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1.
Int J Clin Pract ; 64(6): 727-38, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20518948

RESUMO

BACKGROUND: Co-administration of niacin with statin offers the potential for additional lipid management and cardiovascular risk reduction. However, niacin is underutilised because of the side effects of flushing, mediated primarily by prostaglandin D(2) (PGD(2)). A combination tablet containing extended-release niacin and laropiprant (ERN/LRPT), a PGD(2) receptor (DP1) antagonist, offers improved tolerability. This study assessed the efficacy and safety of ERN/LRPT added to statin vs. doubling the dose of statin in patients with primary hypercholesterolaemia or mixed dyslipidaemia who were not at their National Cholesterol Education Program Adult Treatment Panel III low-density lipoprotein cholesterol (LDL-C) goal based on their coronary heart disease risk category (high, moderate or low). METHODS: After a 2- to 6-week run-in statin (simvastatin 10 or 20 mg or atorvastatin 10 mg) period, 1216 patients were randomised equally to one of two treatment groups in a double-blind fashion: group 1 received ERN/LRPT (1 g) plus the run-in statin dose and advanced to ERN/LRPT (2 g) after 4 weeks for an additional 8 weeks, with no adjustments to the run-in statin dose; group 2 received simvastatin or atorvastatin at twice their run-in statin dose and remained on this stable dose for 12 weeks. RESULTS: ERN/LRPT added to statin (pooled across statin and statin dose) significantly improved key lipid parameters vs. the doubled statin dose (pooled): the between-treatment group difference in least squares mean per cent change [95% confidence interval (CI)] from baseline to week 12 in LDL-C (primary end-point) was -4.5% (-7.7, -1.3) and in high-density lipoprotein cholesterol (HDL-C) was 15.6% (13.4, 17.9) and in median per cent change for triglyceride (TG) was -15.4% (-19.2, -11.7). Treatment-related adverse experiences (AEs) related to flushing, pruritis, rash, gastrointestinal upset and elevations in liver transaminases and fasting serum glucose occurred more frequently with ERN/LRPT added to statin vs. statin dose doubled. CONCLUSIONS: The addition of ERN/LRPT to ongoing statin treatment produced significantly improved lipid-modifying benefits on LDL-C, HDL-C and TG and all other lipid parameters compared with doubling the statin dose in patients with primary hypercholesterolaemia or mixed dyslipidaemia. The types of AEs that occurred at a greater frequency in the ERN/LRPT group were those typically associated with niacin.


Assuntos
Dislipidemias/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hipolipemiantes/administração & dosagem , Indóis/administração & dosagem , Niacina/administração & dosagem , Prostaglandina D2/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hipercolesterolemia/tratamento farmacológico , Hipolipemiantes/efeitos adversos , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Niacina/efeitos adversos , Resultado do Tratamento , Adulto Jovem
2.
Curr Med Res Opin ; 25(1): 15-22, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19210135

RESUMO

OBJECTIVE: The objective of this study was to compare pharmacokinetic parameters of niacin extended-release tablets (NER uncoated) and niacin extended-release caplet formation (NER coated). RESEARCH DESIGN AND METHODS: Twenty-five healthy male and female subjects were enrolled in a four-period, open-label, randomized, crossover study. Both NER uncoated and NER coated were given as 1 x 1000 mg or 2 x 500 mg tablets. Similarity of NER coated 1 x 1000 mg and NER uncoated 2 x 500 mg was declared if 90% confidence intervals for the geometric mean ratio (GMR) for nicotinuric acid (NUA) Cmax fell within the pre-specified bounds of [0.7, 1.43]. RESULTS: The GMRs for NUA Cmax demonstrated similarity in the pharmacokinetics of NER uncoated 2 x 500 mg, NER coated 1 x 1000 mg, and NER coated 2 x 500 mg. Although less stringent comparability bounds were prespecified for the primary pharmacokinetic endpoint (i.e., Cmax of plasma NUA), inspection of the primary comparison of interest indicated that a hypothesis with more stringent bioequivalence bounds of [0.8, 1.25] would have been satisfied. The NUA Cmax for NER uncoated 1 x 1000 mg was approximately 40% higher than that seen for the other three treatments. In contrast, total urinary excretion of niacin and its metabolites, an approximate measure of bioavailability, was similar for all four treatments. CONCLUSION: The pharmacokinetic profile of the original NER uncoated formulation dosed as 2 x 500 mg was similar to the new film-coated formulation, NER coated, dosed as 1 x 1000 mg.


Assuntos
Niacina/farmacocinética , Adulto , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Preparações de Ação Retardada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Niacina/administração & dosagem , Niacina/sangue , Niacina/urina
3.
Int J Clin Pract ; 62(6): 896-904, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18410350

RESUMO

INTRODUCTION: Niacin is underutilised because of flushing. Lack of a quantitative tool to assess niacin-induced flushing has precluded the objective evaluation of flushing associated with extended-release (ER) niacin formulations. We developed the Flushing Symptom Questionnaire((c)) (FSQ), a quantitative tool to assess patient-reported flushing, and assessed its ability to characterise ER niacin-induced flushing. METHODS: This study focused on the responses to one question in the FSQ, the Global Flushing Severity Score (GFSS), reported on a 0-10 scale (none = 0, mild = 1-3, moderate = 4-6, severe = 7-9 and extreme = 10) to assess flushing during ER niacin initiation (week 1) and maintenance (weeks 2-8). RESULTS: Flushing severity with ER niacin was greatest during week 1 and remained greater than placebo for the study duration. During weeks 2-8, 40% of patients on ER niacin vs. 8% of those on placebo had > 1 day/week with 'moderate or greater' GFSS. CONCLUSIONS: In conclusion, the GFSS component of the FSQ was a sensitive and responsive quantitative measure of ER niacin-induced flushing that will aid in the objective comparison of novel strategies intended to improve tolerability and adherence to niacin, an agent proven to reduce cardiovascular risk.


Assuntos
Rubor/induzido quimicamente , Niacina/efeitos adversos , Vasodilatadores/efeitos adversos , Adolescente , Adulto , Idoso , Preparações de Ação Retardada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Niacina/administração & dosagem , Inquéritos e Questionários , Resultado do Tratamento , Vasodilatadores/administração & dosagem , Adulto Jovem
4.
Int J Clin Pract ; 62(12): 1959-70, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19166443

RESUMO

BACKGROUND: Improving lipids beyond low-density lipoprotein cholesterol (LDL-C) lowering with statin monotherapy may further reduce cardiovascular risk. Niacin has complementary lipid-modifying efficacy to statins and cardiovascular benefit, but is underutilised because of flushing, mediated primarily by prostaglandin D(2) (PGD(2)). Laropiprant (LRPT), a PGD(2) receptor (DP1) antagonist that reduces niacin-induced flushing has been combined with extended-release niacin (ERN) into a fixed-dose tablet. METHODS AND RESULTS: Dyslipidaemic patients were randomised to ERN/LRPT 1 g (n = 800), ERN 1 g (n = 543) or placebo (n = 270) for 4 weeks. Doses were doubled (2 tablets/day; i.e. 2 g for active treatments) for 20 weeks. ERN/LRPT 2 g produced significant changes vs. placebo in LDL-C (-18.4%), high-density lipoprotein cholesterol (HDL-C; 20.0%), LDL-C:HDL-C (-31.2%), non-HDL-C (-19.8%), triglycerides (TG; -25.8%), apolipoprotein (Apo) B (-18.8%), Apo A-I (6.9%), total cholesterol (TC; -8.5%), TC:HDL-C (-23.1%) and lipoprotein(a) (-20.8%) across weeks 12-24. ERN/LRPT produced significantly less flushing than ERN during initiation (week 1) and maintenance (weeks 2-24) for all prespecified flushing end-points (incidence, intensity and discontinuation because of flushing). Except for flushing, ERN/LRPT had a safety/tolerability profile comparable with ERN. CONCLUSION: Extended-release niacin/LRPT 2 g produced significant, durable improvements in multiple lipid/lipoprotein parameters. The improved tolerability of ERN/LRPT supports a simplified 1 g-->2 g dosing regimen of niacin, a therapy proven to reduce cardiovascular risk.


Assuntos
Dislipidemias/tratamento farmacológico , Hipercolesterolemia/tratamento farmacológico , Hipolipemiantes/administração & dosagem , Indóis/administração & dosagem , Niacina/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Preparações de Ação Retardada , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Hipolipemiantes/efeitos adversos , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Niacina/efeitos adversos , Resultado do Tratamento , Adulto Jovem
5.
Int J Clin Pharmacol Ther ; 44(2): 83-92, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16502768

RESUMO

OBJECTIVE: To assess the bioequivalence of an ezetimibe/simvastatin (EZE/SIMVA) combination tablet compared to the coadministration of ezetimibe and simvastatin as separate tablets (EZE + SIMVA). METHODS: In this open-label, randomized, 2-part, 2-period crossover study, 96 healthy subjects were randomly assigned to participate in each part of the study (Part I or II), with each part consisting of 2 single-dose treatment periods separated by a 14-day washout. Part I consisted of Treatments A (EZE 10 mg + SIMVA 10 mg) and B (EZE/SIMVA 10/10 mg/mg) and Part II consisted of Treatments C (EZE 10 mg + SIMVA 80 mg) and D (EZE/SIMVA 10/80 mg/mg). Blood samples were collected up to 96 hours post-dose for determination of ezetimibe, total ezetimibe (ezetimibe + ezetimibe glucuronide), simvastatin and simvastatin acid (the most prevalent active metabolite of simvastatin) concentrations. Ezetimibe and simvastatin acid AUC(0-last) were predefined as primary endpoints and ezetimibe and simvastatin acid Cmax were secondary endpoints. Bioequivalence was achieved if 90% confidence intervals (CI) for the geometric mean ratios (GMR) (single tablet/coadministration) of AUC(0-last) and Cmax fell within prespecified bounds of (0.80, 1.25). RESULTS: The GMRs of the AUC(0-last) and Cmax for ezetimibe and simvastatin acid fell within the bioequivalence limits (0.80, 1.25). EZE/ SIMVA and EZE + SIMVA were generally well tolerated. CONCLUSIONS: The lowest and highest dosage strengths of EZE/SIMVA tablet were bioequivalent to the individual drug components administered together. Given the exact weight multiples of the EZE/SIMVA tablet and linear pharmacokinetics of simvastatin across the marketed dose range, bioequivalence of the intermediate tablet strengths (EZE/SIMVA 10/20 mg/mg and EZE/SIMVA 10/40 mg/mg) was inferred, although these dosages were not tested directly. These results indicate that the safety and efficacy profile of EZE + SIMVA coadministration therapy can be applied to treatment with the EZE/SIMVA tablet across the clinical dose range.


Assuntos
Anticolesterolemiantes/farmacocinética , Azetidinas/farmacocinética , Sinvastatina/farmacocinética , Adolescente , Adulto , Análise de Variância , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/efeitos adversos , Área Sob a Curva , Azetidinas/administração & dosagem , Azetidinas/efeitos adversos , Estudos Cross-Over , Combinação de Medicamentos , Quimioterapia Combinada , Ezetimiba , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Sinvastatina/administração & dosagem , Sinvastatina/efeitos adversos , Comprimidos , Equivalência Terapêutica , Fatores de Tempo , Resultado do Tratamento
6.
J Immunol ; 153(6): 2704-17, 1994 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-8077676

RESUMO

The chemokines are a family of immune mediators involved in a wide range of inflammatory processes, most importantly as chemoattractants of monocytes, neutrophils, lymphocytes, and fibroblasts to sites of inflammation. Nuclear magnetic resonance and x-ray crystallographic studies have shown that IL-8 and macrophage-inflammatory protein-1 beta (MIP-1 beta) form noncovalent dimers and that platelet factor-4 (PF-4) forms noncovalent dimers and tetramers, leading to the assumption that, as a family, the chemokines would form multimeric structures. In this study, we analyze the association states of the chemokines IL-8, monocyte chemoattractant protein-1 (MCP-1), and I-309, by using a combination of size exclusion HPLC, sedimentation equilibrium ultracentrifugation, and chemical cross-linking. We find that the association states of MCP-1 and IL-8 are characterized by an equilibrium between monomers and dimers: although dimers predominate at concentrations above 100 microM, these chemokines are almost exclusively monomeric at the nanomolar concentrations at which they display maximal chemotactic activity. I-309, by contrast, remains a monomer at all concentrations tested. I-309 contains two additional cysteine residues (C26 and C68) that are not found in any other members of the chemokine family. We used cyanogen bromide and trypsin digestion strategies to demonstrate that these two residues are linked in a unique intramolecular disulfide bond. Furthermore, by using site-directed mutagenesis, we show that the integrity of this bond is crucial for protein secretion.


Assuntos
Quimiocinas CC , Fatores Quimiotáticos/química , Interleucina-8/química , Sequência de Aminoácidos , Sequência de Bases , Biopolímeros , Linhagem Celular , Quimiocina CCL2 , Cromatografia Líquida , Reagentes de Ligações Cruzadas , Brometo de Cianogênio , Dissulfetos , Dados de Sequência Molecular , Conformação Proteica , Transfecção/métodos , Tripsina , Ultracentrifugação
7.
J Magn Reson Imaging ; 2(2): 135-42, 1992.
Artigo em Inglês | MEDLINE | ID: mdl-1562764

RESUMO

The accuracy and reproducibility of cardiac ejection fraction (EF) measurements based on cine magnetic resonance (MR) imaging, radionuclide multigated acquisition (MUGA) blood pool imaging, and angiographic ventriculography were evaluated by comparing them with a volumetrically determined standard. A biventricular, compliant, fluid-filled heart phantom was developed to mimic normal cardiac anatomy and physiology. Ventricular EFs were measured with cine MR imaging by summation of nine contiguous 10-mm-thick sections in short and long axis, with single-plane ventriculography, and with MUGA. Three measurements were performed with each modality for each of three EFs. Ventriculography was least accurate, with average relative errors ranging from 7.9% for the largest EF to 60.1% for the smallest. Cine MR was most accurate, with average relative errors ranging from 4.4% to 8.5%. MUGA EF measurements showed good correlation, with average relative errors ranging from 7.1% to 22.4%. Comparison of the error variances for the three modalities with the F test revealed that MR and MUGA EF measurements were significantly more accurate than those based on ventriculography (P less than .01). No significant difference was demonstrated between the accuracy of short- and long-axis cine MR acquisitions.


Assuntos
Imagem do Acúmulo Cardíaco de Comporta , Imageamento por Ressonância Magnética/métodos , Filmes Cinematográficos , Volume Sistólico , Ventriculografia de Primeira Passagem , Humanos , Técnicas In Vitro , Modelos Estruturais
8.
Invest Ophthalmol Vis Sci ; 32(9): 2473-82, 1991 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-1714428

RESUMO

The antigenic composition of the human corneal endothelium, a cellular layer essential for maintaining corneal function, has not been well characterized. A novel corneal endothelial antigen was identified by generating a monoclonal antibody (MAb) against normal human corneal endothelial cells. This MAb, designated 2B4.14.1, reacted strongly by immunoperoxidase staining with the endothelium of corneas from all human donors tested but not with other corneal components, including epithelium and stroma. Positive immunohistologic reactions of 2B4.14.1 with several other human tissues, including kidney (parietal epithelium of Bowman's capsule, proximal convoluted tubule, ascending limb of Henle's loop, and distal convoluted tubule), glandular epithelia of numerous organs, and mesothelial linings of several thoracic and abdominal viscera, also were observed. One of the renal antigens recognized by 2B4.14.1 was identified as Tamm-Horsfall glycoprotein (THGP), based on the ability of the antibody to recognize THGP in western immunoblots and the abrogation of immunohistologic reactivity of the antibody by preincubation with purified THGP. These findings raise the possibility that the human cornea expresses a molecule with homeostatic properties similar to those ascribed to THGP. However, it is unlikely that the corneal antigen recognized by 2B4.14.1 is conventional THGP; a MAb specific for THGP did not react with corneal endothelium.


Assuntos
Antígenos/imunologia , Endotélio Corneano/imunologia , Animais , Anticorpos Monoclonais , Western Blotting , Endotélio Corneano/metabolismo , Imunofluorescência , Cobaias , Humanos , Rim/imunologia , Camundongos , Camundongos Endogâmicos , Mucoproteínas/metabolismo , Coelhos , Ratos , Coloração e Rotulagem , Distribuição Tecidual , Uromodulina
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