter (160 and 240 mg/d) compared with placebo. Oral TU significantly increased LBM at Months 6 and 12 for all oral TU groups compared with placebo. BFM significantly decreased at Month 6 (all oral TU groups) and Month 12 (160 mg/d) compared with placebo. The effects on BMD and body composition showed a clear dose response. CONCLUSIONS: Treatment with oral TU led to improvement in BMD, LBM and BFM in aging men with symptomatic TD.
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Envejecimiento/efectos de los fármacos , Composición Corporal/efectos de los fármacos , Densidad Ósea/efectos de los fármacos , Testosterona/análogos & derivados , Testosterona/deficiencia , Absorciometría de Fotón/métodos , Administración Oral , Anciano , Anciano de 80 o más Años , Enfermedades Carenciales/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Fuerza Muscular/efectos de los fármacos , Estudios Prospectivos , Valores de Referencia , Medición de Riesgo , Testosterona/administración & dosificación , Resultado del TratamientoRESUMEN
OBJECTIVES: We examined the prevalence of low testosterone (LT) in the subset of men in the Proscar Long-term Efficacy and Safety Study (PLESS) who had serum total testosterone (TT) measured at baseline. METHODS: PLESS enrolled 3040 men with benign prostatic hyperplasia (BPH). Of these men, 299 had TT and body mass index (BMI) measurements at baseline. Patients were classified as having LT if their baseline TT was <300 ng/dl. RESULTS: Of the 299 PLESS patients with baseline TT and BMI measurements, 65 (21.7%) had LT. The prevalence of LT increased with increasing BMI, occurring in 8/78 (10.3%) normal weight patients (baseline BMI <25 kg/m2), 35/160 (21.9%) overweight patients (baseline BMI ≥25-<30 kg/m2), and 22/61 (36.1%) obese patients (baseline BMI ≥30 kg/m2). CONCLUSIONS: LT was observed in more than one in five PLESS patients with baseline TT and BMI measurements. The prevalence of LT increased with increasing BMI - more than one in three obese PLESS patients with baseline TT measurements had LT.
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Índice de Masa Corporal , Enfermedades Carenciales/epidemiología , Hiperplasia Prostática/sangre , Testosterona/sangre , Distribución por Edad , Anciano , Composición Corporal , Estudios de Cohortes , Enfermedades Carenciales/diagnóstico , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Seguridad del Paciente , Prevalencia , Antígeno Prostático Específico/sangre , Hiperplasia Prostática/diagnóstico , Hiperplasia Prostática/epidemiología , Valores de Referencia , Medición de Riesgo , Índice de Severidad de la Enfermedad , Testosterona/deficienciaRESUMEN
BACKGROUND: Coadministration of mometasone furoate (MF) and formoterol fumarate (F) produces additive effects for improving symptoms and lung function and reduces exacerbations in patients with asthma and chronic obstructive pulmonary disease (COPD). The present study assessed the relative systemic exposure to MF and characterized the pharmacokinetics of MF and formoterol in patients with COPD. METHODS: This was a single-center, randomized, open-label, multiple-dose, three-period, three-treatment crossover study. The following three treatments were self-administered by patients (n = 14) with moderate-to-severe COPD: MF 400 µg/F 10 µg via a metered-dose inhaler (MF/F MDI; DULERA(®)/ZENHALE(®)) without a spacer device, MF/F MDI with a spacer, or MF 400 µg via a dry-powder inhaler (DPI; ASMANEX(®) TWISTHALER(®)) twice daily for 5 days. Plasma samples for MF and formoterol assay were obtained predose and at prespecified time points after the last (morning) dose on day 5 of each period of the crossover. The geometric mean ratio (GMR) as a percent and the corresponding 90% confidence intervals (CI) were calculated for treatment comparisons. RESULTS: Systemic MF exposure was lower (GMR 77%; 90% CI 58, 102) following administration by MF/F MDI compared to MF DPI. Additionally, least squares geometric mean systemic exposures of MF and formoterol were lower (GMR 72%; 90% CI 61, 84) and (GMR 62%; 90% CI 52, 74), respectively, following administration by MF/F MDI in conjunction with a spacer compared to MF/F MDI without a spacer. MF/F MDI had a similar adverse experience profile as that seen with MF DPI. All adverse experiences were either mild or moderate in severity; no serious adverse experience was reported. CONCLUSION: Systemic MF exposures were lower following administration by MF/F MDI compared with MF DPI. Additionally, systemic MF and formoterol exposures were lower following administration by MF/F MDI with a spacer versus without a spacer. The magnitude of these differences with respect to systemic exposure was not clinically relevant.
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Antiinflamatorios/farmacocinética , Broncodilatadores/farmacocinética , Etanolaminas/farmacocinética , Pregnadienodioles/farmacocinética , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Anciano , Antiinflamatorios/administración & dosificación , Antiinflamatorios/sangre , Broncodilatadores/administración & dosificación , Broncodilatadores/sangre , Estudios Cruzados , Combinación de Medicamentos , Inhaladores de Polvo Seco , Etanolaminas/administración & dosificación , Etanolaminas/sangre , Femenino , Fumarato de Formoterol , Humanos , Masculino , Inhaladores de Dosis Medida , Persona de Mediana Edad , Furoato de Mometasona , Pregnadienodioles/administración & dosificación , Pregnadienodioles/sangreRESUMEN
This randomized, open-label, parallel group study examined the effects of food, antacid, and age on the pharmacokinetics of vorapaxar. In total, 101 subjects were enrolled including 83 young adults (18-45 years) and 18 elderly subjects (>65 years). Subjects received single-dose vorapaxar 40 mg after a 10-hour fast (young and elderly) or with extra-strength antacid, food, or 1 or 2 hours after food (young only). Vorapaxar 40 mg was rapidly absorbed after a fast (median Tmax : 1 hour). Administration with food or 1 or 2 hours post-meal modestly increased vorapaxar mean area under the curve (AUC) and Cmax and prolonged median Tmax by 1 hour. Concomitant food modestly increased vorapaxar AUC from time zero to infinity [AUC(I)] and Cmax 43% and 31%, respectively. Antacid modestly decreased vorapaxar AUC(I) by 15% and Cmax by 38%, and increased median Tmax by 1 hour. Vorapaxar AUC(I) and Cmax were 41% and 29% higher, respectively, in elderly versus young subjects. Concomitant food and older age were associated with modest increases, and antacid was associated with a small decrease in vorapaxar exposure, which are not expected to affect the drug's safety or efficacy.
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BACKGROUND: Vorapaxar, a novel antiplatelet agent in advanced clinical development for the prevention and treatment of atherothrombotic disease, is a potent, orally bioavailable thrombin receptor antagonist selective for the protease-activated receptor 1 (PAR-1). METHODS: Since race/ethnicity may affect the safety, efficacy and dosage of drugs, this study was conducted to evaluate potential differences in the pharmacodynamics, pharmacokinetics and safety of vorapaxar after single (5, 10, 20, or 40 mg) or multiple (0.5, 1, or 2.5 mg once daily) doses in healthy Japanese and matched (gender, age, height, and weight) Caucasian volunteers. RESULTS: Vorapaxar was well tolerated in both Japanese and Caucasian subjects. Pharmacodynamic and pharmacokinetic profiles of vorapaxar in the two racial/ethnic groups were similar. In both racial groups, complete inhibition of platelet aggregation was achieved most rapidly with vorapaxar 40 mg and was consistently achieved and maintained with a 2.5 mg daily maintenance dose. CONCLUSION: There were no substantial differences in the safety, pharmacokinetics or pharmacodynamics of vorapaxar between Japanese and Caucasian subjects.
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Lactonas/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Agregación Plaquetaria/efectos de los fármacos , Piridinas/farmacología , Receptor PAR-1/antagonistas & inhibidores , Adolescente , Adulto , Pueblo Asiatico , Femenino , Humanos , Lactonas/sangre , Lactonas/farmacocinética , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/sangre , Inhibidores de Agregación Plaquetaria/farmacocinética , Piridinas/sangre , Piridinas/farmacocinética , Población Blanca , Adulto JovenRESUMEN
PURPOSE: This post hoc analysis of the Medical Therapy of Prostatic Symptoms trial examined the effect of finasteride alone compared to placebo on the clinical progression of benign prostatic hyperplasia in men with a baseline prostate volume less than 30 ml, or 30 ml or greater. MATERIALS AND METHODS: Men were randomized to placebo (737), 4 to 8 mg doxazosin alone (756), 5 mg finasteride alone (768) or doxazosin plus finasteride (786) (average followup was 4.5 years). Approximately 50% of patients had a baseline prostate volume of 30 ml or greater. The present analysis was based on the finasteride alone and placebo arms only, and included patients for whom baseline and end of study data were available. We examined the effect of treatment on the cumulative percentage of men who did not experience clinical progression of benign prostatic hyperplasia by study end. RESULTS: In men with baseline prostate volume 30 ml or greater treatment with finasteride produced a significant (p <0.001) increase relative to placebo in the cumulative percentage of patients who did not experience clinical progression of benign prostatic hyperplasia (finasteride 88.1% vs placebo 77.8%). There was no significant (p = 0.441) between-group difference in men with baseline prostate volume less than 30 ml (91.4% vs 89.1%, respectively). CONCLUSIONS: Long-term treatment with finasteride led to a significant beneficial effect compared to placebo on the clinical progression of benign prostatic hyperplasia in patients with lower urinary tract symptoms with an enlarged prostate (baseline prostate volume 30 ml or greater). Finasteride had no significant effect compared to placebo on the clinical progression of benign prostatic hyperplasia in patients with lower urinary tract symptoms with a smaller prostate (baseline prostate volume less than 30 ml).
Asunto(s)
Inhibidores de 5-alfa-Reductasa/uso terapéutico , Finasterida/uso terapéutico , Hiperplasia Prostática/tratamiento farmacológico , Progresión de la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Tamaño de los Órganos , Hiperplasia Prostática/patología , Factores de TiempoRESUMEN
OBJECTIVE: We previously examined the inverse relationship between total serum testosterone (T) and the occurrence of the metabolic syndrome in ageing men using baseline data from two lipid treatment studies. We further examined baseline data from a subset of US men participating in one of these two studies to assess the relationship between T and the cardiovascular risk factor lipid, lipoprotein(a) [Lp(a)]. METHODS: Baseline T, lipid, glycaemic and anthropometric data were obtained from 107 men (mean age: 55 years). Inclusion criteria included low-density lipoprotein cholesterol > or = 3.4-4.9 mmol/l and triglycerides < or = 4.0 mmol/l. Baseline Lp(a) levels were examined across the following baseline T subgroups: <15 nmol/l (low/low-normal T) and > or = 15 nmol/l (normal T). RESULTS: There was an overall trend for a higher incidence of clinically significant Lp(a) elevations in men with low T; 17.1% of men in the low/low-normal T subgroup had an Lp(a) level > or = 3 times the upper limit of normal compared to 8.1% in the normal T subgroup. CONCLUSIONS: The data from this descriptive analysis suggest that ageing men with low serum T levels may have an increase in marked elevations in Lp(a), which would be expected to be associated with a significant increase in their cardiovascular event risk.
Asunto(s)
Envejecimiento/sangre , Enfermedades Cardiovasculares/epidemiología , Hipercolesterolemia/sangre , Lipoproteína(a)/sangre , Testosterona/sangre , Anciano , Humanos , Lipoproteínas LDL/sangre , Masculino , Síndrome Metabólico/sangre , Persona de Mediana Edad , Triglicéridos/sangre , Estados Unidos/epidemiologíaRESUMEN
OBJECTIVE: We examined baseline data from a lipid treatment study to assess the relationship between testosterone (T) and the cardiovascular inflammatory marker, high sensitivity C-reactive protein (hsCRP). METHODS: The baseline T, hsCRP, lipid, glycemic, and anthropometric data were obtained from 467 men (mean age: 52 years). Inclusion criteria included low-density lipoprotein cholesterol > or = 3.4 to 4.9 mmol/l and triglycerides < or = 4.0 mmol/l. The baseline hsCRP levels were examined across the following T subgroups: <6.9 nmol/l (moderate to severe hypogonadism), 6.9 to <10.4 nmol/l (mild to moderate hypogonadism), 10.4 to <15 nmol/l (low-normal T), and > or = 15 nmol/l (normal T). RESULTS: The median hsCRP levels were significantly (p = 0.041) different across the four T subgroups; patients in the lower T subgroups had higher median hsCRP levels than patients in the higher T subgroups. The percentage of men with elevated hsCRP (>2 mg/l) was also significantly (p = 0.038) different across the four T subgroups; 83% of men with T < 6.9 nmol/l had elevated hsCRP compared with 40% with T > or = 15 nmol/l. CONCLUSIONS: This analysis demonstrated an inverse relationship between serum T and hsCRP in aging men. Urologists need to be aware that low T levels may not only adversely affect sexual function but also may worsen cardiovascular risk in aging, hypogonadal men.
Asunto(s)
Envejecimiento/sangre , Proteína C-Reactiva/análisis , Testosterona/sangre , Enfermedades Cardiovasculares/sangre , LDL-Colesterol/sangre , Humanos , Hipogonadismo/sangre , Masculino , Persona de Mediana Edad , Factores de Riesgo , Triglicéridos/sangreRESUMEN
OBJECTIVES: To determine the effect of finasteride relative to placebo on prostate cancer (PCa) risk at each individual Gleason score in the Prostate Cancer Prevention Trial using a post hoc generalization of a prespecified, exploratory, biopsy sampling density-adjusted analysis. METHODS: The Prostate Cancer Prevention Trial enrolled 18 882 men aged >or=55 years with a prostate-specific antigen level of <3.0 ng/mL and normal digital rectal examination findings, and randomized them to finasteride 5 mg daily or placebo. PCa data from evaluable biopsies obtained within 7 years plus Asunto(s)
Inhibidores de 5-alfa-Reductasa
, Finasterida/administración & dosificación
, Antígeno Prostático Específico/sangre
, Neoplasias de la Próstata/tratamiento farmacológico
, Neoplasias de la Próstata/patología
, Administración Oral
, Factores de Edad
, Anciano
, Biopsia con Aguja
, Relación Dosis-Respuesta a Droga
, Esquema de Medicación
, Detección Precoz del Cáncer
, Humanos
, Inmunohistoquímica
, Modelos Logísticos
, Masculino
, Persona de Mediana Edad
, Estadificación de Neoplasias
, Prevención Primaria/métodos
, Neoplasias de la Próstata/sangre
, Neoplasias de la Próstata/prevención & control
, Medición de Riesgo
, Resultado del Tratamiento
, Carga Tumoral/efectos de los fármacos
RESUMEN
BACKGROUND: Dyslipidemia and high blood pressure are both major cardiovascular disease risk factors. Niacin is an effective lipid-altering agent that has been reported to reduce the risk of cardiovascular disease. However, the more widespread use of niacin is limited, mainly due to the occurrence of flushing. Laropiprant (LRPT) is a selective antagonist of prostaglandin D(2) receptor subtype 1 that reduces extended-release niacin (ERN)-induced flushing without affecting its beneficial lipid effects. While the lipid effects of ERN are well known, the blood pressure effects are unclear. OBJECTIVE: The aim of this analysis was to examine the blood pressure effects of ERN and ERN/LRPT. METHODS: This was a post hoc analysis of a 24-week, worldwide, multicenter, double-blind, randomized, placebo-controlled, parallel, Phase III, previously published study of dyslipidemic patients, which examined the effect of ERN and ERN/LRPT on systolic blood pressure (SBP) and diastolic blood pressure (DBP). RESULTS: A total of 1613 men and women, aged 21 to 85 years, with primary hypercholesterolemia or mixed dyslipidemia (66% on statins), were included in the original analysis. ERN alone, or in combination with LRPT, was associated with significant reductions in SBP and DBP at 24 weeks from baseline. The placebo-adjusted mean changes from baseline at week 24 in SBP were -2.2 and -3.1 mm Hg for the ERN and ERN/LRPT groups, respectively (P < 0.05 and P < 0.001). Similar changes in DBP were observed; -2.7 and -2.5 mm Hg in the ERN and ERN/ LRPT groups, respectively (both, P < 0.001). CONCLUSION: This post hoc analysis of a 24-week trial found that ERN alone, or in combination with LRPT, was associated with significant placebo-adjusted reductions from baseline in blood pressure in these hyperlipidemic hypertensive or normotensive subjects.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Hipolipemiantes/farmacología , Indoles/farmacología , Niacina/farmacología , Adulto , Anciano , Anciano de 80 o más Años , Ensayos Clínicos Fase III como Asunto , Preparaciones de Acción Retardada , Método Doble Ciego , Combinación de Medicamentos , Dislipidemias/complicaciones , Dislipidemias/tratamiento farmacológico , Femenino , Humanos , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Hipolipemiantes/administración & dosificación , Hipolipemiantes/efectos adversos , Indoles/administración & dosificación , Masculino , Persona de Mediana Edad , Niacina/administración & dosificación , Niacina/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Adulto JovenRESUMEN
PURPOSE: In the present analysis we examined data from the MTOPS (Medical Therapy of Prostatic Symptoms) trial to determine the effect of long-term finasteride treatment, either alone or in combination with doxazosin, on total prostate volume across the full range of baseline total prostate volume values in men enrolled in this study. MATERIALS AND METHODS: In this trial a total of 3,047 patients with lower urinary tract symptoms were randomized to placebo, doxazosin (4 to 8 mg), finasteride (5 mg) or the combination of doxazosin and finasteride (average length of treatment 4.5 years). Total prostate volume was measured by transrectal ultrasound in all patients at baseline, yearly and at study end or at termination of participation. RESULTS: Long-term treatment with finasteride led to a consistent reduction of approximately 25% in total prostate volume compared to placebo in men with a relatively small prostate (less than 25 to 30 ml), as well as in those with a moderate size (30 to less than 40 ml) or enlarged prostate (40 ml or greater) at baseline. CONCLUSIONS: In this MTOPS data analysis long-term (more than 4 years) treatment with finasteride, either alone or in combination with doxazosin, led to a consistent, clinically significant reduction in total prostate volume compared to placebo in patients with lower urinary tract symptoms and benign prostatic hyperplasia whose baseline prostate size ranged from relatively small (less than 25 to 30 ml) to enlarged (40 ml or greater).