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1.
COPD ; 16(5-6): 344-353, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31682162

RESUMO

Mitogen-activated protein kinase p38 is a key regulator in the inflammation pathway and is activated in the lungs of chronic obstructive pulmonary disease (COPD) patients. Acumapimod is a potent, selective, oral, p38 inhibitor under investigation for treatment of acute exacerbations of COPD (AECOPD). In this Phase II, double-blind, randomized, placebo-controlled dose-exploration study of acumapimod in patients with moderate or severe AECOPD (NCT01332097), patients presenting with AECOPD were randomized to receive single-dose acumapimod (20 mg or 75 mg) on Day 1, repeated single-dose acumapimod (20 mg or 75 mg) on Days 1 and 6, oral prednisone 40 mg (10 days), or placebo. Primary outcome: improvement in forced expiratory volume in 1 s (FEV1) versus placebo at Day 5 (single doses) and Day 10 (repeated doses). N = 183 patients were randomized; 169 (92%) patients completed the study. Although the primary endpoint (FEV1 at Day 10) was not met (p = 0.082), there was a significant improvement in FEV1 with acumapimod repeat-dose 75 mg versus placebo at Day 8 (p = 0.022) which, though not a prespecified endpoint, was part of an overall trend. Differences at lower doses did not achieve significance. Mean change in FEV1 AUC from baseline to Day 14 in the 75 mg repeat-dose group was significantly higher versus placebo (p = 0.02), prednisone (p = 0.01), and 20 mg single-dose groups (p = 0.015) (post-hoc analysis). EXACT-PRO showed numerical differences versus placebo that did not reach significance. Acumapimod was well tolerated. In conclusion, repeated single-dose acumapimod showed a clinically relevant improvement in FEV1 over placebo at Day 8, along with consistent numerical differences in EXACT-PRO. These data can be used to determine dose regimens for a proof-of-clinical-concept trial.

3.
Eur J Heart Fail ; 21(8): 998-1007, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31134724

RESUMO

AIMS: To assess tolerability and optimal time point for initiation of sacubitril/valsartan in patients stabilised after acute heart failure (AHF). METHODS AND RESULTS: TRANSITION was a randomised, multicentre, open-label study comparing two treatment initiation modalities of sacubitril/valsartan. Patients aged ≥ 18 years, hospitalised for AHF were stratified according to pre-admission use of renin-angiotensin-aldosterone system inhibitors and randomised (n = 1002) after stabilisation to initiate sacubitril/valsartan either ≥ 12-h pre-discharge or between Days 1-14 post-discharge. Starting dose (as per label) was 24/26 mg or 49/51 mg bid with up- or down-titration based on tolerability. The primary endpoint was the proportion of patients attaining 97/103 mg bid target dose after 10 weeks. Median time of first dose of sacubitril/valsartan from the day of discharge was Day -1 and Day +1 in the pre-discharge group and the post-discharge group, respectively. Comparable proportions of patients in the pre- and post-discharge initiation groups met the primary endpoint [45.4% vs. 50.7%; risk ratio (RR) 0.90; 95% confidence interval (CI) 0.79-1.02]. The proportion of patients who achieved and maintained for ≥ 2 weeks leading to Week 10, either 49/51 or 97/103 mg bid was 62.1% vs. 68.5% (RR 0.91; 95% CI 0.83-0.99); or any dose was 86.0% vs. 89.6% (RR 0.96; 95% CI 0.92-1.01). Discontinuation due to adverse events occurred in 7.3% vs. 4.9% of patients (RR 1.49; 95% CI 0.90-2.46). CONCLUSIONS: Initiation of sacubitril/valsartan in a wide range of heart failure with reduced ejection fraction patients stabilised after an AHF event, either in hospital or shortly after discharge, is feasible with about half of the patients achieving target dose within 10 weeks. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02661217.

4.
J Card Fail ; 25(3): 176-187, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30721735

RESUMO

OBJECTIVE: The significance of liver stiffness (LS) in the setting of cardiovascular congestion during the course of acute decompensated heart failure (ADHF) is under investigation. The aim of this study was to assess LS with the use of transient elastography (TE) and its associations with volume overload as determined by means of bioimpedance vector analysis (BIVA) in ADHF. METHODS AND RESULTS: TE (Fibroscan 502; Echosens) and BIVA (ABC-01, Medass) were performed in the first 48 hours of admission and on the day of discharge in 149 ADHF patients without known primary chronic liver disease or acute hepatitis. During hospitalization the median value of LS decreased from 12.2 kPa (interquartile range 6.3-23.6) to 8.7 (5.9-14.4) kPa (P < .001). Changes in LS correlated (P < .001) with changes in weight and BIVA parameters. LS was compared with histologic features of livers of ADHF patients who died (n = 7). Liver fibrosis 2B-4 was observed but was not associated with LS. LS at discharge was associated with increased risk of 12-month all-cause death, HF readmission, and the combined end point. CONCLUSIONS: There was a moderate association between LS with clinical congestion and volume overload according to BIVA and no correlation with degree of histologic liver fibrosis. LS may be a marker of negative HF outcomes.


Assuntos
Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/epidemiologia , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/epidemiologia , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
5.
Clin Ther ; 40(5): 704-718.e6, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29703432

RESUMO

PURPOSE: Elbasvir (MK-8742) and grazoprevir (MK-5172; Merck & Co, Inc, Kenilworth, New Jersey) are hepatitis C virus (HCV)-specific inhibitors of the nonstructural protein 5A phosphoprotein and the nonstructural protein 3/4A protease, respectively. The aims of these studies were to evaluate the antiviral activity and safety of different doses of elbasvir or grazoprevir each administered as monotherapy to participants infected with either HCV genotype (GT) 1 or GT3. METHODS: These 2 double-blind, randomized, placebo-controlled, sequential-panel, multiple ascending dose studies were conducted to assess the safety and pharmacodynamics of 5 days of once-daily elbasvir or 7 days of once-daily grazoprevir in adult male participants chronically infected with either HCV GT1 or GT3. FINDINGS: Oral administration of elbasvir or grazoprevir once daily exhibited potent antiviral activity in participants with chronic GT1 or GT3 HCV infections. HCV RNA levels declined rapidly (within 1 day for elbasvir and 2 days for grazoprevir). At 50 mg of elbasvir once daily, the mean maximum reductions in HCV RNA from baseline were 5.21, 4.17, and 3.12 log10 IU/mL for GT1b-, GT1a-, and GT3-infected participants, respectively. At 100 mg of grazoprevir once daily, the mean maximum reductions in HCV RNA from baseline were 4.74 and 2.64 log10 IU/mL for GT1- and GT3-infected participants. IMPLICATIONS: The results in the elbasvir monotherapy study showed that 10 to 50 mg of elbasvir was associated with a rapid decline in HCV viral load; the results in the grazoprevir monotherapy study suggest that doses of 50 mg of grazoprevir and higher are on the maximum response plateau of the dose-response curve for GT1-infected participants. The results of these proof-of-concept studies provided preliminary data for the selection of the dosages of elbasvir and grazoprevir to test in Phase II and III clinical studies. ClinicalTrials.gov identifiers: NCT00998985 (Protocol 5172-004) and NCT01532973 (Protocol 8742-002).


Assuntos
Antivirais/uso terapêutico , Benzofuranos/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Imidazóis/uso terapêutico , Quinoxalinas/uso terapêutico , Adulto , Método Duplo-Cego , Genótipo , Hepacivirus/genética , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral
6.
Minerva Gastroenterol Dietol ; 64(3): 208-219, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29431335

RESUMO

BACKGROUND: The effect of oral and/or parenteral ademetionine (500 mg intravenous [IV] and tablet formulation) on clinical symptoms and biochemical markers of intrahepatic cholestasis (IHC) was investigated in subjects with alcoholic liver disease (ALD) and compensated liver function. METHODS: Prospective, multicenter, open-label study consisting of a screening period and an 8-week treatment period and performed in subjects (18-75 years) with compensated ALD and confirmed IHC. Subjects with a baseline serum conjugated bilirubin value above normal range were initially treated with IV ademetionine for two weeks (500-800 mg daily) and continued with oral ademetionine 1500 mg daily for a further six weeks. Subjects with a baseline serum conjugated bilirubin value within normal range were treated with oral ademetionine for eight weeks. RESULTS: A total of 72 subjects were treated; 41 initially with IV ademetionine and 31 with oral ademetionine. Clinical symptoms status improved from baseline to end of treatment with an increase in the proportion of subjects with no symptoms. Ademetionine showed significant improvements in primary efficacy parameters alkaline phosphatase (ALP) and γ-glutamyltransferase (γGT) (P<0.0001). Although decreases of ALP were higher for subjects initially treated with IV ademetionine, these subjects also had higher baseline values. No safety concerns with ademetionine arose with respect to the severity or frequency of adverse events (AEs) during the treatment period, laboratory parameters, and vital signs. CONCLUSIONS: Administration of oral or IV/oral ademetionine step-therapy for 8 weeks to subjects with IHC due to ALD was safe and provided a significant improvement of disease burden.


Assuntos
Colestase Intra-Hepática/tratamento farmacológico , S-Adenosilmetionina/administração & dosagem , Adolescente , Adulto , Idoso , Colestase Intra-Hepática/complicações , Feminino , Humanos , Hepatopatias Alcoólicas/complicações , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
7.
J Hypertens ; 36(4): 824-833, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29324585

RESUMO

OBJECTIVE: The aim of the Advanced Approach to Arterial Stiffness study was to compare arterial stiffness measured simultaneously with two different methods in different age groups of middle-aged and older adults with or without metabolic syndrome (MetS). The specific effects of the different MetS components on arterial stiffness were also studied. METHODS: This prospective, multicentre, international study included 2224 patients aged 40 years and older, 1664 with and 560 without MetS. Patients were enrolled in 32 centres from 18 European countries affiliated to the International Society of Vascular Health & Aging. Arterial stiffness was evaluated using the cardio-ankle vascular index (CAVI) and the carotid-femoral pulse wave velocity (CF-PWV) in four prespecified age groups: 40-49, 50-59, 60-74, 75-90 years. In this report, we present the baseline data of this study. RESULTS: Both CF-PWV and CAVI increased with age, with a higher correlation coefficient for CAVI (comparison of coefficients P < 0.001). Age-adjusted and sex-adjusted values of CF-PWV and CAVI were weakly intercorrelated (r = 0.06, P < 0.001). Age-adjusted and sex-adjusted values for CF-PWV but not CAVI were higher in presence of MetS (CF-PWV: 9.57 ±â€Š0.06 vs. 8.65 ±â€Š0.10, P < 0.001; CAVI: 8.34 ±â€Š0.03 vs. 8.29 ±â€Š0.04, P = 0.40; mean ±â€ŠSEM; MetS vs. no MetS). The absence of an overall effect of MetS on CAVI was related to the heterogeneous effects of the components of MetS on this parameter: CAVI was positively associated with the high glycaemia and high blood pressure components, whereas lacked significant associations with the HDL and triglycerides components while exhibiting a negative association with the overweight component. In contrast, all five MetS components showed positive associations with CF-PWV. CONCLUSION: This large European multicentre study reveals a differential impact of MetS and age on CAVI and CF-PWV and suggests that age may have a more pronounced effect on CAVI, whereas MetS increases CF-PWV but not CAVI. This important finding may be due to heterogeneous effects of MetS components on CAVI. The clinical significance of these original results will be assessed during the longitudinal phase of the study.


Assuntos
Artérias/fisiopatologia , Hiperglicemia/fisiopatologia , Hipertensão/fisiopatologia , Síndrome Metabólica/fisiopatologia , Rigidez Vascular , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Índice Tornozelo-Braço , Glicemia/metabolismo , Pressão Sanguínea , Estudos de Casos e Controles , Dislipidemias/fisiopatologia , Feminino , Humanos , Lipoproteínas HDL/sangue , Masculino , Pessoa de Meia-Idade , Obesidade/fisiopatologia , Estudos Prospectivos , Análise de Onda de Pulso , Triglicerídeos/sangue
8.
N Engl J Med ; 377(12): 1119-1131, 2017 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-28845751

RESUMO

BACKGROUND: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. METHODS: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1ß, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P=0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P=0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P=0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P=0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P=0.31). CONCLUSIONS: Antiinflammatory therapy targeting the interleukin-1ß innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846 .).


Assuntos
Anti-Inflamatórios/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Aterosclerose/tratamento farmacológico , Interleucina-1beta/antagonistas & inibidores , Infarto do Miocárdio/tratamento farmacológico , Idoso , Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Aterosclerose/sangue , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/mortalidade , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Incidência , Interleucina-1beta/imunologia , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/prevenção & controle , Neutropenia/induzido quimicamente , Prevenção Secundária , Acidente Vascular Cerebral/prevenção & controle
9.
Br J Clin Pharmacol ; 83(12): 2678-2686, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28722153

RESUMO

AIMS: Human cytomegalovirus constitutes a prevalent and serious threat to immunocompromised individuals and requires new treatments. Letermovir is a novel viral-terminase inhibitor that has demonstrated prophylactic/pre-emptive activity against human cytomegalovirus in Phase 2 and 3 transplant trials. As unchanged letermovir is primarily excreted via the liver by bile, this trial aimed to assess the effect of hepatic impairment on letermovir pharmacokinetics. METHODS: Phase 1, open-label, parallel-group pharmacokinetic and safety comparison of multiple once-daily oral letermovir in female subjects with hepatic impairment and healthy matched controls. For 8 days, subjects with moderate hepatic impairment (n = 8) and their matched healthy controls (n = 9) received 60 mg letermovir/day and those with severe hepatic impairment (n = 8) and their matched healthy controls (n = 8) received 30 mg letermovir/day. Pharmacokinetic parameters were determined from blood samples. RESULTS: For subjects with moderate hepatic impairment, maximal observed concentration at steady state (Css,max ) and the area under the concentration vs. time curve over a dosing interval at steady state (AUCτ,ss ) for total letermovir were 1.37-fold (90% confidence interval: 0.87, 2.17) and 1.59-fold (0.98, 2.57) higher, respectively, than in healthy subjects. For subjects with severe hepatic impairment, Css,max and AUCτ,ss values of total letermovir were 2.34-fold (1.91, 2.88) and 3.82-fold (2.94, 4.97) higher, respectively, compared with healthy subjects. CONCLUSIONS: Moderate hepatic impairment increased exposure to letermovir <2-fold, while severe hepatic impairment increased letermovir exposure approximately 4-fold as compared with healthy subjects. Letermovir 60/30 mg/day was generally well-tolerated in subjects with hepatic impairment.


Assuntos
Acetatos/farmacocinética , Antivirais/farmacocinética , Infecções por Citomegalovirus/tratamento farmacológico , Hepatopatias/metabolismo , Fígado/metabolismo , Quinazolinas/farmacocinética , Acetatos/administração & dosagem , Acetatos/efeitos adversos , Acetatos/sangue , Administração Oral , Adolescente , Adulto , Idoso , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/sangue , Área Sob a Curva , Esquema de Medicação , Feminino , Meia-Vida , Humanos , Fígado/fisiopatologia , Hepatopatias/diagnóstico , Hepatopatias/fisiopatologia , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Quinazolinas/sangue , Federação Russa , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
10.
Cardiovasc Ther ; 34(4): 191-8, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26990595

RESUMO

AIMS: Concomitant renin-angiotensin-aldosterone system blockade and natriuretic peptide system enhancement may provide unique therapeutic benefits to patients with heart failure and reduced ejection fraction (HFrEF). This study assessed the pharmacodynamics and pharmacokinetics of LCZ696 in patients with HFrEF. METHODS: This was an open-label, noncontrolled single-sequence study. After a 24-h run-in period, patients (n = 30) with HFrEF (EF ≤ 40%; NYHA class II-IV) received LCZ696 100 mg twice daily (bid) for 7 days and 200 mg bid for 14 days, along with standard treatment for heart failure (HF) (except angiotensin-converting enzyme inhibitors [ACEIs] or angiotensin receptor blockers [ARBs]). RESULTS: On Day 21, significant increases were observed in the plasma biomarkers indicative of neprilysin and RAAS inhibition (ratio-to-baseline: cyclic guanosine monophosphate [cGMP], 1.38; renin concentration and activity, 3.50 and 2.27, respectively; all, P < 0.05). Plasma NT-proBNP levels significantly decreased at all the time points on Days 7 and 21; plasma aldosterone and endothelin-1 levels significantly decreased on Day 21 (all, P < 0.05). Following administration of LCZ696, the Cmax of sacubitril (neprilysin inhibitor prodrug), LBQ657 (active neprilysin inhibitor), and valsartan were reached within 0.5, 2.5, and 2 h. Between 100- and 200-mg doses, the Cmax and AUC0-12 h for sacubitril and LBQ657 were approximately dose-proportional while that of valsartan was less than dose-proportional. CONCLUSIONS: Treatment with LCZ696 for 21 days was well tolerated and resulted in plasma biomarker changes indicative of neprilysin and RAAS inhibition in patients with HF. The pharmacokinetic exposure of the LCZ696 analytes in patients with HF observed in this study is comparable to that observed in the pivotal Phase III study.


Assuntos
Aminobutiratos/farmacocinética , Antagonistas de Receptores de Angiotensina/farmacocinética , Insuficiência Cardíaca/tratamento farmacológico , Volume Sistólico , Tetrazóis/farmacocinética , Função Ventricular Esquerda , Idoso , Aldosterona/sangue , Aminobutiratos/administração & dosagem , Antagonistas de Receptores de Angiotensina/administração & dosagem , Antagonistas de Receptores de Angiotensina/efeitos adversos , Antagonistas de Receptores de Angiotensina/sangue , Área Sob a Curva , Biomarcadores/sangue , Doença Crônica , Esquema de Medicação , Endotelina-1/sangue , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Neprilisina/antagonistas & inibidores , Neprilisina/metabolismo , Fragmentos de Peptídeos/sangue , Sistema Renina-Angiotensina/efeitos dos fármacos , Federação Russa , Tetrazóis/administração & dosagem , Resultado do Tratamento
11.
J Clin Pharmacol ; 56(3): 316-23, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26183800

RESUMO

The pharmacokinetics (PK) and safety of single-dose buparlisib (30 mg) were assessed in subjects with mild to severe hepatic impairment (n = 6 each) relative to healthy controls (n = 13). Blood samples were collected until 336 hours postdose and evaluated by liquid chromatography tandem mass spectrometry. PK parameters (including area under the curve [AUC∞ ] and Cmax ) were derived using noncompartmental analysis. Buparlisib was rapidly absorbed in all groups (median Tmax 1.0-1.3 h). Buparlisib exposure (AUC∞ ) was moderately increased in subjects with mild (geometric mean ratio [GMR] 1.16; 90%CI 0.81, 1.65), moderate (GMR 1.14; 90%CI 0.80, 1.63), or severe (GMR 1.20; 90%CI 0.84, 1.72) hepatic impairment, relative to healthy controls. Apparent oral clearance was similar across groups. Due to a higher unbound fraction in the severe group (0.21) than all other groups (0.17), subjects with severe hepatic impairment had greater exposure to unbound buparlisib (GMR relative to healthy controls: AUC∞ 1.52; 90%CI 1.09, 2.13; Cmax 1.83; 90%CI 1.42, 2.36). The results indicate that a buparlisib dose adjustment may not be necessary for patients with mild to moderate hepatic impairment. The safety and therapeutic indices should be considered before determining if a dose adjustment is appropriate for patients with severe hepatic impairment.


Assuntos
Aminopiridinas/administração & dosagem , Aminopiridinas/farmacocinética , Hepatopatias/sangue , Hepatopatias/diagnóstico , Morfolinas/administração & dosagem , Morfolinas/farmacocinética , Administração Oral , Adolescente , Adulto , Idoso , Aminopiridinas/efeitos adversos , Aminopiridinas/sangue , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Morfolinas/sangue , Índice de Gravidade de Doença , Adulto Jovem
12.
Int J Clin Pharmacol Ther ; 53(10): 847-54, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26308173

RESUMO

OBJECTIVE: This study assessed the pharmacokinetics and tolerability of fingolimod and its metabolites in severe renal impairment and healthy subjects. METHODS: In this single-dose, open-label study, 9 severe renal impairment subjects and 9 demographically matched healthy subjects were included. Each subject received a single oral dose of fingolimod 1.25 mg, and their blood and urine samples were assessed. The pharmacokinetics of fingolimod and its metabolites, fingolimod-phosphate (active metabolite, fingolimod-P), M2, and M3, were compared in both groups. Safety and tolerability were also assessed. RESULTS: In severe renal impairment subjects, mean±standard deviation values of Cmax (ng/mL) of fingolimod and fingolimod-P were 0.878±0.256 and 1.13±0.293 vs. 0.653±0.138 and 0.904±0.229 in healthy subjects, respectively. The overall drug exposures (AUCinf (ngxh/mL)) for fingolimod and fingolimod-P were 131±90.7 and 75.5±33.6 in severe renal impairment subjects vs. 82.3±36.9 and 65.9±30.6 in healthy subjects, respectively. t1/2 (hours) for fingolimod and fingolimod-P was comparable in severe renal impairment subjects (94±53 and 95±50) and healthy subjects (85±25 and 101±46). All adverse events were as expected for fingolimod 1.25 mg. CONCLUSIONS: The exposure to fingolimod and fingolimod-P was moderately increased (90% CI, 0.94-2.18) in severe renal impairment subjects, while half-lives and protein binding were similar to those in healthy subjects. Given that these changes are not clinically meaningful, fingolimod dose adjustment is considered unnecessary in patients with mild, moderate, or severe renal impairment.


Assuntos
Cloridrato de Fingolimode/farmacocinética , Insuficiência Renal/metabolismo , Adulto , Feminino , Cloridrato de Fingolimode/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade
13.
Br J Clin Pharmacol ; 79(6): 937-45, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25511105

RESUMO

AIMS: Serelaxin is a recombinant form of human relaxin-2 in development for treatment of acute heart failure. This study aimed to evaluate the pharmacokinetics (PK) of serelaxin in patients with hepatic impairment. Secondary objectives included evaluation of immunogenicity, safety and tolerability of serelaxin. METHODS: This was an open-label, parallel group study (NCT01433458) comparing the PK of serelaxin following a single 24 h intravenous (i.v.) infusion (30 µg kg(-1) day(-1) ) between patients with mild, moderate or severe hepatic impairment (Child-Pugh class A, B, C) and healthy matched controls. Blood sampling and standard safety assessments were conducted. Primary non-compartmental PK parameters [including area under the serum concentration-time curve AUC(0-48 h) and AUC(0-∞) and serum concentration at 24 h post-dose (C24h )] were compared between each hepatic impairment group and healthy controls. RESULTS: A total of 49 subjects (including 25 patients with hepatic impairment) were enrolled, of which 48 subjects completed the study. In all groups, the serum concentration of serelaxin increased over the first few hours of infusion, reached steady-state at 12-24 h and then declined following completion of infusion, with a mean terminal half-life of 7-8 h. All PK parameter estimates were comparable between each group of patients with hepatic impairment and healthy controls. No serious adverse events, discontinuations due to adverse events or deaths were reported. No serelaxin treatment-related antibodies developed during this study. CONCLUSIONS: The PK and safety profile of serelaxin were not affected by hepatic impairment. No dose adjustment is needed for serelaxin treatment of 48 h i.v. infusion in patients with hepatic impairment.


Assuntos
Fármacos Cardiovasculares/farmacocinética , Hepatopatias/metabolismo , Fígado/metabolismo , Relaxina/farmacocinética , Área Sob a Curva , Fármacos Cardiovasculares/administração & dosagem , Fármacos Cardiovasculares/efeitos adversos , Fármacos Cardiovasculares/sangue , Esquema de Medicação , Feminino , Alemanha , Humanos , Infusões Intravenosas , Fígado/fisiopatologia , Hepatopatias/sangue , Hepatopatias/diagnóstico , Hepatopatias/fisiopatologia , Testes de Função Hepática , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Modelos Biológicos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/sangue , Proteínas Recombinantes/farmacocinética , Relaxina/administração & dosagem , Relaxina/efeitos adversos , Relaxina/sangue , Federação Russa , Índice de Gravidade de Doença
14.
Med Devices (Auckl) ; 7: 91-7, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24833924

RESUMO

BACKGROUND: The objective of this study was to validate the novel integration of oscillometric (Vasotens(®)) technology into a BPLab(®) ambulatory blood pressure (BP) monitoring system to measure central BP, the aortic augmentation index, and pulse wave velocity (PWV) compared with the recommended and widely accepted tonometric method. METHODS: The ARTERY Society guidelines for comparison of PWV measurement techniques were used as the basis for recruitment of 99 individuals (mean age 44±19 years, 52 males). The standard for comparison was the conventional "classic" SphygmoCor device. RESULTS: Accordance of the two methods was satisfactory (r=0.98, mean difference of 2.9±3.5 mmHg for central systolic BP; r=0.98, mean difference of -1.1±2.3 mmHg for central diastolic BP; r=0.83, mean difference of -2.6%±13% for aortic augmentation index; r=0.85, mean difference of 0.69±1.4 for PWV). CONCLUSION: The performance of Vasotens algorithms using an oscillometric ambulatory BP monitoring system is feasible for accurate diagnosis, risk assessment, and evaluation of the effects of antihypertensive drugs.

15.
Curr Med Res Opin ; 30(5): 805-11, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24400847

RESUMO

OBJECTIVES: The primary objective of this study was to establish the proportion of patients with stable angina and arterial hypertension on beta-blocker (BB) treatment reaching target resting heart rates (RHR) of 55-60 beats per min in clinical cardiology and general practice in Russia. Secondary objectives included the association between achievement of target RHR and mean BB doses, Seattle Angina Questionnaire (SAQ) scores and achievement of target blood pressure (BP) levels (systolic/diastolic BP <140/90 mmHg). RESEARCH DESIGN AND METHODS: ATHENA (AchievemenT of target resting HEart rate on beta-blockers in patients with stable angiNA and hypertension) was a non-interventional, cross-sectional, observational study conducted in 20 sites in Russia (NCT01321242). The study population comprised patients aged ≥18 years with stable angina (class I-III) and primary hypertension, on BB treatment for ≥2 months prior to enrollment. RESULTS: Of 399 study participants, 62 (15.5%; 95% confidence interval [CI]: 0.121 to 0.195) achieved target RHR. Clinical characteristics associated with significant differences between subgroups achieving and not achieving target RHR were systolic BP (131.1 vs 138.2 mmHg, P = 0.006), diastolic BP (78.6 vs 83.5 mmHg, P < 0.001) and frequency of nitroglycerin administration (1.5% vs 3.0%, P = 0.045). Most patients were taking bisoprolol (48.9%) and metoprolol (36.1%), with mean daily doses of 5.5 mg and 73.7 mg, respectively. Median SAQ scores were: 52.8 physical limitation, 50.0 angina stability, 60.0 angina frequency, 75.0 treatment satisfaction, 50.0 disease perception (quality of life) and 59.6 total score, with no significant differences between subgroups. Patients achieving target RHR were significantly more likely also to achieve target BP, compared with patients not achieving target RHR (72.6% vs 53.4%; P = 0.005; odds ratio: 2.309; 95% CI: 1.270 to 4.197). CONCLUSION: In a Russian population with stable angina and hypertension on BB treatment, RHR control was suboptimal. ClinicalTrials.gov identifier: NCT01321242.


Assuntos
Antagonistas Adrenérgicos beta/administração & dosagem , Angina Estável/tratamento farmacológico , Angina Estável/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Angina Estável/epidemiologia , Estudos Transversais , Feminino , Humanos , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Federação Russa/epidemiologia
16.
Clin Ther ; 35(3): 215-25, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23453404

RESUMO

BACKGROUND: Although the pharmacokinetics of everolimus, an oral mammalian target of rapamycin inhibitor, have been characterized in patients with moderate hepatic impairment, they have not been assessed in those with mild or severe hepatic impairment. OBJECTIVE: The goal of this study was to assess the pharmacokinetics and safety of everolimus in healthy volunteers with normal hepatic function and patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment in otherwise good health to inform dosing in the clinical setting. METHODS: A multicenter, open-label, Phase I study in which all enrollees received a single, 10-mg, oral everolimus dose was conducted. Blood samples for pharmacokinetic assessment were collected at predetermined time points up to 168 hours postdosing. Safety was also assessed. Proposed dose recommendations based on Child-Pugh status at baseline and day 8 were calculated based on AUC0-∞ geometric mean ratios and their associated 90% CIs. Post hoc analysis of the relationship between pharmacokinetic parameters and markers of hepatic function was also performed to identify thresholds for dose adjustment. RESULTS: Thirteen subjects with normal hepatic function and 7 patients with mild, 8 patients with moderate, and 6 patients with severe hepatic impairment were enrolled. Compared with normal subjects, everolimus AUC0-∞ for patients with mild, moderate, and severe hepatic impairment increased by 1.60-, 3.26-, and 3.64-fold, respectively. Based on Child-Pugh classification at day 8, the everolimus doses required to adjust the exposure of patients with mild, moderate, and severe hepatic impairment to that of normal subjects were 6.25, 3.07, and 2.75 mg, respectively. Thresholds for 2-fold everolimus dose reduction were 15.0 µmol/L for bilirubin, 43.1 g/L for albumin, and 1.1 for the international normalized ratio; using these thresholds could lead to underdosing or overdosing in some patients. Most adverse events were of grade 1 severity, ≤1 day in duration, and not everolimus related. CONCLUSIONS: Everolimus exposure after a single 10-mg dose was influenced by the degree of hepatic impairment. Child-Pugh classification was found to be the most conservative means of guiding dose adjustment in patients with hepatic impairment. Based on these data, as well as previously reported data for patients with moderate hepatic impairment, everolimus once-daily dosing should be 7.5 mg and 5 mg in patients with mild and moderate impairment, respectively. Everolimus is not recommended in patients with severe hepatic impairment unless benefits outweigh risks; in that case, 2.5 mg once daily should not be exceeded. ClinicalTrials.gov identifier: NCT00968591.


Assuntos
Imunossupressores/farmacocinética , Fígado/fisiopatologia , Sirolimo/análogos & derivados , Adulto , Área Sob a Curva , Everolimo , Feminino , Humanos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Sirolimo/efeitos adversos , Sirolimo/farmacocinética
17.
Clin Ther ; 30(3): 482-98, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18405787

RESUMO

BACKGROUND: Placebo-controlled trials have found that angiotensin-converting enzyme inhibitors (ACEIs) decrease proteinuria and slow the progression of nondiabetic nephropathies. However, head-to-head comparisons of ACEIs and calcium channel blockers (CCBs) have shown conflicting results. Indeed, a recent metaanalysis concluded that there is still uncertainty about the greater renoprotection seen with ACEIs or angiotensin II receptor blockers in nondiabetic patients with renal disease, particularly when using true glomerular filtration rate (GFR) as the primary outcome. OBJECTIVE: The objective of this 3-year, randomized, multicenter, double-blind, placebo-controlled study was to compare true GFR decline (measured by yearly 51Cr-EDTA blood clearance) in nondiabetic, nonnephrotic adult hypertensive patients with estimated creatinine clearance of 20 to 60 mL/min.1.73 m(2), when randomized to a CCB (amlodipine, 5-10 mg/d) or an ACEI (enalapril, 5-20 mg/d). METHODS: Patients (aged 18-80 years) entered a 4-week placebo run-in washout period and previous antihypertensive drugs were tapered off over 2 weeks. Add-on treatments were atenolol (50-100 mg/d), loop diuretics (furosemide, 20-500 mg/d or torsemide, 5-200 mg/d), alpha-blockers (prazosin, 2.5-5 mg/d or doxazosin, 1-16 mg/d), and centrally acting drugs (rilmenidine, 1-2 mg/d or methyldopa, 250-500 mg/d). The primary end point was true GFR measured by yearly (51)Cr-EDTA blood clearance. Secondary end points included a clinical composite of renal events and tolerability collected by a full clinical and laboratory evaluation at each study visit. Post hoc analyses for the change in GFR, proteinuria, and time to clinical events were also planned on baseline proteinuria subgroups (<1 and >or=1 g/d) before unblinding the database. RESULTS: Three hundred eighteen patients entered the run-in period and 263 patients (156 men/107 women; mean age, 58 years) were randomized to receive either amlodipine (5 mg/d, n=132) or enalapril (5 mg/d, n=131). Blood pressure declined from 165/102 mm Hg to 138/84 mm Hg and 138/85 mm Hg with amlodipine and enalapril, respectively (no between-group significance). Only 20.8% of the patients randomized to ACEI treatment received diuretics at the last observation. No statistically significant difference was found between amlodipine and enalapril in GFR decline (-4.92 and -3.98 mL/min.1.73 m(2), respectively, at last observation) and composite secondary end point after a median follow-up of 2.9 years, including in the subgroup of patients with proteinuria >1 g/d at baseline. Protein excretion rate decreased significantly from baseline in patients taking enalapril plus diuretics (median -270 mg/d; P<0.001) but not in patients taking amlodipine plus diuretics (-25 mg/d at last observation). CONCLUSION: In this cohort of nondiabetic, nonnephrotic hypertensive patients, no statistically significant difference in true GFR decline was found over 3 years between amlodipine-treated patients and enalapril-treated patients with main add-on treatment with ss-blockers, including in the subgroup of patients with proteinuria >1 g/d.


Assuntos
Anlodipino/farmacologia , Anti-Hipertensivos/farmacologia , Enalapril/farmacologia , Hipertensão/tratamento farmacológico , Nefropatias/complicações , Rim/efeitos dos fármacos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Pressão Sanguínea/efeitos dos fármacos , Estudos de Coortes , Creatinina/sangue , Método Duplo-Cego , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Hipertensão/complicações , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Resultado do Tratamento
18.
High Blood Press Cardiovasc Prev ; 15(4): 275-82, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23355130

RESUMO

OBJECTIVE: To assess the efficacy and acceptability of indapamide sustained-release (SR) monotherapy in elderly high-risk patients with moderate to severe hypertension. METHODS: 1277 hypertensive patients older than 55 years with moderate to severe hypertension, including 91% with systolic blood pressure (SBP) >160 mmHg and at least one cardiovascular risk factor (age >65 years, male, diabetes mellitus, coronary heart disease [CHD], cerebrovascular disease, dyslipidaemia, obesity, smoking) were enrolled in this observational study. They received indapamide SR 1.5 mg, one tablet daily, for 3 months. Blood pressure (BP) was assessed monthly by sphygmomanometer. Statistical analyses were performed using the χ(2) test, analysis of variance, and the Newman-Keuls test. RESULTS: After 3 months of treatment with indapamide SR, SBP had decreased by 34 ± 3 mmHg and diastolic BP (DBP) by 12 ± 6 mmHg (both p < 0.001). Ninety-two percent of patients responded to therapy (SBP/DBP reduction >20/10 mmHg) and 52% were normalized (SBP <140 mmHg and DBP <90 mmHg). BP targets were reached in 48% of patients older than 65 years, 31% of diabetic patients, and 33% of patients with CHD. There were no changes in serum creatinine, glucose or lipid parameters, and 3% of patients had hypokalaemia (<3.5 mmol/L). The patients self-assessment scores regarding general state of health improved and 34% of patients reported 'excellent' health after treatment. CONCLUSIONS: In the high-risk patients of the ARGUS study, monotherapy with indapamide SR showed antihypertensive efficacy with good acceptability and no changes in metabolic parameters over a 3-month period. Indapamide SR monotherapy normalized BP in half of the patients treated and proved an appropriate first-line treatment in hypertensive patients older than 55 years with added cardiovascular risk factors.

19.
Eur Heart J ; 27(23): 2823-32, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17074775

RESUMO

AIMS: Ularitide is a synthetic form of urodilatin, a natriuretic peptide produced in the kidney with vasodilating, natriuretic, and diuretic effects, that offers promise for the management of decompensated heart failure (DHF). We assessed the efficacy and safety of ularitide in treating patients with DHF. METHODS AND RESULTS: In this Phase II randomized, double-blind, placebo-controlled trial, 221 DHF patients received either placebo (n=53) or ularitide at 7.5 ng/kg/min (n=60), 15 ng/kg/min (n=53), or 30 ng/kg/min (n=55) as a 24-h continuous infusion. At 6 h, ularitide demonstrated a significant decrease in pulmonary capillary wedge pressure (P=0.052, P=0.000004, P=0.000002, respectively) and improved dyspnoea score in the 7.5, 15, and 30 ng/kg/min ularitide group (P=0.0026, P=0.0026, P=0.0013, respectively). Ularitide reduced systemic vascular resistance and increased cardiac index for the 15 and 30 ng/kg/min groups (P=0.017, P=0.00002, respectively). Systolic blood pressure (BP) decreased dose dependency. Heart rate and serum creatinine were unchanged through day 3. Most frequently reported drug-related adverse events through day 3 in all ularitide groups were dose-dependent BP decrease and hypotension. CONCLUSION: Ularitide lowered cardiac filling pressures and improved dyspnoea without apparent early deleterious effects on renal function in DHF patients. These results suggest that ularitide may play a role in the management of DHF.


Assuntos
Fator Natriurético Atrial/administração & dosagem , Diuréticos/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Vasodilatadores/administração & dosagem , Fator Natriurético Atrial/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , Diuréticos/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/efeitos adversos , Micção/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacos , Vasodilatadores/efeitos adversos
20.
Blood Press Monit ; 11(2): 87-90, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16534410

RESUMO

OBJECTIVE: To perform validation for an arm-type oscillometric TM-2655 device (A&D Company Ltd, Tokyo, Japan) for blood pressure measurement according to the British Hypertension Society protocol. METHODS: Eighty-five study participants (33 men and 52 women) were included in the study. Mean age was 52.9+/-15.0 years, systolic blood pressure range was 84-208 mmHg and diastolic blood pressure range was 48-120 mmHg. For each participant, three readings of TM-2655 were compared with sequential auscultatory measurements by two trained independent observers. The observers used a calibrated mercury sphygmomanometer and dual stethoscope. The results were graded according to the British Hypertension Society protocol 1993. RESULTS: The average difference between mercury sphygmomanometer and TM-2655 readings for systolic blood pressure was -1.0+5.2 mmHg (mean+/-SD) and for diastolic blood pressure -0.9+/-4.7 mmHg. The proportions of values agreeing to within 5, 10 and 15 mmHg were 72.5, 93.7 and 99.6% for systolic blood pressure and 78.8, 96.9 and 100% for diastolic blood pressure between the observers and the device (A/A British Hypertension Society grade). CONCLUSIONS: The TM-2655 device achieved British Hypertension Society grade A/A and therefore can be recommended for blood pressure measurement in an adult population.


Assuntos
Determinação da Pressão Arterial/instrumentação , Adulto , Idoso , Monitores de Pressão Arterial/normas , Feminino , Humanos , Hipertensão/diagnóstico , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Oscilometria/instrumentação , Esfigmomanômetros
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