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1.
Thromb Haemost ; 120(5): 747-757, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32369846

RESUMO

BACKGROUND: The currently published population pharmacokinetic (PK) models used for PK-guided dosing in hemophilia patients are based on clinical trial data and usually not externally validated in clinical practice. The aim of this study was to validate a published model for recombinant factor VIII-Fc fusion protein (rFVIII-Fc) concentrate and to develop an enriched model using independently collected clinical data if required. METHODS: Clinical data from hemophilia A patients treated with rFVIII-Fc concentrate (Elocta) participating in the United Kingdom Extended Half-Life Outcomes Registry were collected. The predictive performance of the published model was assessed using mean percentage error (bias) and mean absolute percentage error (inaccuracy). An extended population PK model was developed using nonlinear mixed-effects modeling (NONMEM). RESULTS: A total of 43 hemophilia A patients (FVIII ≤ 2 IU/dL), aged 5 to 70 years, were included. The prior model was able to predict the collected 244 rFVIII-Fc levels without significant bias (-1.0%, 95% CI: -9.4 to 7.3%) and with acceptable accuracy (12.9%). However, clearance and central distribution volume were under predicted in patients <12 years, which was expected as this age group was not represented in the previous model population. An enriched population PK model was constructed, which was able to successfully characterize PK profiles of younger children. CONCLUSION: We concluded that the existing rFVIII-Fc population PK model is valid for patients ≥ 12 years. However, it is not reliable in younger patients. Our alternative model, constructed from real world patient data including children, allows for better description of patients ≥5 years.


Assuntos
Fator VIII/farmacocinética , Hemofilia A/tratamento farmacológico , Hemostáticos/farmacocinética , Modelos Biológicos , Proteínas Recombinantes de Fusão/farmacocinética , Adolescente , Adulto , Fatores Etários , Idoso , Criança , Fator VIII/administração & dosagem , Fator VIII/efeitos adversos , Hemofilia A/sangue , Hemofilia A/diagnóstico , Hemostáticos/administração & dosagem , Hemostáticos/efeitos adversos , Humanos , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Países Baixos , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Sistema de Registros , Reprodutibilidade dos Testes , Reino Unido , Adulto Jovem
2.
Value Health ; 23(4): 434-440, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32327160

RESUMO

OBJECTIVES: Outcomes-based contracts tie rebates and discounts for expensive drugs to outcomes. The objective was to estimate the utility of outcomes-based contracts for diabetes medications using real-world data and to identify methodologic limitations of this approach. METHODS: A population-based cohort study of adults newly prescribed a medication for diabetes with a publicly announced outcomes-based contract (ie, exenatide microspheres ["exenatide"], dulaglutide, or sitagliptin) was conducted. The comparison group included patients receiving canagliflozin or glipizide. The primary outcome was announced in the outcomes-based contract: the percentage of adults with a follow-up hemoglobin A1C <8% up to 1 year later. Secondary outcomes included the percentage of patients diagnosed with hypoglycemia and the cost of a 1-month supply. RESULTS: Thousands of adults newly filled prescriptions for exenatide (n = 5079), dulaglutide (n = 6966), sitagliptin (n = 40 752), canagliflozin (n = 16 404), or glipizide (n = 59 985). The percentage of adults subsequently achieving a hemoglobin A1C below 8% ranged from 83% (dulaglutide, sitagliptin) to 71% (canagliflozin). The rate of hypoglycemia was 25 per 1000 person-years for exenatide, 37 per 1000 person-years for dulaglutide, 28 per 1000 person-years for sitagliptin, 18 per 1000 person-years for canagliflozin, and 34 per 1000 person-years for glipizide. The cash price for a 1-month supply was $847 for exenatide, $859 for dulaglutide, $550 for sitagliptin, $608 for canagliflozin, and $14 for glipizide. CONCLUSION: Outcomes-based pricing of diabetes medications has the potential to lower the cost of medications, but using outcomes such as hemoglobin A1C may not be clinically meaningful because similar changes in A1C can be achieved with generic medications at a far lower cost.


Assuntos
Contratos/economia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Avaliação de Resultados em Cuidados de Saúde/métodos , Idoso , Canagliflozina/administração & dosagem , Canagliflozina/economia , Estudos de Coortes , Diabetes Mellitus Tipo 2/economia , Exenatida/administração & dosagem , Exenatida/economia , Feminino , Seguimentos , Glipizida/administração & dosagem , Glipizida/economia , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Peptídeos Semelhantes ao Glucagon/economia , Humanos , Hipoglicemiantes/economia , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos Fc das Imunoglobulinas/economia , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/economia , Fosfato de Sitagliptina/administração & dosagem , Fosfato de Sitagliptina/economia
3.
Proc Natl Acad Sci U S A ; 117(14): 7981-7989, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32209664

RESUMO

Human infection by Zika virus (ZIKV) during pregnancy can lead to vertical transmission and fetal aberrations, including microcephaly. Prophylactic administration of antibodies can diminish or prevent ZIKV infection in animal models, but whether passive immunization can protect nonhuman primates and their fetuses during pregnancy has not been determined. Z004 and Z021 are neutralizing monoclonal antibodies to domain III of the envelope (EDIII) of ZIKV. Together the two antibodies protect nonpregnant macaques against infection even after Fc modifications to prevent antibody-dependent enhancement (ADE) in vitro and extend their half-lives. Here we report on prophylactic coadministration of the Fc-modified antibodies to pregnant rhesus macaques challenged three times with ZIKV during first and second trimester. The two antibodies did not entirely eliminate maternal viremia but limited vertical transmission, protecting the fetus from neurologic damage. Thus, maternal passive immunization with two antibodies to EDIII can shield primate fetuses from the harmful effects of ZIKV.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Complicações Infecciosas na Gravidez/prevenção & controle , Infecção por Zika virus/prevenção & controle , Zika virus/imunologia , Animais , Animais Recém-Nascidos , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/genética , Anticorpos Neutralizantes/imunologia , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Feto/imunologia , Feto/virologia , Células HEK293 , Humanos , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos Fc das Imunoglobulinas/genética , Fragmentos Fc das Imunoglobulinas/imunologia , Imunoglobulina G/administração & dosagem , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Gravidez , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/virologia , Engenharia de Proteínas , RNA Viral/isolamento & purificação , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Zika virus/genética , Zika virus/patogenicidade , Infecção por Zika virus/imunologia , Infecção por Zika virus/transmissão , Infecção por Zika virus/virologia
4.
Drugs ; 80(2): 197-208, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32002850

RESUMO

Subcutaneous dulaglutide (Trulicity®) is a once-weekly glucagon-like peptide-1 receptor agonist that is approved in numerous countries as an adjunct to diet and exercise for the treatment of adults with type 2 diabetes (T2D). In the clinical trial and real-world settings, once-weekly subcutaneous dulaglutide, as monotherapy or add-on therapy to other antihyperglycaemic agents (including oral antihyperglycaemic drugs and insulin), was an effective and generally well tolerated treatment in adults with inadequately controlled T2D, including in high-risk patients [e.g. obese and elderly patients, those with stage 3 or 4 chronic kidney disease (CKD) and/or cardiovascular (CV) disease]. In the REWIND CV outcomes trial in patients with T2D with or without CV disease, dulaglutide was associated with a significant reduction in the risk of a major adverse cardiac event (MACE; primary composite outcome comprising CV death, nonfatal myocardial infarction or nonfatal stroke) at a median of 5.4 years' follow-up. Given its durable glycaemic efficacy, beneficial effects on bodyweight and MACE outcomes, low inherent risk of hypoglycaemia and convenient once-weekly regimen, dulaglutide remains an important option in the management of T2D.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Hipoglicemiantes/administração & dosagem , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Injeções Subcutâneas , Proteínas Recombinantes de Fusão/administração & dosagem
5.
Metabolism ; 106: 154190, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32109448

RESUMO

INTRODUCTION AND AIM: Real-word data on the head-to-head comparisons among glucagon-like peptide-1 receptor agonists (GLP-1RA) are scant. Therefore, we aimed to compare the effectiveness of dulaglutide versus liraglutide and exenatide once weekly (exeOW) in type 2 diabetic (T2D) patients under routine care. METHODS: This was a retrospective, multicenter, real-world study on patients with T2D (aged 18-80) initiating a GLP-1RA between 2010 and 2018 at specialist outpatient clinics. We compared the effectiveness of dulaglutide versus liraglutide and exeOW on the changes in HbA1c (primary outcome), body weight, blood pressure and fasting glucose (secondary outcomes). Average follow-up was 5.9 months. Channelling biases were addressed with propensity score matching or multivariable adjustment. Meta-analyses of observational studies, covering the same comparisons, are also presented. RESULTS: 849, 1371 and 198 patients were included in the dulaglutide, liraglutide and exeOW groups, respectively. The reduction of HbA1c was greater with dulaglutide than with liraglutide (-0.24 ±â€¯0.08%; p = 0.003), and was confirmed in the meta-analysis of observational studies. In our study, dulaglutide showed similar effectiveness compared to exeOW. When these results were pooled with other observational studies, dulaglutide showed a greater reduction of HbA1c (-0.19%; p = 0.003) and body weight (-0.8 kg; p = 0.007). CONCLUSIONS: In a real-world scenario, dulaglutide reduced HbA1c more than liraglutide. Conversely, we found similar effect of dulaglutide and exeOW, with statistical differences arising solely when results were meta-analysed with those from other observational studies. Lack of up-titration for liraglutide and higher discontinuation rate for exeOW likely influenced the estimated treatment difference.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Exenatida/administração & dosagem , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Liraglutida/administração & dosagem , Estudos Observacionais como Assunto/estatística & dados numéricos , Proteínas Recombinantes de Fusão/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Esquema de Medicação , Quimioterapia Combinada , Exenatida/efeitos adversos , Feminino , Seguimentos , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Humanos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Liraglutida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
6.
BMC Immunol ; 20(1): 44, 2019 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-31801459

RESUMO

BACKGROUND: High-dose intravenous immunoglobulin (IVIg), and more recently, subcutaneously-delivered Ig (SCIg), are used to treat a variety of autoimmune diseases; however, there are challenges associated with product production, availability, access and efficacy. These challenges have provided incentives to develop a human recombinant Fc as a more potent alternative to IVIg and SCIg for the treatment of autoimmune diseases. Recently, a recombinant human IgG1 Fc hexamer (Fc-µTP-L309C) was shown to be more efficacious than IVIg in a variety of autoimmune mouse models. We have now examined its efficacy compared to IVIg and SCIg in the K/BxN mouse model of endogenous, chronic rheumatoid arthritis (RA). RESULT: Using the serum-transfer K/BxN model and the endogenous autoimmune model, amelioration of the arthritis was achieved. Effective treatment required high and frequent doses of IVIg, SCIg and Fc-µTP-L309C. However, Fc-µTP-L309C was efficacious at 10-fold lower doses that IVIg/SCIg. Also, arthritis could be prevented when Fc-µTP-L309C was given prior to onset of the arthritis in both the endogenous model and in the serum transfer model. CONCLUSIONS: Our results show that Fc-µTP-L309C is a powerful treatment for the prevention and amelioration of severe, chronic arthritis in a true autoimmune mouse model of RA. Thus, the K/BxN endogenous arthritis model should be useful for testing potential therapeutics for RA. Our findings provide rationale for further examination of the treatment efficacy of immunoglobulin-based therapeutics in rheumatoid arthritis.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Fragmentos Fc das Imunoglobulinas/farmacologia , Imunoglobulinas Intravenosas/farmacologia , Fatores Imunológicos/farmacologia , Animais , Artrite Reumatoide/patologia , Doença Crônica , Modelos Animais de Doenças , Humanos , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Imunoglobulina G/química , Imunoglobulinas Intravenosas/administração & dosagem , Fatores Imunológicos/administração & dosagem , Camundongos , Resultado do Tratamento
7.
Medicine (Baltimore) ; 98(48): e17750, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31770193

RESUMO

The aim of this study was to evaluate the cost-effectiveness of Anbainuo (ABN) plus methotrexate (MTX) (ABN + MTX) versus conventional disease-modifying anti-rheumatic drugs (cDMARDs) in rheumatoid arthritis (RA) patients.Forty-eight moderate to severe RA patients underwent ABN + MTX or cDMARDs treatment were consecutively enrolled and assigned to ABN + MTX group (n = 26) and control group (n = 22). Patients were followed up and their disease activity and quality of life (QoL) were evaluated at 3rd month, 6th month and 12th month after initiation of treatment. Treatment costs of 2 groups were calculated, then pharmacoeconomic analysis was performed.ABN + MTX increased drug cost and total cost while decreased indirect cost compared with cDMARDs after 12-month treatment. ABN + MTX group gained additional 0.22 quality-adjusted life years (QALY) and yielded an incremental cost-effectiveness ratio (ICER) of ¥104,293.6 per QALY after treatment. Sensitivity analysis reveals that rising ABN price by 20% produced an ICER of ¥130,403.6 per QALY, which was still lower than 3 times of the mean gross domestic product (GDP) per capita during the same period in China (¥165,960). Besides, ABN + MTX was more cost-effective in severe RA patients compared to moderate RA patients.ABN + MTX is cost-effective in treating moderate to severe RA patients compared with cDMARDs, although the total cost of ABN + MTX is relatively higher.


Assuntos
Antirreumáticos/economia , Artrite Reumatoide/tratamento farmacológico , Medicamentos Biossimilares/economia , Custos de Medicamentos/estatística & dados numéricos , Fragmentos Fc das Imunoglobulinas/economia , Metotrexato/economia , Receptores Tipo II do Fator de Necrose Tumoral/economia , Proteínas Recombinantes de Fusão/economia , Idoso , Antirreumáticos/administração & dosagem , Artrite Reumatoide/economia , Medicamentos Biossimilares/administração & dosagem , Análise Custo-Benefício , Quimioterapia Combinada/economia , Feminino , Humanos , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Anos de Vida Ajustados por Qualidade de Vida , Receptores Tipo II do Fator de Necrose Tumoral/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Índice de Gravidade de Doença , Resultado do Tratamento
8.
Endocr Regul ; 53(3): 187-190, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31517629

RESUMO

OBJECTIVE: While dulaglutide has been approved inpatients with type 2 diabetes (T2DM) in combination with insulin, it has not been studied in insulin-deficient patients, not whether they have type 1 diabetes (T1DM) or T2DM. The aim of this study is to assess the efficacy and safety of dulaglutide 0.75 mg/once weekly (QW) in patients with absolute insulin deficiency (n=10). SUBJECTS AND RESULTS: Significant reductions of HbA1c (9.30±1.03% to 8.61±1.21%; p<0.02) and body mass index (BMI; 23.61±3.95 to 23.41±4.24; p<0.02) levels were observed at 3 months with the addition of dulaglutide to the existing pharmacotherapy. However, in all the patients, post-meal C-peptide levels remained undetectable. One patient had gastrointestinal adverse events and discontinue dulaglutide within the first month. One patient was a non-responder, who had little if any changes in HbA1c levels at 3 months. CONCLUSIONS: The results indicate that dulaglutide is effective in patients with T1DM or T2DM with absolute insulin deficiency, though gastrointestinal adverse events might be of concern. The improvements in glycemic control could not be due to enhanced insulin secretion, but may be as a result of a combination of the other effects of glucagon like peptide 1 (GLP-1), such as postprandial glucagon suppression, delayed gastric emptying, and weight loss.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Insulina/deficiência , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Idoso , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Esquema de Medicação , Quimioterapia Combinada , Feminino , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Hemoglobina A Glicada/análise , Hemoglobina A Glicada/efeitos dos fármacos , Hemoglobina A Glicada/metabolismo , Humanos , Insulina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
9.
Virology ; 536: 49-57, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31400549

RESUMO

Molecular adjuvants are vaccine delivery vehicle to increase specific antigens effectiveness. Herein, we concentrated on IgG Fc, an effective molecular adjuvant, to develop novel pseudorabies virus (PRV) subunit vaccines. Two major protective antigen genes of PRV were constructed and linked into the mouse IgG Fc fragment. The gD, gD-IgG2aFc, gB and gB-IgG2aFc proteins were expressed using a baculovirus system. Mice intranasally immunized with gD-IgG2aFc or gB-IgG2aFc subunit vaccine exhibited significantly higher PRV-specific antibodies, neutralizing antibodies and intracellular cytokines than the mice intranasally immunized with gD or gB subunit vaccine. Moreover, no histopathological lesions were observed in mice immunized with gB-IgG2aFc subunit vaccine via histopathology examination. Further, the gB-IgG2aFc subunit vaccine was efficient for PRV infection compared with live attenuated vaccine. Overall, these results suggest that IgG2a Fc fragment, as a potential molecular adjuvant, fused with PRV antigen might be a promising and efficient PRV vaccine candidate.


Assuntos
Herpesvirus Suídeo 1/efeitos dos fármacos , Fragmentos Fc das Imunoglobulinas/biossíntese , Vacinas contra Pseudorraiva/biossíntese , Pseudorraiva/prevenção & controle , Proteínas Recombinantes de Fusão/biossíntese , Proteínas do Envelope Viral/biossíntese , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/biossíntese , Adjuvantes Imunológicos/genética , Animais , Anticorpos Antivirais/biossíntese , Baculoviridae/genética , Baculoviridae/metabolismo , Citocinas/genética , Citocinas/imunologia , Células Epiteliais/patologia , Células Epiteliais/virologia , Feminino , Glicoproteínas/administração & dosagem , Glicoproteínas/biossíntese , Glicoproteínas/genética , Herpesvirus Suídeo 1/genética , Herpesvirus Suídeo 1/imunologia , Herpesvirus Suídeo 1/patogenicidade , Imunização , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos Fc das Imunoglobulinas/genética , Imunoglobulina G/administração & dosagem , Imunoglobulina G/biossíntese , Imunoglobulina G/genética , Rim/patologia , Rim/virologia , Camundongos , Camundongos Endogâmicos BALB C , Pseudorraiva/imunologia , Pseudorraiva/mortalidade , Pseudorraiva/virologia , Vacinas contra Pseudorraiva/administração & dosagem , Vacinas contra Pseudorraiva/genética , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/genética , Análise de Sobrevida , Suínos , Vacinas de Subunidades , Proteínas do Envelope Viral/administração & dosagem , Proteínas do Envelope Viral/genética
10.
Gynecol Oncol ; 154(2): 294-301, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31174889

RESUMO

OBJECTIVES: The WNT pathway is an important oncologic driver of epithelial ovarian cancer (EOC). The first-in-class recombinant fusion protein ipafricept (IPA) blocks Wnt signaling through binding of Wnt ligands. This phase Ib trial was designed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RPh2) for IPA in combination with taxane and platinum therapy (C/P). METHODS: Dose escalation started with a standard 3 + 3 design for IPA/C/P with q3w intravenous IPA on Day 1, in cycles 1 to 6 with C (AUC = 5 mg/ml·min) and P (175 mg/m2). For enhanced bone safety the trial was revised to 6-patient cohorts with a q3w regimen of IPA on Day 1 and C/P on Day 3 (IPA → C/P). RESULTS: 37 patients have been treated; 30 of whom were treated following protocol revision to q3w IPA(D1) → C/P(D3) (2 & 4 mg/kg). IPA-related TEAEs that occurred in ≥15% included: fatigue (40%); nausea (35%); diarrhea and decreased appetite (22%) each; dysgeusia (19%); and vomiting (16.2%). 22% reported ≥1 IPA related TEAE Grade ≥3 the most common of which was neutropenia at 16%. There were no DLTs; the MTD was not reached. The maximum administered dose based on bone safety was 6 mg/kg. The overall response rate (ORR) was 75.7%. Median PFS was 10.3 months (95% CI 8.5-14.2) and OS 33 months (95% CI 23.4-NR). CONCLUSIONS: IPA is well tolerated in combination with sequential C/P. ORR, PFS and OS are comparable to historical data but bone toxicity at efficacy doses of this particular Wnt inhibitor limit further development in EOC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Receptores Acoplados a Proteínas-G/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Idoso , Antineoplásicos Fitogênicos , Osso e Ossos/efeitos dos fármacos , Carboplatina/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Fragmentos Fc das Imunoglobulinas/farmacologia , Dose Máxima Tolerável , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos
11.
J Diabetes Res ; 2019: 6423987, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31183384

RESUMO

Objective: To evaluate the effects of once-weekly dulaglutide injection and once-daily glimepiride on glucose fluctuation in patients with type 2 diabetes mellitus (T2DM) using the Continuous Glucose Monitoring System (CGMS). Methods: A total of 23 patients with T2DM were randomly assigned into two groups for 26 weeks: the dulaglutide group (n = 13) and the glimepiride group (n = 10). 72-hour CGMS was applied to all patients: before and after the treatment. General clinical data were collected and measured, such as fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), tumor necrosis factor-α (TNF-α), 8-iso-prostaglandin F2α (8-iso-PGF2α), and interleukin-6 (IL-6). Results: HbA1c of the dulaglutide group was reduced from 8.38 ± 0.93% to 6.68 ± 0.73% after the treatment (P < 0.05); similarly, it was reduced from 7.91 ± 0.98% to 6.67 ± 0.74% (P < 0.05) in the glimepiride group. The levels of serum 8-iso-PGF2α, TNF-α, and IL-6 all decreased significantly in both groups after treatment, and there was no significant difference found between the two groups (P > 0.05). The Mean Blood Glucose (MBG) of the two groups declined significantly after therapy (P < 0.05). However, the Standard Deviation of Blood Glucose (SDBG) decreased significantly only in the dulaglutide group (from 2.57 ± 0.74 mmol/L to 1.98 ± 0.74 mmol/L, P < 0.05). There were no significant changes of Mean Amplitude of Glycemic Excursion (MAGE) and Absolute Means of Daily Difference (MODD) after treatment in both groups. Furthermore, no statistically significant difference was found between the two groups in MBG, SDBG, MAGE, and MODD (P > 0.05). The percentage time (PT) (>10 mmol/L and 3.9-10 mmol/L) of the two groups was significantly changed after the treatment (P < 0.05). However, this was not seen in the PT < 3.9 mmol/L after the treatment (P > 0.05). Conclusion: Once-weekly dulaglutide injection has the same effectiveness as daily glimepiride on lowering blood glucose and decreasing oxidation stress and inflammation and is more effective in controlling glucose fluctuation as compared with glimepiride. This trial is registered with ClinicalTrials.gov NCT01644500.


Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Esquema de Medicação , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/administração & dosagem , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Compostos de Sulfonilureia/administração & dosagem , Automonitorização da Glicemia , Dinoprosta/análogos & derivados , Dinoprosta/metabolismo , Feminino , Seguimentos , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Hemoglobina A Glicada/metabolismo , Humanos , Inflamação , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Monitorização Ambulatorial , Estresse Oxidativo , Fator de Necrose Tumoral alfa/metabolismo
12.
J Med Econ ; 22(10): 997-1005, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31044636

RESUMO

Aims: This analysis evaluated the cost-effectiveness of once-weekly semaglutide vs glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes (T2D) uncontrolled on metformin or basal insulin in Sweden. Materials and methods: This cost-effectiveness analysis (CEA) was conducted using the Swedish Institute of Health Economics (IHE) Diabetes Cohort Model. Analyses were conducted from the Swedish societal perspective over a time horizon of 40 years. For patients uncontrolled on metformin, dulaglutide was the comparator, and data from the SUSTAIN 7 clinical trial was used. For patients uncontrolled on basal insulin, lixisenatide was chosen as the comparator and data was obtained from a network meta-analysis (NMA). Results: The results show that, in patients with inadequate control on metformin, semaglutide 1.0 mg dominated (i.e. provided greater clinical benefit, and was less costly) dulaglutide 1.5 mg. In patients with inadequate control on basal insulin, semaglutide 1.0 mg dominated lixisenatide. The reduction in costs is largely driven by the reduction in complications seen with once-weekly semaglutide. Limitations and conclusions: It is likely that this analysis is conservative in estimating the cardiovascular (CV) cost benefits associated with treatment with once-weekly semaglutide. In patients inadequately controlled on basal insulin, the analyses vs lixisenatide were based on results from an NMA, as no head-to-head clinical trial has been conducted for this comparison. These CEA results show that once-weekly semaglutide is a cost-effective GLP-1 RA therapy for the treatment of T2D in patients inadequately controlled on metformin or basal insulin, addressing many current clinician, patient, and payer unmet needs in Sweden.


Assuntos
Glicemia/efeitos dos fármacos , Análise Custo-Benefício , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/economia , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos Fc das Imunoglobulinas/economia , Peptídeos/administração & dosagem , Peptídeos/economia , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/economia , Feminino , Financiamento Pessoal , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/economia , Humanos , Masculino , Pessoa de Meia-Idade , Suécia
13.
J Med Econ ; 22(8): 806-813, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31010349

RESUMO

Aims: Several glucagon like peptide-1 (GLP-1) receptor agonists are available as weekly injections for treatment of type 2 diabetes. These medications vary in their injection devices, and these differences could impact quality-of-life and patient preference. The purpose of this study was to examine patient preferences and estimate health state utilities associated with injection devices for two weekly GLP-1 therapies. Materials and methods: Participants with type 2 diabetes in Italy (Milan, Rome) valued three health state vignettes in time trade-off interviews. The health states had identical descriptions of type 2 diabetes, but differed in description of the treatment process: (1) oral treatment regimen, (2) oral plus weekly dulaglutide injection, and (3) oral plus weekly semaglutide injection. Results: A total of 216 participants completed interviews (57.9% male; mean age = 60.5). Almost all patients (99.5%) preferred the oral health state over either injection health state. Comparing between the two injections, 88.4% preferred the dulaglutide health state, while 11.6% preferred the semaglutide state. Mean (SD) utilities were 0.907 (0.076) for oral, 0.894 (0.085) for dulaglutide, and 0.887 (0.087) for semaglutide. The mean (SD) utility difference between the injection device health states was 0.007 (0.019). Limitations: Although the health states were designed to match the injection device instructions for use as closely as possible, vignette-based methods are inherently limited because results are based on perceptions of the health states rather than actual patient experience with the devices. Conclusions: Results provide insight into patient preferences associated with injection devices for weekly GLP-1 receptor agonists. The majority of patients preferred the dulaglutide device over the semaglutide device, and for some patients, this difference had an impact on utility valuations. Patient preferences for injection devices could be an important factor to consider when selecting treatments for type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Preferência do Paciente , Proteínas Recombinantes de Fusão/uso terapêutico , Administração Oral , Idoso , Glicemia/efeitos dos fármacos , Análise Custo-Benefício , Quimioterapia Combinada , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Hemoglobina A Glicada/efeitos dos fármacos , Humanos , Hipoglicemiantes/administração & dosagem , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Injeções Subcutâneas , Itália , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Proteínas Recombinantes de Fusão/administração & dosagem
14.
Cancer ; 125(14): 2400-2408, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-30951193

RESUMO

BACKGROUND: In a prior open-label study, the combination of dalantercept, a novel antiangiogenic targeting activin receptor-like kinase 1 (ALK1), plus axitinib was deemed safe and tolerable with a promising efficacy signal in patients with advanced renal cell carcinoma (RCC). METHODS: In the current phase 2, randomized, double-blind, placebo-controlled study, patients with clear cell RCC previously treated with 1 prior angiogenesis inhibitor were randomized 1:1 to receive axitinib plus dalantercept versus axitinib plus placebo. Randomization was stratified by the type of prior therapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were PFS in patients with ≥2 prior lines of anticancer therapy, overall survival, and the objective response rate. RESULTS: Between June 10, 2014, and February 23, 2017, a total of 124 patients were randomly assigned to receive axitinib plus dalantercept (59 patients) or placebo (65 patients). The median PFS was not found to be significantly different between the treatment groups (median, 6.8 months vs 5.6 months; hazard ratio, 1.11 [95% CI, 0.71-1.73; P = .670]). Neither group reached the median overall survival (hazard ratio, 1.39 [95% CI, 0.70-2.77; P = .349]). The objective response rate was 19.0% (11 of 58 patients; 95% CI, 9.9%-31.4%) in the dalantercept plus axitinib group and 24.6% (15 of 61 patients; 95% CI, 14.5%-37.3%) in the placebo plus axitinib group. At least 1 treatment-emergent adverse event of ≥grade 3 was observed in 59% of patients (34 of 58 patients) in the dalantercept group and 64% of patients (39 of 61 patients) in the placebo group. One treatment-related death occurred in the placebo plus axitinib group. CONCLUSIONS: Although well tolerated, the addition of dalantercept to axitinib did not appear to improve treatment-related outcomes in previously treated patients with advanced RCC.


Assuntos
Receptores de Activinas Tipo II/uso terapêutico , Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Axitinibe/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Receptores de Activinas Tipo II/administração & dosagem , Receptores de Activinas Tipo II/efeitos adversos , Receptores de Activinas Tipo II/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Axitinibe/administração & dosagem , Axitinibe/efeitos adversos , Carcinoma de Células Renais/mortalidade , Diarreia/etiologia , Método Duplo-Cego , Fadiga/etiologia , Feminino , Humanos , Hipertensão/etiologia , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Fragmentos Fc das Imunoglobulinas/metabolismo , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/metabolismo
15.
Int J Mol Sci ; 20(7)2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30934882

RESUMO

GLP-1 (glucagon-like peptide-1) has been reported to play a vital role in neuroprotection. Experimental autoimmune encephalomyelitis (EAE) is a well-established animal model widely used to study human multiple sclerosis, a chronic demyelination disease in the central nervous system (CNS). Recently, important studies have designated that the signaling axis of GLP-1 and its receptor controls the clinical manifestations and pathogenesis of EAE. However, it is elusive whether GLP-1 receptor signaling regulates the phenotype of autoreactive T cells in the CNS. We administered dulaglutide, a well-established GLP-1 receptor agonist (GLP-1 RA), to treat EAE mice prophylactically or semi-therapeutically and subsequently analyzed the mononuclear cells of the CNS. In this study, dulaglutide treatment significantly alleviates the clinical manifestations and histopathological outcomes of EAE. Dulaglutide decreases incidences of encephalitogenic Th1/Th17 cells and Th1 granulocyte-macrophage-colony-stimulating factor (GM-CSF) expression in the CNS. Administration of dulaglutide failed to control the chemotactic abilities of encephalitogenic Th1 and Th17 cells; however, prophylactic treatment considerably decreased the populations of dendritic cells and macrophages in the CNS parenchyma. These results obtained indicate that dulaglutide modulates the differentiation of encephalitogenic Th1/Th17 and the pathogenicity of Th1 cells by influencing antigen presenting cells quantities, providing mechanism insight on T cells regulation in ameliorating EAE by GLP-1.


Assuntos
Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Células Th1/imunologia , Células Th17/imunologia , Animais , Quimiotaxia/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Progressão da Doença , Regulação para Baixo/efeitos dos fármacos , Encefalomielite Autoimune Experimental/patologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/farmacologia , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Imunização , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos Fc das Imunoglobulinas/farmacologia , Subpopulações de Linfócitos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/farmacologia , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos
16.
Biomed Pharmacother ; 112: 108677, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30798123

RESUMO

Recombinant human interleukin-15 (IL-15) is a potent cancer immunotherapeutic candidate due to its excellent immune stimulating effects. Previous work demonstrated that IL-15 appeared with short half-life in circulation system, while the complex with its receptor can prolong the half-life as well as benefit its activities in vivo. Therefore, IL-15 complex was more favorably considered for clinical development. Herein we developed IL-15·sIL-15Rα/Fc, a complex comprising of IL-15 and the extracellular region of its receptor alpha subunit which fused to Immunoglobulin G (IgG1) Fc to further prolong the half-life in plasma. Through transient gene expression in HEK293 cells, we expressed the superagonist by co-transfection of plasmids encoding IL-15 and sIL-15Rα/Fc respectively, yielding 36 mg/L of product after purification. Pharmacokinetic study demonstrated that the combination profoundly prolonged the half-life of IL-15 to 13.1 h in mice, about 18 folds longer than that of IL-15 monomer which is around 0.7 h. The bioactivity of the superagonist was characterized by CTLL-2 cells proliferation assay in vitro, showing its capability of stimulating the expansion of memory CD8+ T cells (cluster of differentiation) in mouse spleen. Using a HT-29 xenograft NOD-SCID mouse model, we observed tumor growth inhibition in all groups that received the superagonist, indicating its anti-tumor efficacy via stimulating infused human immune cells. In addition, combo cancer treatment by IL-15·sIL-15Rα/Fc and programmed death-1 (PD-1) antibody have shown stronger inhibitory effects as compared with treatment with either single molecule. Therefore, we developed IL-15·sIL-15Rα/Fc to be a long half-life potential cancer immunotherapy candidate that can be applied alone or in synergy with PD-1/PD-L1 blockade.


Assuntos
Antineoplásicos Imunológicos/imunologia , Desenvolvimento de Medicamentos/métodos , Fragmentos Fc das Imunoglobulinas/imunologia , Subunidade alfa de Receptor de Interleucina-15/imunologia , Interleucina-15/imunologia , Receptor de Morte Celular Programada 1/imunologia , Animais , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/metabolismo , Feminino , Células HEK293 , Células HT29 , Meia-Vida , Humanos , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos Fc das Imunoglobulinas/metabolismo , Imunoglobulina G/administração & dosagem , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Interleucina-15/administração & dosagem , Interleucina-15/metabolismo , Subunidade alfa de Receptor de Interleucina-15/administração & dosagem , Subunidade alfa de Receptor de Interleucina-15/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
17.
Appl Microbiol Biotechnol ; 103(4): 1703-1712, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30607490

RESUMO

Staphylococcus aureus-induced bovine mastitis causes significant losses to the dairy industry and available vaccines do not confer adequate protection. As a more attractive alternative, we propose the use of antibody (Ab) therapy. In our previous study, we constructed a bovine single-chain variable fragment (scFv) Ab phage display and successfully obtained scFvs that bound to S. aureus antigens with high affinity. Here, we describe a novel Ab against S. aureus (scFv-Fc Ab). To construct the scFv-Fc Ab, the scFv Ab was genetically fused to the Fc fragment of a bovine IgG1 Ab. Western blot analysis showed that the bovine scFvs-Fc Abs were successfully expressed with horseradish peroxidase-conjugated goat-anti-bovine IgG (Fc) Ab in Escherichia coli cells. The purified bovine scFvs-Fc Abs had good binding activity to S. aureus and effectively inhibited the bacterial growth in culture medium and bovine scFvs-Fc Abs enhanced phagocytosis of S. aureus by neutrophils isolated from peripheral blood in a dose-dependent manner. In the experiment of bovine scFvs-Fc Abs for the treatment of S. aureus-induced bovine mastitis, the total effective percentage reached 82% (9/11). These novel bovine scFvs-Fc Abs may be useful as therapeutic candidates for the prevention and treatment of S. aureus-induced bovine mastitis.


Assuntos
Antibacterianos/administração & dosagem , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Mastite Bovina/tratamento farmacológico , Anticorpos de Cadeia Única/administração & dosagem , Infecções Estafilocócicas/veterinária , Animais , Bovinos , Fragmentos Fc das Imunoglobulinas/genética , Fragmentos Fc das Imunoglobulinas/isolamento & purificação , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/isolamento & purificação , Anticorpos de Cadeia Única/genética , Anticorpos de Cadeia Única/isolamento & purificação , Infecções Estafilocócicas/tratamento farmacológico , Resultado do Tratamento
18.
Diabetes Obes Metab ; 21(2): 234-243, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30129089

RESUMO

AIM: To compare the efficacy and safety of once-weekly dulaglutide with that of insulin glargine in combination with metformin and/or a sulphonylurea in mainly Asian patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: In this 52-week, randomized, parallel-arm open-label study, we enrolled patients aged ≥18 years with T2DM for at least 6 months and a glycated haemoglobin (HbA1c) concentration ≥53.0 mmol/mol (7.0%) and ≤96.7 mmol/mol (11.0%). The primary outcome was change in HbA1c from baseline to week 26 to determine non-inferiority of dulaglutide 1.5 mg versus glargine. RESULTS: A total of 774 patients from China, South Korea, Mexico and Russia were randomly assigned (1:1:1) to dulaglutide 1.5 mg, dulaglutide 0.75 mg or glargine treatment groups. The patients' mean age was 55 years and the average T2DM duration was ~8 years. The least squares mean (SE) changes from baseline in HbA1c at 26 weeks were - 18.9 (0.73) mmol/mol (-1.73 [0.067]%) for dulaglutide 1.5 mg and -14.5 (0.73) mmol/mol (-1.33 [0.067]%) for dulaglutide 0.75 mg, compared with -12.7 (0.73) mmol/mol (-1.16 [0.067]%) for glargine. Statistical criteria for superiority were met with both dulaglutide 1.5 mg and dulaglutide 0.75 mg. More patients in the dulaglutide 1.5 and 0.75 mg groups achieved HbA1c target <53.0 mmol/mol (<7.0%) than in the glargine group at week 26 (P < 0.001 and P = 0.004, respectively). Body weight decreased with dulaglutide and increased with glargine. The incidence and rate of total hypoglycaemia were lower with dulaglutide versus glargine. Gastrointestinal adverse events, including diarrhoea and nausea, were the most frequently reported for patients taking dulaglutide. CONCLUSIONS: Once-weekly dulaglutide provides greater improvement in HbA1c, with weight loss and less hypoglycaemia, than once-daily insulin glargine in a population of mainly Asian patients with T2DM who had failed to achieve optimal glycaemic control on metformin and/or a sulphonylurea.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Insulina Glargina/administração & dosagem , Metformina/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Compostos de Sulfonilureia/administração & dosagem , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , China/epidemiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etnologia , Esquema de Medicação , Quimioterapia Combinada , Feminino , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Hemoglobina A Glicada/análise , Hemoglobina A Glicada/metabolismo , Humanos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Insulina Glargina/efeitos adversos , Masculino , Metformina/efeitos adversos , México/epidemiologia , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/efeitos adversos , República da Coreia/epidemiologia , Federação Russa/epidemiologia , Compostos de Sulfonilureia/efeitos adversos , Resultado do Tratamento
19.
Diabetes Obes Metab ; 21(3): 611-621, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30362224

RESUMO

AIMS: Glucagon-like peptide-1 (GLP-1) receptor agonists are appealing as glucose-lowering therapy for individuals with type 2 diabetes mellitus (T2DM) as they also reduce body weight and are associated with low rates of hypoglycaemia. This analysis assessed the long-term cost-effectiveness of semaglutide 0.5 and 1 mg vs dulaglutide 1.5 mg (two once-weekly GLP-1 receptor agonists) from a UK healthcare payer perspective, based on the head-to-head SUSTAIN 7 trial, to inform healthcare decision making. MATERIALS AND METHODS: Long-term outcomes were projected using the IQVIA CORE Diabetes Model (version 9.0). Baseline cohort characteristics, changes in physiological parameters and adverse event rates were derived from the 40-week SUSTAIN 7 trial. Costs to a healthcare payer were assessed, and these captured pharmacy costs and costs of complications. Utilities were taken from published sources. RESULTS: Once-weekly semaglutide 0.5 and 1 mg were associated with improvements in quality-adjusted life expectancy of 0.04 and 0.10 quality-adjusted life years, respectively, compared with dulaglutide 1.5 mg. Clinical benefits were achieved at reduced costs, with lifetime cost savings of GBP 35 with once-weekly semaglutide 0.5 mg and GBP 106 with the once-weekly semaglutide 1 mg, resulting from fewer diabetes-related complications due to better glycaemic control. Therefore, both doses of once-weekly semaglutide were considered dominant vs dulaglutide 1.5 mg (improving outcomes and reducing costs). CONCLUSIONS: Compared with treatment with dulaglutide, once-weekly semaglutide represents a cost-effective option for treating individuals in the UK with T2DM who are not achieving glycaemic control with metformin, projected to both improve clinical outcomes and reduce costs.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/economia , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Ensaios Clínicos como Assunto/estatística & dados numéricos , Análise Custo-Benefício , Complicações do Diabetes/economia , Complicações do Diabetes/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Esquema de Medicação , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/economia , Custos de Cuidados de Saúde/estatística & dados numéricos , Recursos em Saúde/economia , Recursos em Saúde/estatística & dados numéricos , Humanos , Fragmentos Fc das Imunoglobulinas/economia , Modelos Econômicos , Anos de Vida Ajustados por Qualidade de Vida , Proteínas Recombinantes de Fusão/economia , Fatores de Tempo , Reino Unido/epidemiologia
20.
Biomed Res Int ; 2019: 2682657, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31950036

RESUMO

Aim. To compare the effects of once-weekly Dulaglutide with once-daily glargine in poorly oral-antidiabetic controlled patients with type 2 diabetes mellitus (T2DM). Method. A total of 25 patients with T2DM admitted into Department of Endocrinology from December 2012 to August 2013 were randomly assigned into two groups: Dulaglutide group (n = 16) and glargine group (n = 9). All patients received either Dulaglutide or glargine treatments for 52 weeks. Continuous glucose monitoring systems (CGMS) were applied to them for two 72 h periods at before and after the treatment each. Patient general clinical data were collected and analyzed. Result. Fast blood glucose (FBG) of the glargine group declined more significantly than the Dulaglutide group after treatment (p < 0.05). The mean blood glucose (MBG), standard deviation of blood glucose (SDBG), mean amplitude of glycemic excursion (MAGE) within a day, the largest amplitude of glycemic excursion (LAGE), M-value, absolute means of daily difference (MODD) of glycemic excursion, the percentage of time (≤2.8 mmol/L, ≤3.9 mmol/L, ≥10.0 mmol/L, ≥13.9 mmol/L, 3.9-7.8 mmol/L, and 9-10.0 mmol/L), maximum glycemic value, and minimum glycemic value were similar between the two groups (p > 0.05). The incidence of hypoglycemia was also similar between the two groups (p > 0.05). Though serum levels of TNF-α, IL-6, and 8-PGF2α all decreased, significant reduction was found in TNF-α and 8-PGF2α. TNF-α was only significantly reduced in the Dulaglutide group, while 8-PGF2α was seen in both groups. Conclusion. For T2DM patients with poorly controlled oral antidiabetic drugs, once-weekly Dulaglutide not only has the same effect on glucose fluctuation as once-daily glargine but also significantly reduced TNF-α and 8-PGF2α after a 52 week treatment protocol. This trial is registered with ClinicalTrials.gov NCT01648582.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemia/tratamento farmacológico , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Insulina Glargina/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Idoso , Glicemia/efeitos dos fármacos , Automonitorização da Glicemia/métodos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Dinoprosta/genética , Quimioterapia Combinada/efeitos adversos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Glucose/metabolismo , Hemoglobina A Glicada/genética , Humanos , Hipoglicemia/genética , Hipoglicemia/patologia , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Insulina Glargina/efeitos adversos , Interleucina-6/genética , Masculino , Metformina/administração & dosagem , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/efeitos adversos , Fator de Necrose Tumoral alfa/genética
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