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1.
Nature ; 586(7828): 275-280, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33029001

RESUMO

The development of intestinal organoids from single adult intestinal stem cells in vitro recapitulates the regenerative capacity of the intestinal epithelium1,2. Here we unravel the mechanisms that orchestrate both organoid formation and the regeneration of intestinal tissue, using an image-based screen to assay an annotated library of compounds. We generate multivariate feature profiles for hundreds of thousands of organoids to quantitatively describe their phenotypic landscape. We then use these phenotypic fingerprints to infer regulatory genetic interactions, establishing a new approach to the mapping of genetic interactions in an emergent system. This allows us to identify genes that regulate cell-fate transitions and maintain the balance between regeneration and homeostasis, unravelling previously unknown roles for several pathways, among them retinoic acid signalling. We then characterize a crucial role for retinoic acid nuclear receptors in controlling exit from the regenerative state and driving enterocyte differentiation. By combining quantitative imaging with RNA sequencing, we show the role of endogenous retinoic acid metabolism in initiating transcriptional programs that guide the cell-fate transitions of intestinal epithelium, and we identify an inhibitor of the retinoid X receptor that improves intestinal regeneration in vivo.


Assuntos
Organoides/citologia , Organoides/fisiologia , Fenótipo , Regeneração/fisiologia , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Enterócitos/citologia , Enterócitos/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Intestinos/citologia , Intestinos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Organoides/efeitos dos fármacos , Organoides/metabolismo , Receptores do Ácido Retinoico/antagonistas & inibidores , Receptores do Ácido Retinoico/metabolismo , Regeneração/efeitos dos fármacos , Análise de Sequência de RNA , Transdução de Sinais/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos , Tretinoína/metabolismo , Vitamina A/farmacologia
2.
Nature ; 569(7754): 66-72, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31019299

RESUMO

Intestinal organoids are complex three-dimensional structures that mimic the cell-type composition and tissue organization of the intestine by recapitulating the self-organizing ability of cell populations derived from a single intestinal stem cell. Crucial in this process is a first symmetry-breaking event, in which only a fraction of identical cells in a symmetrical sphere differentiate into Paneth cells, which generate the stem-cell niche and lead to asymmetric structures such as the crypts and villi. Here we combine single-cell quantitative genomic and imaging approaches to characterize the development of intestinal organoids from single cells. We show that their development follows a regeneration process that is driven by transient activation of the transcriptional regulator YAP1. Cell-to-cell variability in YAP1, emerging in symmetrical spheres, initiates Notch and DLL1 activation, and drives the symmetry-breaking event and formation of the first Paneth cell. Our findings reveal how single cells exposed to a uniform growth-promoting environment have the intrinsic ability to generate emergent, self-organized behaviour that results in the formation of complex multicellular asymmetric structures.


Assuntos
Intestinos/citologia , Organoides/citologia , Organoides/crescimento & desenvolvimento , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas de Ligação ao Cálcio , Proteínas de Ciclo Celular , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos , Organoides/metabolismo , Celulas de Paneth/citologia , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Análise de Célula Única , Proteínas de Sinalização YAP
3.
Development ; 146(12)2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31249009

RESUMO

Complex 3D tissues arise during development following tightly organized events in space and time. In particular, gene regulatory networks and local interactions between single cells lead to emergent properties at the tissue and organism levels. To understand the design principles of tissue organization, we need to characterize individual cells at given times, but we also need to consider the collective behavior of multiple cells across different spatial and temporal scales. In recent years, powerful single cell methods have been developed to characterize cells in tissues and to address the challenging questions of how different tissues are formed throughout development, maintained in homeostasis, and repaired after injury and disease. These approaches have led to a massive increase in data pertaining to both mRNA and protein abundances in single cells. As we review here, these new technologies, in combination with in toto live imaging, now allow us to bridge spatial and temporal information quantitatively at the single cell level and generate a mechanistic understanding of tissue development.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , Homeostase , Regeneração , Análise de Célula Única/métodos , Animais , Linhagem da Célula , Biologia do Desenvolvimento , Humanos , Hibridização in Situ Fluorescente , Camundongos , Proteoma , RNA Mensageiro/metabolismo , RNA Citoplasmático Pequeno/metabolismo
4.
Gastroenterology ; 153(6): 1662-1673.e10, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28923495

RESUMO

BACKGROUND & AIMS: Fibrolamellar hepatocellular carcinoma (FL-HCC) is a primary liver cancer that predominantly affects children and young adults with no underlying liver disease. A somatic, 400 Kb deletion on chromosome 19 that fuses part of the DnaJ heat shock protein family (Hsp40) member B1 gene (DNAJB1) to the protein kinase cAMP-activated catalytic subunit alpha gene (PRKACA) has been repeatedly identified in patients with FL-HCC. However, the DNAJB1-PRKACA gene fusion has not been shown to induce liver tumorigenesis. We used the CRISPR/Cas9 technique to delete in mice the syntenic region on chromosome 8 to create a Dnajb1-Prkaca fusion and monitored the mice for liver tumor development. METHODS: We delivered CRISPR/Cas9 vectors designed to juxtapose exon 1 of Dnajb1 with exon 2 of Prkaca to create the Dnajb1-Prkaca gene fusion associated with FL-HCC, or control Cas9 vector, via hydrodynamic tail vein injection to livers of 8-week-old female FVB/N mice. These mice did not have any other engineered genetic alterations and were not exposed to liver toxins or carcinogens. Liver tissues were collected 14 months after delivery; genomic DNA was analyzed by PCR to detect the Dnajb1-Prkaca fusion, and tissues were characterized by histology, immunohistochemistry, RNA sequencing, and whole-exome sequencing. RESULTS: Livers from 12 of the 15 mice given the vectors to induce the Dnajb1-Prkaca gene fusion, but none of the 11 mice given the control vector, developed neoplasms. The tumors contained the Dnajb1-Prkaca gene fusion and had histologic and cytologic features of human FL-HCCs: large polygonal cells with granular, eosinophilic, and mitochondria-rich cytoplasm, prominent nucleoli, and markers of hepatocytes and cholangiocytes. In comparing expression levels of genes between the mouse tumor and non-tumor liver cells, we identified changes similar to those detected in human FL-HCC, which included genes that affect cell cycle and mitosis regulation. Genomic analysis of mouse neoplasms induced by the Dnajb1-Prkaca fusion revealed a lack of mutations in genes commonly associated with liver cancers, as observed in human FL-HCC. CONCLUSIONS: Using CRISPR/Cas9 technology, we found generation of the Dnajb1-Prkaca fusion gene in wild-type mice to be sufficient to initiate formation of tumors that have many features of human FL-HCC. Strategies to block DNAJB1-PRKACA might be developed as therapeutics for this form of liver cancer.


Assuntos
Biomarcadores Tumorais/genética , Proteínas Associadas a CRISPR/genética , Sistemas CRISPR-Cas , Carcinoma Hepatocelular/genética , Transformação Celular Neoplásica/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/genética , Edição de Genes/métodos , Fusão Gênica , Proteínas de Choque Térmico HSP40/genética , Neoplasias Hepáticas/genética , Animais , Biomarcadores Tumorais/metabolismo , Proteínas Associadas a CRISPR/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/metabolismo , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Proteínas de Choque Térmico HSP40/metabolismo , Neoplasias Hepáticas/metabolismo , Camundongos , Fenótipo , Fatores de Tempo
5.
Antimicrob Agents Chemother ; 55(2): 473-7, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21098255

RESUMO

Albinterferon alfa-2b (albIFN) is being developed, in combination with ribavirin, for the treatment of hepatitis C virus infection. This study was designed to evaluate the pharmacokinetics, safety, and tolerability of a 900-µg dose of albIFN administered as a single subcutaneous injection in end-stage renal disease (ESRD) patients on hemodialysis and matched healthy volunteers (by age [±5 years], weight [±5 kg], and gender). The maximum concentration in plasma (C(max)) and the area under the concentration-time curve from time zero to infinity (AUC(0-∞)) were 42.8 ± 14.0 ng/ml and 16,414 ± 4,203 ng·h/ml, respectively, for healthy volunteers, while the C(max) and AUC(0-∞) were 49.9 ± 20.9 ng/ml and 18,919 ± 8,008 ng·h/ml, respectively, for ESRD patients. The geometric least-squares mean ratios were 1.15 (90% confidence interval [CI], 0.78, 1.68) for C(max) and 1.11 (90% CI, 0.83, 1.48) for AUC(0-∞). Adverse events were as expected for an interferon (e.g., flu-like symptoms), with the main laboratory adverse event being a decline in total white blood cell count, which was specifically related to a decline in the neutrophil count. This effect was somewhat greater in the ESRD patients, with the maximal decreases in neutrophil counts from those at the baseline being (-2.6 ± 0.32) × 10(9) and (-2.19 ± 0.58) × 10(9) cells/liter for the ESRD patients and the healthy volunteers, respectively. This study indicates no significant effect of renal failure on the pharmacokinetics of albIFN. Safety and tolerability were as expected for an interferon.


Assuntos
Albuminas/efeitos adversos , Albuminas/farmacocinética , Antivirais/efeitos adversos , Antivirais/farmacocinética , Interferon-alfa/efeitos adversos , Interferon-alfa/farmacocinética , Falência Renal Crônica/metabolismo , Diálise Renal , Adulto , Albuminas/administração & dosagem , Antivirais/administração & dosagem , Área Sob a Curva , Relação Dose-Resposta a Droga , Feminino , Humanos , Injeções Subcutâneas , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes , Resultado do Tratamento
6.
J Clin Endocrinol Metab ; 93(2): 459-64, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18042650

RESUMO

OBJECTIVE: Pharmacological inhibition with the dipeptidyl peptidase 4 (DPP-4) inhibitor vildagliptin prolongs the action of endogenously secreted incretin hormones leading to improved glycemic control in patients with type 2 diabetes mellitus (T2DM). We undertook a double-blinded, randomized-order, crossover study to examine the vildagliptin mechanisms of action on islet function and glucose utilization. RESEARCH DESIGN AND METHODS: Participants with T2DM (n = 16) who had a baseline hemoglobin A(1c) of 7.1 +/- 0.2% completed a crossover study with 6 wk of treatment with vildagliptin and 6 wk with placebo. At the completion of each arm, participants had a study of postprandial metabolism and a two-step glucose clamp performed at 20 and 80 mU/min x m(2) insulin infusions. RESULTS: Vildagliptin increased postprandial glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide by 3- and 2-fold, respectively, reduced fasting plasma glucose and postprandial plasma glucose by 1.3 +/- 0.3 mmol/liter and 1.6 +/- 0.3 mmol/liter (both P <0.01), and improved glucose responsiveness of insulin secretion by 50% (P < 0.01). Vildagliptin lowered postprandial glucagon by 16% (P <0.01). Examined by glucose clamp, insulin sensitivity and glucose clearance improved after vildagliptin (P < 0.01). CONCLUSIONS: Vildagliptin improves islet function in T2DM and improves glucose metabolism in peripheral tissues.


Assuntos
Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Glucose/metabolismo , Ilhotas Pancreáticas/metabolismo , Nitrilas/uso terapêutico , Pirrolidinas/uso terapêutico , Adamantano/uso terapêutico , Glicemia/metabolismo , Proteína C-Reativa/metabolismo , Estudos Cross-Over , Método Duplo-Cego , Feminino , Polipeptídeo Inibidor Gástrico/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Humanos , Insulina/sangue , Ilhotas Pancreáticas/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Vildagliptina
7.
Clin Endocrinol (Oxf) ; 69(5): 737-44, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18331607

RESUMO

OBJECTIVES: The incretin hormone glucagon-like peptide-1 (GLP-1) retards gastric emptying and decreases caloric intake. It is unclear whether increased GLP-1 concentrations achieved by inhibition of the inactivating enzyme dipeptidyl peptidase-4 (DPP-4) alter gastric volumes and satiation in people with type 2 diabetes. METHODS: In a double-blind, placebo-controlled crossover design, 14 subjects with type 2 diabetes received vildagliptin (50 mg bid) or placebo for 10 days in random order separated by a 2-week washout. On day 7, fasting and postmeal gastric volumes were measured by a (99m)Tc single-photon emission computed tomography (SPECT) method. On day 8, a liquid Ensure meal was consumed at 30 ml/min, and maximum tolerated volume (MTV) and symptoms 30 min later were measured using a visual analogue scale (VAS) to assess effects on satiation. On day 10, subjects ingested water until maximum satiation was achieved. The volume ingested was recorded and symptoms similarly measured using a VAS. RESULTS: Vildagliptin raised plasma GLP-1 concentrations. However, fasting (248 +/- 21 vs. 247 +/- 19 ml, P = 0.98) and fed (746 +/- 28 vs. 772 +/- 26 ml, P = 0.54) gastric volumes did not differ when subjects received vildagliptin or placebo. Treatment with vildagliptin did not alter the MTV of Ensure (1657 +/- 308 vs. 1389 +/- 197 ml, P = 0.15) or water compared to placebo (1371 +/- 141 vs. 1172 +/- 156 ml, P = 0.23). Vildagliptin was associated with decreased peptide YY (PYY) concentrations 60 min after initiation of the meal (166 +/- 27 vs. 229 +/- 34 pmol/l, P = 0.01). CONCLUSIONS: Vildagliptin does not alter satiation or gastric volume in people with type 2 diabetes despite elevated GLP-1 concentrations. Compensatory changes in enteroendocrine secretion could account for the lack of gastrointestinal symptoms.


Assuntos
Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/patologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Células Enteroendócrinas/efeitos dos fármacos , Nitrilas/farmacologia , Pirrolidinas/farmacologia , Saciação/efeitos dos fármacos , Estômago/efeitos dos fármacos , Adamantano/farmacologia , Estudos Cross-Over , Diabetes Mellitus Tipo 2/metabolismo , Método Duplo-Cego , Ingestão de Líquidos/fisiologia , Ingestão de Alimentos/fisiologia , Células Enteroendócrinas/metabolismo , Jejum/sangue , Jejum/metabolismo , Esvaziamento Gástrico/efeitos dos fármacos , Esvaziamento Gástrico/fisiologia , Grelina/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Humanos , Hipoglicemiantes/farmacologia , Pessoa de Meia-Idade , Tamanho do Órgão/efeitos dos fármacos , Placebos , Período Pós-Prandial/efeitos dos fármacos , Saciação/fisiologia , Estômago/patologia , Vildagliptina
8.
Clin Pharmacokinet ; 46(7): 577-88, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17596103

RESUMO

BACKGROUND: Vildagliptin is a dipeptidyl peptidase IV (DPP-4) inhibitor currently under development for the treatment of type 2 diabetes mellitus. OBJECTIVES: To assess the pharmacokinetic and pharmacodynamic characteristics and tolerability of vildagliptin at doses of 10 mg, 25 mg and 100 mg twice daily following oral administration in patients with type 2 diabetes. METHODS: Thirteen patients with type 2 diabetes were enrolled in this randomised, double-blind, double-dummy, placebo-controlled, four-period, crossover study. Patients received vildagliptin 10 mg, 25 mg and 100 mg as well as placebo twice daily for 28 days. RESULTS: Vildagliptin was absorbed rapidly (median time to reach maximum concentration 1 hour) and had a mean terminal elimination half-life ranging from 1.32 to 2.43 hours. The peak concentration and total exposure increased in an approximately dose-proportional manner. Vildagliptin inhibited DPP-4 (>90%) at all doses and demonstrated a dose-dependent effect on the duration of inhibition. The areas under the plasma concentration-time curves of glucagon-like peptide-1 (GLP-1) [p < 0.001] and glucose-dependent insulinotropic peptide (GIP) [p < 0.001] were increased whereas postprandial glucagon was significantly reduced at the 25 mg (p = 0.006) and 100mg (p = 0.005) doses compared with placebo. As compared with placebo treatment, mean plasma glucose concentrations were decreased by 1.4 mmol/L with the vildagliptin 25 mg dosing regimen and by 2.5 mmol/L with the 100 mg dosing regimen, corresponding to a 10% and 19% reduction, respectively. Vildagliptin was generally well tolerated. CONCLUSION: Vildagliptin is likely to be a useful therapy for patients with type 2 diabetes based on the inhibition of DPP-4 and the subsequent increase in incretin hormones, GLP-1 and GIP, and the decrease in glucose and glucagon levels.


Assuntos
Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nitrilas/farmacocinética , Pirrolidinas/farmacocinética , Adamantano/farmacocinética , Adamantano/uso terapêutico , Administração Oral , Adulto , Idoso , Área Sob a Curva , Glicemia/metabolismo , Estudos Cross-Over , Diabetes Mellitus Tipo 2/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Polipeptídeo Inibidor Gástrico/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Meia-Vida , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacocinética , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Nitrilas/uso terapêutico , Pirrolidinas/uso terapêutico , Resultado do Tratamento , Vildagliptina , Vômito/induzido quimicamente
9.
J Clin Pharmacol ; 46(8): 895-904, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16855074

RESUMO

The purpose of this double-blind, placebo-controlled study was to measure the effects of FTY720, a novel immunomodulator, on heart rate and rhythm in healthy volunteers. Subjects (n = 66) were randomized to FTY720 1.25 mg or 5 mg or placebo administered once daily for 7 days. Continuous telemetry revealed an acute, dose-dependent decrease in mean heart rate (10-bpm decrease vs placebo) following the first dose of FTY720, with a nadir generally 4 hours postdose. Although a persistent FTY720-related decrease in heart rate was measured from day 2 to day 7, additional doses of FTY720 after day 2 resulted in no further incremental decreases. Mean PR interval increased by approximately 8 to 10 msec in FTY720-treated subjects on day 1. FTY720 did not increase the QRS or QT interval. These results confirm that the first dose of FTY720 has a mild to moderate negative chronotropic effect.


Assuntos
Sistema de Condução Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Imunossupressores/farmacologia , Propilenoglicóis/farmacologia , Esfingosina/análogos & derivados , Adolescente , Adulto , Arritmias Cardíacas/induzido quimicamente , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Eletrocardiografia Ambulatorial/efeitos dos fármacos , Teste de Esforço , Feminino , Cloridrato de Fingolimode , Humanos , Imunossupressores/efeitos adversos , Masculino , Propilenoglicóis/efeitos adversos , Valores de Referência , Esfingosina/efeitos adversos , Esfingosina/farmacologia
10.
J Clin Pharmacol ; 45(9): 1038-47, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16100298

RESUMO

Prolongation of QT interval on an electrocardiogram is a valuable predictor of a drug's ability to cause potentially fatal ventricular tachyarrhythmia (torsades de pointes). Darifenacin is a muscarinic M3 selective receptor antagonist developed for the treatment of overactive bladder, a debilitating condition that is particularly prevalent in the older population. This 7-day, randomized, parallel-group study (n=188) measured QT/QTc interval in healthy volunteers receiving once-daily darifenacin at steady-state therapeutic (15 mg) and supratherapeutic (75 mg) doses, alongside controls receiving placebo or moxifloxacin (positive control, 400 mg) once daily. There was no significant increase in QTcF interval with darifenacin treatment compared with placebo. Mean changes from baseline at pharmacokinetic Tmax versus placebo were -0.4 and -2.2 milliseconds in the darifenacin 15 mg and 75 mg groups, respectively, compared with +11.6 milliseconds in the moxifloxacin group (P<.01). This study demonstrates that darifenacin does not prolong QT/QTc interval.


Assuntos
Benzofuranos/farmacologia , Eletrocardiografia/efeitos dos fármacos , Pirrolidinas/farmacologia , Receptor Muscarínico M3/antagonistas & inibidores , Incontinência Urinária/tratamento farmacológico , Adolescente , Adulto , Idoso , Benzofuranos/efeitos adversos , Benzofuranos/farmacocinética , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , DNA/análise , Dextrometorfano/sangue , Dextrorfano/sangue , Feminino , Genótipo , Humanos , Síndrome do QT Longo , Masculino , Pessoa de Meia-Idade , Fenótipo , Pirrolidinas/efeitos adversos , Pirrolidinas/farmacocinética
11.
Cornea ; 34(12): 1551-6, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26418434

RESUMO

PURPOSE: To evaluate whether inhibition of the proinflammatory cytokines IL-1ß or IL-17A by canakinumab or secukinumab, respectively, influence the signs and symptoms of dry eye. METHODS: In a randomized, double-masked, placebo-controlled, outpatient clinical trial, 72 patients with moderate to severe dry eye were randomly assigned in a 1:1:1 ratio to treatment with a single intravenous dose of canakinumab, of secukinumab, or of placebo. Signs and symptoms of dry eye were evaluated on the treatment day and 1 week, 4 weeks, and 8 weeks after treatment. The prespecified primary efficacy endpoint was corneal staining in the study eye 4 weeks after treatment. Secondary endpoints included tear production (Schirmer test), tear film breakup time, conjunctival redness, the ocular surface disease index (OSDI), the frequency of a desire for a topical ocular lubricant, and visual acuity. RESULTS: Of the 71 patients included in the analysis of safety, the rate of adverse events was similar between treatment groups. The course of corneal staining scores from baseline to 4 weeks, respectively, were for canakinumab 1.46 to 1.33 (P = 0.62 compared with placebo), for secukinumab 1.46 to 1.23 (P = 0.22), and for placebo 1.68 to 1.42. There were no changes in the other measures of efficacy beyond what was within the range expected for stochastic day-to-day variation. CONCLUSIONS: The results suggest that the inhibition of IL-1ß or IL-17A obtained by systemic administration of neutralizing drugs does not influence the severity of dry eye.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Síndromes do Olho Seco/diagnóstico , Síndromes do Olho Seco/tratamento farmacológico , Interleucina-17/antagonistas & inibidores , Interleucina-1beta/antagonistas & inibidores , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados , Método Duplo-Cego , Feminino , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Lágrimas/fisiologia , Adulto Jovem
12.
Clin Pharmacol Drug Dev ; 3(6): 487-92, 2014 11.
Artigo em Inglês | MEDLINE | ID: mdl-27129123

RESUMO

A double fixed dose combination of amlodipine/valsartan and triple fixed dose combination of amlodipine/valsartan/HCTZ tablets have been developed to treat patients with moderate-to-severe hypertension. Here, we present the effect of food on the oral bioavailability of these two fixed dose combination tablets from two separate clinical studies in healthy subjects. Single oral doses of amlodipine/valsartan (10/160 mg) and amlodipine/valsartan/HCTZ (10/320/25 mg were administered under fasted or fed conditions. Blood samples were collected in both studies to determine the pharmacokinetic parameters of amlodipine, valsartan, and/or HCTZ using non-compartmental analysis. Following amlodipine/valsartan administration, the geometric mean ratios (GMRs, 90% CI) of AUC0-∞ and Cmax were 1.09 (1.05-1.13) and 1.03 (0.97-1.09) for amlodipine, and 0.94 (0.81-1.10) and 0.86 (0.73-1.02) for valsartan, respectively. Following amlodipine/valsartan/HCTZ administration, the GMRs (90%CI) of AUC0-∞ and Cmax were 1.09 (1.04-1.15) and 1.11 (1.05-1.08) for amlodipine, 1.14 (0.99-1.31) and 1.12 (0.98-1.29) for valsartan, and 1.09 (1.02-1.16) and 0.86 (0.79-0.93) for HCTZ, respectively. Considering the sample size and pharmacokinetic variability associated with analytes, these study results indicate that food effect is minimal or none when fixed dose combination tablets are administered with food. In conclusion, both fixed dose combination tablets can be administered without regards to meals.


Assuntos
Combinação Anlodipino e Valsartana/administração & dosagem , Combinação Anlodipino e Valsartana/farmacocinética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacocinética , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacocinética , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/farmacocinética , Interações Alimento-Droga , Hidroclorotiazida/administração & dosagem , Hidroclorotiazida/farmacocinética , Administração Oral , Adolescente , Adulto , Combinação Anlodipino e Valsartana/efeitos adversos , Combinação Anlodipino e Valsartana/sangue , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/sangue , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/sangue , Área Sob a Curva , Disponibilidade Biológica , Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/sangue , Estudos Cross-Over , Gorduras na Dieta/administração & dosagem , Combinação de Medicamentos , Monitoramento de Medicamentos , Feminino , Voluntários Saudáveis , Humanos , Hidroclorotiazida/efeitos adversos , Hidroclorotiazida/sangue , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Comprimidos , Adulto Jovem
13.
Antiviral Res ; 89(3): 238-45, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21255610

RESUMO

BACKGROUND: Cyclophilin inhibitors have shown activity against a variety of viruses, including HCV. NIM811, a novel, non-immunosuppressive cyclophilin inhibitor was studied in ascending doses in a randomized, double-blind, placebo-controlled 14-day trial in genotype 1 HCV patients. Doses of 10 up to 600 mg were given orally once or twice daily as monotherapy (9:3 randomization of NIM811:placebo). 600 mg or placebo bid for 14 days was then co-administered with pegylated interferon alpha (PEG-IFN-α) administered on days 1 and 8 to genotype 1 relapsers. RESULTS: NIM811 was well tolerated at all doses. Although lack of antiviral effect was noted in the monotherapy arms, liver transaminase normalization occurred at doses over 75 mg. Mild, clinically non-significant elevations of bilirubin, and significant declines in platelet numbers were observed in the 400 and 600 mg bid groups. In the combination group, the mean HCV RNA decline was 2.85 log, compared to a 0.56 log in the PEG-IFN alone arm. The mean ALT (alanine transaminase) declined significantly by day 14 in the combination, but was unchanged in the PEG-IFN alone group. In the combination therapy group, the mean platelets were 203×10(9)/L at baseline and fell to 105×10(9)/L by day 14; for patients treated with PEG-IFN the values were 177×10(9)/L and 139×10(9)/L. There was a significant increase in bilirubin, although this did not reach clinically concerning levels. There were no severe or serious adverse events. The pharmacokinetics in both monotherapy and combination arms were dose linear and not affected by PEG-INF. CONCLUSION: NIM811 monotherapy resulted in a normalization of liver transaminases in the absence of significant virological response. The combination of NIM811 and pegylated interferon alpha showed significant antiviral activity compared to interferon alone in genotype 1 HCV relapsers. The use of oral cyclophilin inhibitors as part of a combination regime for treatment of hepatitis C, especially to deter resistance, holds promise.


Assuntos
Antivirais/efeitos adversos , Antivirais/farmacocinética , Ciclosporina/efeitos adversos , Ciclosporina/farmacocinética , Hepatite C/tratamento farmacológico , Interferon-alfa/efeitos adversos , Interferon-alfa/farmacocinética , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/farmacocinética , Adolescente , Adulto , Idoso , Antivirais/administração & dosagem , Ciclosporina/administração & dosagem , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Polietilenoglicóis/administração & dosagem , Proteínas Recombinantes , Transaminases/sangue , Resultado do Tratamento , Adulto Jovem
14.
Diabetes Care ; 32(1): 14-8, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18931099

RESUMO

OBJECTIVE: The purpose of this study was to determine the mechanism by which dipeptidyl peptidase-4 inhibitors lower postprandial glucose concentrations. RESEARCH DESIGN AND METHODS: We measured insulin secretion and action as well as glucose effectiveness in 14 subjects with type 2 diabetes who received vildagliptin (50 mg b.i.d.) or placebo for 10 days in random order separated by a 3-week washout. On day 9 of each period, subjects ate a mixed meal. Insulin sensitivity (S(I)), glucose effectiveness, and beta-cell responsivity indexes were estimated using the oral glucose and C-peptide minimal models. At 300 min 0.02 unit/kg insulin was administered intravenously. RESULTS: Vildagliptin reduced postprandial glucose concentrations (905 +/- 94 vs. 1,008 +/- 104 mmol/6 h, P = 0.02). Vildagliptin did not alter net S(I) (7.71 +/- 1.28 vs. 6.41 +/- 0.84 10(-4) dl x kg(-1) x min(-1) x muU(-1) x ml(-1), P = 0.13) or glucose effectiveness (0.019 +/- 0.002 vs. 0.018 +/- 0.002 dl x kg(-1) x min(-1), P = 0.65). However, the net beta-cell responsivity index was increased (35.7 +/- 5.2 vs. 28.9 +/- 5.2 10(-9) min(-1), P = 0.03) as was total disposition index (381 +/- 48 vs. 261 +/- 35 10(-14) dl x kg(-1) x min(-2) x pmol(-1) x l(-1), P = 0.006). Vildagliptin lowered postprandial glucagon concentrations (27.0 +/- 1.1 vs. 29.7 +/- 1.5 microg x l(-1) x 6 h(-1), P = 0.03), especially after administration of exogenous insulin (81.5 +/- 6.4 vs. 99.3 +/- 5.6 ng/l, P = 0.02). CONCLUSIONS: Vildagliptin lowers postprandial glucose concentrations by stimulating insulin secretion and suppressing glucagon secretion but not by altered insulin action or glucose effectiveness. A novel observation is that vildagliptin alters alpha-cell responsiveness to insulin administration, but the significance of this action is as yet unclear.


Assuntos
Adamantano/análogos & derivados , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Digestão/fisiologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/uso terapêutico , Insulina/metabolismo , Nitrilas/uso terapêutico , Pirrolidinas/uso terapêutico , Adamantano/uso terapêutico , Glicemia/efeitos dos fármacos , Peptídeo C/sangue , Estudos Cross-Over , Diabetes Mellitus Tipo 2/fisiopatologia , Digestão/efeitos dos fármacos , Método Duplo-Cego , Glucagon/sangue , Glucagon/metabolismo , Humanos , Insulina/sangue , Secreção de Insulina , Placebos , Período Pós-Prandial/efeitos dos fármacos , Período Pós-Prandial/fisiologia , Resposta de Saciedade/efeitos dos fármacos , Vildagliptina
15.
Diabetes ; 56(5): 1475-80, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17303799

RESUMO

OBJECTIVE: We sought to determine whether alterations in meal absorption and gastric emptying contribute to the mechanism by which inhibitors of dipeptidyl peptidase-4 (DPP-4) lower postprandial glucose concentrations. RESEARCH DESIGN AND METHODS: We simultaneously measured gastric emptying, meal appearance, endogenous glucose production, and glucose disappearance in 14 subjects with type 2 diabetes treated with either vildaglipitin (50 mg b.i.d.) or placebo for 10 days using a double-blind, placebo-controlled, randomized, crossover design. RESULTS: Fasting (7.3 +/- 0.5 vs. 7.9 +/- 0.5 mmol/l) and peak postprandial (14.1 +/- 0.6 vs. 15.9 +/- 0.9 mmol/l) glucose concentrations were lower (P < 0.01) after vildagliptin treatment than placebo. Despite lower glucose concentrations, postprandial insulin and C-peptide concentrations did not differ during the two treatments. On the other hand, the integrated (area under the curve) postprandial glucagon concentrations were lower (20.9 +/- 1.6 vs. 23.7 +/- 1.3 mg/ml per 5 h, P < 0.05), and glucagon-like peptide 1 (GLP-1) concentrations were higher (1,878 +/- 270 vs. 1,277 +/- 312 pmol/l per 5 h, P = 0.001) during vildagliptin administration compared with placebo. Gastric emptying and meal appearance did not differ between treatments. CONCLUSIONS: Vildagliptin does not alter gastric emptying or the rate of entry of ingested glucose into the systemic circulation in humans. DPP-4 inhibitors do not lower postprandial glucose concentrations by altering the rate of nutrient absorption or delivery to systemic circulation. Alterations in islet function, secondary to increased circulating concentrations of active GLP-1, are associated with the decreased postprandial glycemic excursion observed in the presence of vildagliptin.


Assuntos
Inibidores de Adenosina Desaminase , Apetite , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Inibidores da Dipeptidil Peptidase IV , Ingestão de Alimentos , Trato Gastrointestinal/fisiopatologia , Glicoproteínas/antagonistas & inibidores , Estudos Cross-Over , Dipeptidil Peptidase 4 , Método Duplo-Cego , Jejum , Esvaziamento Gástrico , Peptídeo 1 Semelhante ao Glucagon/sangue , Humanos , Período Pós-Prandial
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