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1.
Cell ; 185(19): 3551-3567.e39, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-36055250

RESUMO

Interactions between cells are indispensable for signaling and creating structure. The ability to direct precise cell-cell interactions would be powerful for engineering tissues, understanding signaling pathways, and directing immune cell targeting. In humans, intercellular interactions are mediated by cell adhesion molecules (CAMs). However, endogenous CAMs are natively expressed by many cells and tend to have cross-reactivity, making them unsuitable for programming specific interactions. Here, we showcase "helixCAM," a platform for engineering synthetic CAMs by presenting coiled-coil peptides on the cell surface. helixCAMs were able to create specific cell-cell interactions and direct patterned aggregate formation in bacteria and human cells. Based on coiled-coil interaction principles, we built a set of rationally designed helixCAM libraries, which led to the discovery of additional high-performance helixCAM pairs. We applied this helixCAM toolkit for various multicellular engineering applications, such as spherical layering, adherent cell targeting, and surface patterning.


Assuntos
Bactérias , Peptídeos , Humanos , Peptídeos/química
2.
Trends Cell Biol ; 34(4): 277-287, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37580241

RESUMO

Intercellular interactions form the cornerstone of multicellular biology. Despite advances in protein engineering, researchers artificially directing physical cell interactions still rely on endogenous cell adhesion molecules (CAMs) alongside off-target interactions and unintended signaling. Recently, methods for directing cellular interactions have been developed utilizing programmable domains such as coiled coils (CCs), nanobody-antigen, and single-stranded DNA (ssDNA). We first discuss desirable molecular- and systems-level properties in engineered CAMs, using the helixCAM platform as a benchmark. Next, we propose applications for engineered CAMs in immunology, developmental biology, tissue engineering, and neuroscience. Biologists in various fields can readily adapt current engineered CAMs to establish control over cell interactions, and their utilization in basic and translational research will incentivize further expansion in engineered CAM capabilities.


Assuntos
Moléculas de Adesão Celular , Comunicação Celular , Humanos , Adesão Celular , Moléculas de Adesão Celular/metabolismo , Transdução de Sinais
3.
ACS Synth Biol ; 13(9): 2753-2763, 2024 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-39194023

RESUMO

Multicellular organisms originate from a single cell, ultimately giving rise to mature organisms of heterogeneous cell type composition in complex structures. Recent work in the areas of stem cell biology and tissue engineering has laid major groundwork in the ability to convert certain types of cells into other types, but there has been limited progress in the ability to control the morphology of cellular masses as they grow. Contemporary approaches to this problem have included the use of artificial scaffolds, 3D bioprinting, and complex media formulations; however, there are no existing approaches to controlling this process purely through genetics and from a single-cell starting point. Here we describe a computer-aided design approach, called CellArchitect, for designing recombinase-based genetic circuits for controlling the formation of multicellular masses into arbitrary shapes in human cells.


Assuntos
Algoritmos , Humanos , Redes Reguladoras de Genes , Análise de Célula Única/métodos , Engenharia Tecidual/métodos , Desenho Assistido por Computador , Forma Celular
4.
FEBS J ; 288(22): 6410-6427, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34043859

RESUMO

Large serine integrases (LSIs) offer tremendous potential for rapid genetic engineering as well as building biological systems capable of responding to stimuli and integrating information. Currently, there is no unified metric for directly measuring the enzymatic characteristics of LSI function, which hinders evaluation of their suitability to specific applications. Here, we present an experimental protocol for recording DNA recombination in HEK293 cells in real-time through fluorophore expression and software which fits the kinetic data to a model tailored to LSI recombination dynamics. Our model captures the activity of LSIs as three parameters: expression level (Kexp ), catalytic rate (kcat ), and substrate affinity (Kd ). The expression level and catalytic rate for phiC31 and Bxb1 varied greatly, suggesting disparate routes to high recombination efficiencies. Moreover, the expression level and substrate affinity jointly impacted downstream reporter expression, potentially by obstructing transcriptional machinery. We validated these observations by swapping between promoters and mutating key recombinase residues and DNA recognition sites to individually modulate each parameter. Our model for identifying key LSI parameters in cellulo provides insight into selecting the optimal recombinase for various applications as well as for guiding the engineering of improved LSIs.


Assuntos
Integrases/metabolismo , Serina/metabolismo , Células Cultivadas , Células HEK293 , Humanos , Integrases/química , Cinética , Modelos Moleculares , Serina/química , Software
5.
Microbiol Spectr ; 9(2): e0031321, 2021 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-34523989

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic has brought about the unprecedented expansion of highly sensitive molecular diagnostics as a primary infection control strategy. At the same time, many laboratories have shifted focus to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) research and diagnostic development, leading to large-scale production of SARS-CoV-2 nucleic acids that can interfere with these tests. We have identified multiple instances, in independent laboratories, in which nucleic acids generated in research settings are suspected to have caused researchers to test positive for SARS-CoV-2 in surveillance testing. In some cases, the affected individuals did not work directly with these nucleic acids but were exposed via a contaminated surface or object. Though researchers have long been vigilant of DNA contaminants, the transfer of these contaminants to SARS-CoV-2 testing samples can result in anomalous test results. The impact of these incidents stretches into the public sphere, placing additional burdens on public health resources, placing affected researchers and their contacts in isolation and quarantine, removing them from the testing pool for 3 months, and carrying the potential to trigger shutdowns of classrooms and workplaces. We report our observations as a call for increased stewardship over nucleic acids with the potential to impact both the use and development of diagnostics. IMPORTANCE To meet the challenges imposed by the COVID-19 pandemic, research laboratories shifted their focus and clinical diagnostic laboratories developed and utilized new assays. Nucleic acid-based testing became widespread and, for the first time, was used as a prophylactic measure. We report 15 cases of researchers at two institutes testing positive for SARS-CoV-2 on routine surveillance tests, in the absence of any symptoms or transmission. These researchers were likely contaminated with nonhazardous nucleic acids generated in the laboratory in the course of developing new SARS-CoV-2 diagnostics. These contaminating nucleic acids were persistent and widespread throughout the laboratory. We report these findings as a cautionary tale to those working with nucleic acids used in diagnostic testing and as a call for careful stewardship of diagnostically relevant molecules. Our conclusions are especially relevant as at-home COVID-19 testing gains traction in the marketplace and these amplicons may impact on the general public.


Assuntos
Teste de Ácido Nucleico para COVID-19/métodos , COVID-19/diagnóstico , Contaminação por DNA , DNA Viral/genética , SARS-CoV-2/genética , Reações Falso-Positivas , Humanos , Técnicas de Diagnóstico Molecular , RNA Viral/genética , SARS-CoV-2/isolamento & purificação
6.
N Engl J Med ; 357(25): 2576-88, 2007 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-18094378

RESUMO

BACKGROUND: Reducing hepatitis B virus (HBV) replication to minimal levels is emerging as a key therapeutic goal for chronic hepatitis B. METHODS: In this double-blind, phase 3 trial, 1370 patients with chronic hepatitis B were randomly assigned to receive 600 mg of telbivudine or 100 mg of lamivudine once daily. The primary efficacy end point was noninferiority of telbivudine to lamivudine for therapeutic response (i.e., a reduction in serum HBV DNA levels to fewer than 5 log10 copies per milliliter, along with loss of hepatitis B e antigen [HBeAg] or normalization of alanine aminotransferase levels). Secondary efficacy measures included histologic response, changes in serum HBV DNA levels, and HBeAg responses. RESULTS: At week 52, a significantly higher proportion of HBeAg-positive patients receiving telbivudine than of those receiving lamivudine had a therapeutic response (75.3% vs. 67.0%, P=0.005) or a histologic response (64.7% vs. 56.3%, P=0.01); telbivudine also was not inferior to lamivudine for these end points in HBeAg-negative patients. In HBeAg-positive and HBeAg-negative patients, telbivudine was superior to lamivudine with respect to the mean reduction in the number of copies of HBV DNA from baseline, the proportion of patients with a reduction in HBV DNA to levels undetectable by polymerase-chain-reaction assay, and development of resistance to the drug. Elevated creatine kinase levels were more common in patients who received telbivudine, whereas elevated alanine aminotransferase and aspartate aminotransferase levels were more common in those who received lamivudine. CONCLUSIONS: Among patients with HBeAg-positive chronic hepatitis B, the rates of therapeutic and histologic response at 1 year were significantly higher in patients treated with telbivudine than in patients treated with lamivudine. In both the HBeAg-negative and the HBeAg-positive groups, telbivudine demonstrated greater HBV DNA suppression with less resistance than did lamivudine. (ClinicalTrials.gov number, NCT00057265 [ClinicalTrials.gov].).


Assuntos
Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Lamivudina/uso terapêutico , Nucleosídeos/uso terapêutico , Pirimidinonas/uso terapêutico , Adolescente , Adulto , Idoso , Antivirais/efeitos adversos , DNA Viral/sangue , DNA Viral/classificação , Método Duplo-Cego , Farmacorresistência Viral/genética , Feminino , Genótipo , Antígenos de Superfície da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Humanos , Lamivudina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mutação , Nucleosídeos/efeitos adversos , Pirimidinonas/efeitos adversos , Telbivudina , Timidina/análogos & derivados
7.
Hepatology ; 47(2): 447-54, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18080339

RESUMO

UNLABELLED: Chronic hepatitis B and its life-threatening sequelae are highly prevalent in China. There is a need for effective new therapies to suppress hepatitis B virus (HBV) replication and ameliorate liver disease. In this study, we compared the efficacy of telbivudine, a nucleoside analogue, with lamivudine in Chinese patients. In this phase III, double-blind, multicenter trial conducted in China, 332 patients with compensated hepatitis B e antigen (HBeAg)-positive or HBeAg-negative chronic hepatitis B were randomly assigned to treatment with 600 mg of telbivudine or 100 mg of lamivudine daily for 104 weeks. The primary efficacy endpoint was reduction in serum HBV DNA levels at week 52 of treatment. Secondary endpoints included clearance of HBV DNA to undetectable levels, HBeAg loss and seroconversion, therapeutic response, and alanine aminotransferase (ALT) normalization. Viral resistance and safety were assessed. At week 52, among 290 HBeAg-positive patients, mean reductions of serum HBV DNA were significantly greater in telbivudine recipients than lamivudine recipients (6.3 log(10) versus 5.5 log(10), P < 0.001), and HBV DNA was polymerase chain reaction-negative in significantly more telbivudine recipients than lamivudine recipients (67% versus 38%, P < 0.001). ALT normalization (87% versus 75%, P = 0.007), therapeutic response (85% versus 62%, P = 0.001), and HBeAg loss (31% versus 20%, P = 0.047) were also significantly more common in the telbivudine group. Treatment effects showed similar patterns in the smaller HBeAg-negative group (n = 42). Viral resistance in telbivudine recipients was approximately half that observed with lamivudine; however, this difference was not statistically significant. Clinical adverse events were similar in the two treatment groups. CONCLUSION: In Chinese patients with chronic hepatitis B, telbivudine treatment for 52 weeks provided greater antiviral and clinical efficacy than lamivudine, with less resistance.


Assuntos
Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Lamivudina/uso terapêutico , Nucleosídeos/uso terapêutico , Pirimidinonas/uso terapêutico , Adolescente , Adulto , China , DNA Viral/análise , Método Duplo-Cego , Feminino , Genótipo , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/genética , Humanos , Masculino , Pessoa de Meia-Idade , Telbivudina , Timidina/análogos & derivados
8.
J Clin Pharmacol ; 46(3): 275-81, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16490803

RESUMO

The influence of food on the pharmacokinetics of telbivudine, a candidate antiviral agent against hepatitis B virus (HBV), was investigated in healthy adult subjects following a 600-mg oral dose administered with and without a high-fat/high-calorie meal. Telbivudine was well tolerated under fasting and fed conditions. Oral absorption of telbivudine as measured by maximum plasma concentration (Cmax), time to reach Cmax (Tmax), and area under the plasma concentration-time curve (AUC(0-t) and AUC(0-infinity)) was not altered by food intake immediately before oral dosing. Values of Cmax, Tmax, and AUC were comparable when telbivudine was administered under fed and fasting conditions. Results from this study indicated that the absorption of telbivudine was not affected by a high-fat/high-calorie meal; telbivudine can therefore be administered orally with no regard to the timing of meals.


Assuntos
Antivirais/farmacocinética , Interações Alimento-Droga , Nucleosídeos/farmacocinética , Pirimidinonas/farmacocinética , Absorção , Administração Oral , Adulto , Antivirais/administração & dosagem , Antivirais/sangue , Área Sob a Curva , Estudos Cross-Over , Gorduras na Dieta/farmacologia , Monitoramento de Medicamentos , Ingestão de Energia , Jejum , Feminino , Alimentos , Humanos , Masculino , Nucleosídeos/administração & dosagem , Nucleosídeos/sangue , Pirimidinonas/administração & dosagem , Pirimidinonas/sangue , Telbivudina , Timidina/análogos & derivados
9.
J Clin Pharmacol ; 46(9): 999-1007, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16920894

RESUMO

The pharmacokinetics of telbivudine, an L-nucleoside with potent activity against hepatitis B virus, was assessed in 42 healthy Chinese volunteers. Subjects were assigned to receive a single oral dose of 200, 400, or 800 mg telbivudine or repeat doses of 600 mg/d. Telbivudine was absorbed rapidly and exhibited dose-related plasma exposure. After reaching maximum concentration (C(max)) at a median time of 2.0 to 2.5 hours, plasma disposition of the drug was biphasic with a mean terminal half-life ranging from 39.4 to 49.1 hours. Telbivudine accumulated slightly after repeat doses, and steady state was reached after 5 to 6 consecutive doses of 600 mg/d. The mean steady-state C(max) and area under the plasma concentration-time curve over the dosing interval of telbivudine 600 mg were 3.7 microg/mL and 26.1 microg x h/mL, respectively. Cumulative urinary excretion of telbivudine over 32 hours represented 24.4% of the administered dose, with a mean renal clearance of 6.6 L/h. Telbivudine was well tolerated in the studied dose range in healthy Chinese subjects, with no pattern of dose-related clinical or laboratory adverse events.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Saúde , Nucleosídeos/efeitos adversos , Nucleosídeos/farmacocinética , Pirimidinonas/efeitos adversos , Pirimidinonas/farmacocinética , Administração Oral , Adulto , China , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Nucleosídeos/administração & dosagem , Nucleosídeos/sangue , Pirimidinonas/administração & dosagem , Pirimidinonas/sangue , Telbivudina , Timidina/análogos & derivados
11.
Clin Ther ; 25(3): 904-18, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12852707

RESUMO

BACKGROUND: According to the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines, hypercholesterolemic patients with greater risk for cardiovascular heart disease require more aggressive lowering of low-density lipoprotein cholesterol (LDL-C) levels. Numerous studies have demonstrated that despite these guidelines, patients often do not reach their target levels, and that physicians frequently do not titrate the drug beyond the starting dose. For these patients, it may be more suitable to initiate treatment with a higher starting dose of statin. With the immediate-release (IR) formulation of fluvastatin, the maximal dose of 80 mg is recommended to be administered in divided doses (40 mg BID). An extended-release (ER) formulation of fluvastatin at a higher dose (fluvastatin ER 80 mg) was designed to provide greater LDL-C lowering with QD dosing. Use of this formulation should bring more patients into compliance with target LDL-C levels. OBJECTIVE: This analysis compared the efficacy and tolerability of fluvastatin ER 80 mg QD and fluvastatin IR 40 mg QD in lowering total cholesterol, LDL-C, triglyceride, and apolipoprotein (apo) B levels and raising high-density lipoprotein cholesterol (HDL-C) and apo A-I levels in patients with hypercholesterolemia over a 12-week treatment period. METHODS: This was a prospective, multicenter, double-blind, double-dummy, randomized, parallel-group, active-controlled study Patients with primary hypercholesterolemia who qualified for lipid-lowering drug therapy based on NCEP ATP II guidelines were randomized to fluvastatin ER 80 mg QD or fluvastatin IR 40 mg QD, and treated for 12 weeks. RESULTS: A total of 173 patients were randomized to treatment: 86 to the fluvastatin ER 80-mg group and 87 to the fluvastatin IR 40-mg group. Compared with fluvastatin IR 40 mg, fluvastatin ER 80 mg produced greater mean reductions in LDL-C (32% vs 22%, respectively; P < 0.001). For each of the 3 coronary heart disease (CHD) risk groups (defined by the NCEP), as well as for the total population studied, more patients from the fluvastatin ER 80-mg group than the IR 40 group achieved NCEP ATP II target LDL-C levels (79% vs 47%, respectively [P = NS], for patients with < 2 risk factors; 58% vs 15%, respectively [P < 0.001], for patients with > or = 2 risk factors; and 40% vs 14%, respectively [P = 0.012], for patients with CHD). The 80-mg ER dose of fluvastatin provided 9.1% greater LDL-C lowering than the 40-mg IR dose. The incidence of elevations in transaminase levels was low and similar for both doses, with 1 patient in each of the treatment groups being discontinued due to repeated elevation of transaminases > 3 x the upper limit of normal (ULN). Clinically relevant elevations in creatine kinase (ie, > or = 10x ULN) were not observed with either dose. Nine patients (5 in the fluvastatin ER group and 4 in the fluvastatin IR group) discontinued because of adverse events. CONCLUSIONS: Treatment with fluvastatin ER 80 mg resulted in greater reductions in LDL-C, total cholesterol, and apo B levels compared with fluvastatin IR 40 mg, with clinically equivalent reduction in triglyceride levels and elevation of HDL-C levels. Furthermore, there were few tolerability concerns of clinical relevance with either formulation and no clinically meaningful difference in the tolerability parameters between the 2 formulations. For patients with higher baseline LDL-C levels, and for patients who require greater LDL-C lowering, it may be appropriate to initiate therapy with fluvastatin ER 80 mg. Use of the higher starting dose likely would bring a greater proportion of high-risk patients into compliance with NCEP ATP II target LDL-C levels and would provide LDL-C lowering that is in the same range that has been proved in clinical trials to be associated with reductions in CHD event rates.


Assuntos
Anticolesterolemiantes/uso terapêutico , Ácidos Graxos Monoinsaturados/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Indóis/uso terapêutico , Cápsulas , Colesterol/sangue , Preparações de Ação Retardada , Método Duplo-Cego , Ácidos Graxos Monoinsaturados/administração & dosagem , Feminino , Fluvastatina , Humanos , Hipercolesterolemia/sangue , Indóis/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Comprimidos , Fatores de Tempo
12.
Antimicrob Agents Chemother ; 51(12): 4231-5, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17875994

RESUMO

This study evaluates the effect of renal impairment on the pharmacokinetics of telbivudine. Thirty-six subjects were assigned, on the basis of creatinine clearance (CL(CR)), to 1 of 5 renal function groups with 6 to 8 subjects per group: normal renal function; mild, moderate, or severe renal impairment; or end-stage renal disease [ESRD] requiring hemodialysis. Subjects received a single oral dose of telbivudine at 600 mg (normal function and mild impairment), 400 mg (moderate impairment), or 200 mg (severe impairment and ESRD); plasma and/or urine samples were collected over a 48-h period for pharmacokinetic analyses. Telbivudine was well tolerated by all subjects. The pharmacokinetics of 600 mg of telbivudine were comparable for subjects with mild renal impairment and normal renal function. Likewise, for subjects with moderate to severe impairment, including ESRD, reduced doses from 200 to 400 mg produced plasma exposure similar to that for subjects with normal renal function. These results indicate that the pharmacokinetics of telbivudine were dependent on renal function, especially for subjects with moderate to severe renal impairment or ESRD. Apparent total plasma clearance, renal clearance (CL(R)), and urinary excretion of telbivudine decreased as renal function deteriorated. A linear relationship was established between CL(R) and CL(CR). In ESRD subjects, a routine 3.5- to 4-h hemodialysis session removed telbivudine from plasma at an extraction ratio of approximately 45%, representing a approximately 23% reduction in total exposure. These results suggest that while no adjustment of the telbivudine dose appears necessary for subjects with mild renal impairment, dose adjustment is warranted for those with moderate to severe renal impairment or ESRD in order to achieve optimal plasma exposure.


Assuntos
Nefropatias/metabolismo , Falência Renal Crônica/metabolismo , Nucleosídeos/farmacocinética , Pirimidinonas/farmacocinética , Adolescente , Adulto , Idoso , Feminino , Humanos , Nefropatias/fisiopatologia , Falência Renal Crônica/fisiopatologia , Testes de Função Renal , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Nucleosídeos/efeitos adversos , Pirimidinonas/efeitos adversos , Telbivudina , Timidina/análogos & derivados
13.
Antimicrob Agents Chemother ; 50(7): 2309-15, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16801406

RESUMO

Two phase I studies were conducted to assess the plasma pharmacokinetics of telbivudine and potential drug-drug interactions between telbivudine (200 or 600 mg/day) and lamivudine (100 mg/day) or adefovir dipivoxil (10 mg/day) in healthy subjects. Study drugs were administered orally. The pharmacokinetics of telbivudine were characterized by rapid absorption with biphasic disposition. The maximum concentrations in plasma (Cmax) were reached at median times ranging from 2.5 to 3.0 h after dosing. Mean single-dose Cmax and area under the plasma concentration-time curve from time zero to infinity (AUC0-infinity) were 1.1 and 2.9 microg/ml and 7.4 and 21.8 microg . h/ml for the 200- and 600-mg telbivudine doses, respectively. Steady state was reached after daily dosing for 5 to 7 days. The mean steady-state Cmax and area under the plasma concentration-time curve over the dosing interval (AUCtau) were 1.2 and 3.4 microg/ml and 8.9 and 27.5 microg . h/ml for the 200- and 600-mg telbivudine repeat doses, respectively. The steady-state AUCtau of telbivudine was 23 to 57% higher than the single-dose values. Concomitant lamivudine or adefovir dipivoxil did not appear to significantly alter the steady-state plasma pharmacokinetics of telbivudine; the geometric mean ratios and associated 90% confidence interval (CI) for the AUCtau of telbivudine alone versus in combination were 106.3% (92.0 to 122.8%) and 98.6% (86.4 to 112.5%) when coadministered with lamivudine and adefovir dipivoxil, respectively. Similarly, the steady-state plasma pharmacokinetics of lamivudine or adefovir were not markedly affected by the coadministration of telbivudine; the geometric mean ratios and associated 90% CI, alone versus in combination with telbivudine, were 99.0% (87.1 to 112.4%) and 92.2% (84.0 to 101.1%), respectively, for the lamivudine and adefovir AUCtau values. Moreover, the combination regimens studied were well tolerated in all subjects. The results from these studies provide pharmacologic support for combination therapy or therapy switching involving telbivudine, lamivudine, and adefovir dipivoxil for the treatment of chronic hepatitis B virus infection.


Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/metabolismo , Antivirais/farmacocinética , Lamivudina/metabolismo , Nucleosídeos/farmacocinética , Organofosfonatos/metabolismo , Pirimidinonas/farmacocinética , Inibidores da Transcriptase Reversa/metabolismo , Adenina/administração & dosagem , Adenina/metabolismo , Administração Oral , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Antivirais/metabolismo , Área Sob a Curva , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Humanos , Lamivudina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Nucleosídeos/administração & dosagem , Nucleosídeos/metabolismo , Organofosfonatos/administração & dosagem , Pirimidinonas/administração & dosagem , Pirimidinonas/metabolismo , Inibidores da Transcriptase Reversa/administração & dosagem , Telbivudina , Timidina/análogos & derivados
14.
Antimicrob Agents Chemother ; 50(3): 874-9, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16495245

RESUMO

The pharmacokinetics of telbivudine were evaluated in adult patients with chronic hepatitis B virus (HBV) infection following once-daily oral administration at escalating doses of 25, 50, 100, 200, 400, and 800 mg/day for 4 weeks. Telbivudine was rapidly absorbed after oral administration, with the median times T(max) to the maximum plasma concentration (C(max)) ranging from 0.8 to 3.0 h postdosing across cohorts. Single-dose and steady-state maximum C(max)s and the areas under the plasma concentration-time curve from time zero to time t (AUC(0-t)s) increased proportionally with dose. At steady-state, the values of C(max) and AUC(0-t) were higher than those obtained after the administration of a single dose, indicative of a slight accumulation, with the ratios of the steady-state value to the value after the administration of a single dose ranging from 1.14 to 1.49 for C(max) and from 1.40 to 1.70 for AUC(0-t). While the elimination of telbivudine from plasma was apparently monophasic over the 8-h sampling period, the substantial steady-state trough plasma levels observed in the groups receiving doses of 100 to 800 mg were clearly indicative of the presence of a second slower elimination phase, with the mean estimated half-lives ranging from 29.5 to 41.3 h by compartmental modeling analysis. Pharmacokinetic and pharmacodynamic analyses by using maximum-effect modeling established a quantitative relationship between a reduction in serum HBV DNA levels and parameters of drug exposure, in particular, the steady-state C(max) and AUC(0-t). In summary, this study showed that telbivudine exhibits dose-proportional plasma pharmacokinetics with sustained steady-state drug exposure and exposure-related antiviral activity, supporting the need for further clinical studies by use of a once-daily regimen in patients with chronic HBV infection.


Assuntos
Antivirais/farmacologia , Antivirais/farmacocinética , Hepatite B Crônica/tratamento farmacológico , Nucleosídeos/farmacologia , Nucleosídeos/farmacocinética , Pirimidinonas/farmacologia , Pirimidinonas/farmacocinética , Administração Oral , Adulto , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Área Sob a Curva , Povo Asiático , China/etnologia , Estudos de Coortes , DNA Viral/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Meia-Vida , Vírus da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/virologia , Humanos , Masculino , Nucleosídeos/administração & dosagem , Nucleosídeos/efeitos adversos , Nucleosídeos/uso terapêutico , Pirimidinonas/administração & dosagem , Pirimidinonas/efeitos adversos , Pirimidinonas/uso terapêutico , Telbivudina , Timidina/análogos & derivados , Fatores de Tempo , Resultado do Tratamento
15.
Antimicrob Agents Chemother ; 50(5): 1721-6, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16641441

RESUMO

This study evaluated the effect of hepatic impairment on the pharmacokinetics of telbivudine, an investigational nucleoside antiviral for the treatment of chronic hepatitis B virus infection. Twenty-four subjects were assigned to four hepatic function groups (normal function and mild, moderate, and severe impairment, with six subjects in each group) on the basis of Child-Pugh scores. The subjects were administered a single oral dose of 600 mg telbivudine, and blood samples were collected over a 48-h interval for pharmacokinetic analyses. Telbivudine was well tolerated by all subjects. Telbivudine plasma concentration-time profiles were similar across the four hepatic function groups. The principal pharmacokinetic parameters of drug exposure, i.e., the maximum plasma concentration and area under the drug concentration-time curve, were comparable between subjects with various degrees of hepatic impairment and those with normal hepatic function. Results from this single-dose pharmacokinetic assessment therefore provide a pharmacologic rationale for further evaluation of the safety and efficacy of telbivudine in hepatitis B virus-infected patients with decompensated liver diseases.


Assuntos
Antivirais/farmacocinética , Hepatopatias/metabolismo , Nucleosídeos/farmacocinética , Pirimidinonas/farmacocinética , Administração Oral , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/sangue , Área Sob a Curva , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Nucleosídeos/administração & dosagem , Nucleosídeos/efeitos adversos , Nucleosídeos/sangue , Pirimidinonas/administração & dosagem , Pirimidinonas/efeitos adversos , Pirimidinonas/sangue , Índice de Gravidade de Doença , Telbivudina , Timidina/análogos & derivados
16.
Gastroenterology ; 129(2): 528-36, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16083710

RESUMO

BACKGROUND & AIMS: A previous 4-week trial of telbivudine in patients with chronic hepatitis B indicated marked antiviral effects with good tolerability, leading to the present 1-year phase 2b trial. METHODS: This randomized, double-blind, multicenter trial evaluated the efficacy and safety of telbivudine 400 or 600 mg/day and telbivudine 400 or 600 mg/day plus lamivudine 100 mg/day (Comb400 and Comb600) compared with lamivudine 100 mg/day in hepatitis B e antigen (HBeAg)-positive adults with compensated chronic hepatitis B. RESULTS: A total of 104 patients were randomized 1:1:1:1:1 among the 5 groups. Median reductions in serum hepatitis B virus (HBV) DNA levels at week 52 (log(10) copies/mL) were as follows: lamivudine, 4.66; telbivudine 400 mg, 6.43; telbivudine 600 mg, 6.09; Comb400, 6.40; and Comb600, 6.05. At week 52, telbivudine monotherapy showed a significantly greater mean reduction in HBV DNA levels (6.01 vs 4.57 log(10) copies/mL; P < .05), clearance of polymerase chain reaction-detectable HBV DNA (61% vs 32%; P < .05), and normalization of alanine aminotransferase levels (86% vs 63%; P < .05) compared with lamivudine monotherapy, with proportionally greater HBeAg seroconversion (31% vs 22%) and less viral breakthrough (4.5% vs 15.8%) (P = NS for both). Combination treatment was not better than telbivudine alone. All treatments were well tolerated. In exploratory scientific analyses, clinical efficacy at 1 year appeared related to reduction in HBV DNA levels in the first 6 months of treatment. CONCLUSIONS: Patients with chronic hepatitis B treated with telbivudine exhibited significantly greater virologic and biochemical responses compared with lamivudine. Results with the combination regimens were similar to those obtained with telbivudine alone. These data support the ongoing phase 3 evaluation of telbivudine for treatment of patients with chronic hepatitis B.


Assuntos
Antígenos E da Hepatite B/imunologia , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/imunologia , Lamivudina/administração & dosagem , Nucleosídeos/administração & dosagem , Pirimidinonas/administração & dosagem , Adolescente , Adulto , Fatores Etários , Idoso , DNA Viral/análise , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , Seguimentos , Antígenos E da Hepatite B/análise , Hepatite B Crônica/diagnóstico , Humanos , Lamivudina/efeitos adversos , Testes de Função Hepática , Assistência de Longa Duração , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Nucleosídeos/efeitos adversos , Pirimidinonas/efeitos adversos , Valores de Referência , Medição de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Telbivudina , Timidina/análogos & derivados , Resultado do Tratamento
17.
Hepatology ; 40(3): 719-26, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15349912

RESUMO

Current therapy for chronic hepatitis B is suboptimal as a result of limited durable response rates, cumulative viral resistance, and/or poor tolerability. Telbivudine has potent antiviral activity against hepatitis B virus (HBV) in vitro and in the woodchuck model and has a promising preclinical safety profile. In this first clinical study of telbivudine, safety, antiviral activity, and pharmacokinetics were assessed in 43 adults with hepatitis B e antigen-positive chronic hepatitis B. This placebo-controlled dose-escalation trial investigated 6 telbivudine daily dosing levels (25, 50, 100, 200, 400, and 800 mg/d); treatment was given for 4 weeks, with 12 weeks' follow-up. Serum HBV DNA levels were monitored via quantitative polymerase chain reaction. The results indicate that telbivudine was well tolerated at all dosing levels, with no dose-related or treatment-related clinical or laboratory adverse events. telbivudine plasma pharmacokinetics were dose-proportional within the studied dose range. Marked dose-related antiviral activity was evident, with a maximum at telbivudine doses of 400 mg/d or more. In the 800 mg/d cohort, the mean HBV DNA reduction was 3.75 log10 copies/mL at week 4, comprising a 99.98% reduction in serum viral load. Correspondingly, posttreatment return of viral load was slowest in the high-dose groups. Viral dynamic analyses suggested a high degree of efficiency of inhibition of HBV replication by telbivudine and helped refine selection of the optimal dose. In conclusion, these results support expanded clinical studies of this new agent for the treatment of hepatitis B.


Assuntos
Antígenos E da Hepatite B/análise , Hepatite B Crônica/tratamento farmacológico , Nucleosídeos/administração & dosagem , Pirimidinonas/administração & dosagem , Adulto , Idoso , DNA Viral/sangue , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Nucleosídeos/efeitos adversos , Nucleosídeos/farmacocinética , Pirimidinonas/efeitos adversos , Pirimidinonas/farmacocinética , Telbivudina , Timidina/análogos & derivados
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