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1.
JAMA ; 322(14): 1360-1370, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31593273

RESUMO

Importance: Sprifermin is under investigation as a disease-modifying osteoarthritis drug. Objective: To evaluate the effects of sprifermin on changes in total femorotibial joint cartilage thickness in the more symptomatic knee of patients with osteoarthritis. Design, Setting, and Participants: FORWARD (FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses) was a 5-year, dose-finding, multicenter randomized clinical trial conducted at 10 sites. Eligible participants were aged 40 to 85 years with symptomatic, radiographic knee osteoarthritis and Kellgren-Lawrence grade 2 or 3. Enrollment began in July 2013 and ended in May 2014; the last participant visit occurred on May 8, 2017. The primary outcome at 2 years and a follow-up analysis at 3 years are reported. Interventions: Participants were randomized to 1 of 5 groups: intra-articular injections of 100 µg of sprifermin administered every 6 months (n = 110) or every 12 months (n = 110), 30 µg of sprifermin every 6 months (n = 111) or every 12 months (n = 110), or placebo every 6 months (n = 108). Each treatment consisted of weekly injections over 3 weeks. Main Outcomes and Measures: The primary end point was change in total femorotibial joint cartilage thickness measured by quantitative magnetic resonance imaging at 2 years. The secondary end points (of 15 total) included 2-year change from baseline in total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores. The minimal clinically important difference (MCID) is unknown for the primary outcome; for total WOMAC score in patients with hip and knee osteoarthritis, the absolute MCID is 7 U (95% CI, 4 to 10 U) and the percentage MCID is 14% (95% CI, 9% to 18%). Results: Among 549 participants (median age, 65.0 years; 379 female [69.0%]), 474 (86.3%) completed 2-year follow-up. Compared with placebo, the changes from baseline to 2 years in total femorotibial joint cartilage thickness were 0.05 mm (95% CI, 0.03 to 0.07 mm) for 100 µg of sprifermin administered every 6 months; 0.04 mm (95% CI, 0.02 to 0.06 mm) for 100 µg of sprifermin every 12 months; 0.02 mm (95% CI, -0.01 to 0.04 mm) for 30 µg of sprifermin every 6 months; and 0.01 mm (95% CI, -0.01 to 0.03 mm) for 30 µg of sprifermin every 12 months. Compared with placebo, there were no statistically significant differences in mean absolute change from baseline in total WOMAC scores for 100 µg of sprifermin administered every 6 months or every 12 months, or for 30 µg of sprifermin every 6 months or every 12 months. The most frequently reported treatment-emergent adverse event was arthralgia (placebo: n = 46 [43.0%]; 100 µg of sprifermin administered every 6 months: n = 45 [41.3%]; 100 µg of sprifermin every 12 months: n = 50 [45.0%]; 30 µg of sprifermin every 6 months: n = 40 [36.0%]; and 30 µg of sprifermin every 12 months: n = 48 [44.0%]). Conclusions and Relevance: Among participants with symptomatic radiographic knee osteoarthritis, the intra-articular administration of 100 µg of sprifermin every 6 or 12 months vs placebo resulted in an improvement in total femorotibial joint cartilage thickness after 2 years that was statistically significant, but of uncertain clinical importance; there was no significant difference for 30 µg of sprifermin every 6 or 12 months vs placebo. Durability of response also was uncertain. Trial Registration: ClinicalTrials.gov Identifier: NCT01919164.


Assuntos
Cartilagem Articular/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/administração & dosagem , Osteoartrite do Joelho/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Cartilagem Articular/patologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Fatores de Crescimento de Fibroblastos/efeitos adversos , Seguimentos , Humanos , Injeções Intra-Articulares , Articulação do Joelho , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/patologia
2.
Diabetes Obes Metab ; 19(12): 1762-1772, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28573777

RESUMO

AIMS: To assess the safety, tolerability, pharmacokinetics and pharmacodynamics of PF-05231023, a long-acting fibroblast growth factor 21 (FGF21) analogue, in obese people with hypertriglyceridaemia on atorvastatin, with or without type 2 diabetes. METHODS: Participants received PF-05231023 or placebo intravenously once weekly for 4 weeks. Safety (12-lead ECGs, vital signs, adverse events [AEs], laboratory tests) and longitudinal weight assessments were performed. Blood samples were collected for pharmacokinetic and pharmacodynamic analyses. Cardiovascular safety studies were also conducted in telemetered rats and monkeys. Blood pressure (BP; mean, systolic and diastolic) and ECGs were monitored. RESULTS: A total of 107 people were randomized. PF-05231023 significantly decreased mean placebo-adjusted fasting triglycerides (day 25, 33%-43%) and increased HDL cholesterol (day 25, 15.7%-28.6%) and adiponectin (day 25, 1574 to 3272 ng/mL) across all doses, without significant changes in body weight (day 25, -0.45% to -1.21%). Modest decreases from baseline were observed for N-terminal propeptides of type 1 collagen (P1NP) on day 25, although C-telopeptide cross-linking of type 1 collagen (CTX-1) increased minimally. Systolic, diastolic BP, and pulse rate increased in a dose- and time-related manner. There were 5 serious AEs (one treatment-related) and no deaths. Three participants discontinued because of AEs. The majority of AEs were gastrointestinal. PF-05231023 increased BP and heart rate in rats, but not in monkeys. CONCLUSIONS: Once-weekly PF-05231023 lowered triglycerides markedly in the absence of weight loss, with modest changes in markers of bone homeostasis. This is the first report showing increases in BP and pulse rate in humans and rats after pharmacological administration of a long-acting FGF21 molecule.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Remodelação Óssea/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/uso terapêutico , Hipertrigliceridemia/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Obesidade/tratamento farmacológico , Animais , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/efeitos adversos , Fármacos Antiobesidade/farmacocinética , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Biomarcadores/sangue , Índice de Massa Corporal , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/efeitos adversos , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/uso terapêutico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Resistência a Medicamentos , Feminino , Fatores de Crescimento de Fibroblastos/administração & dosagem , Fatores de Crescimento de Fibroblastos/efeitos adversos , Fatores de Crescimento de Fibroblastos/farmacocinética , Seguimentos , Meia-Vida , Humanos , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Hipertrigliceridemia/sangue , Hipertrigliceridemia/complicações , Hipolipemiantes/administração & dosagem , Hipolipemiantes/efeitos adversos , Hipolipemiantes/farmacocinética , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/complicações , Índice de Gravidade de Doença , Especificidade da Espécie
3.
Cochrane Database Syst Rev ; 6: CD011741, 2017 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-28594443

RESUMO

BACKGROUND: Peripheral artery disease (PAD) is associated with a high clinical and socioeconomic burden. Treatments to alleviate the symptoms of PAD and decrease the risks of amputation and death are a high societal priority. A number of growth factors have shown a potential to stimulate angiogenesis. Growth factors delivered directly (as recombinant proteins), or indirectly (e.g. by viral vectors or DNA plasmids encoding these factors), have emerged as a promising strategy to treat patients with PAD. OBJECTIVES: To assess the effects of growth factors that promote angiogenesis for treating people with PAD of the lower extremities. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Specialised Register (June 2016) and CENTRAL (2016, Issue 5). We searched trial registries for details of ongoing or unpublished studies. We also checked the reference lists of relevant publications and, if necessary, tried to contact the trialists for details of the studies. SELECTION CRITERIA: We included randomised controlled trials comparing growth factors (delivered directly or indirectly) with no intervention, placebo or any other intervention not based on the growth factor's action in patients with PAD of the lower extremities. The primary outcomes were limb amputation, death and adverse events. The secondary outcomes comprised walking ability, haemodynamic measures, ulceration and rest pain. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials and assessed the risk of bias. We used outcomes of the studies at low risk of bias for the main analysis and of all studies in the sensitivity analyses. We calculated odds ratios (OR) for dichotomous outcomes and mean differences for continuous outcomes with 95% confidence intervals (CI). We evaluated statistical heterogeneity using the I2 statistic and Cochrane's Q test. We conducted meta-analysis for the overall effect and for each growth factor as a subgroup analysis using OR in a fixed-effect model. We evaluated the robustness of the results in a sensitivity analysis using risk ratio (RR) and/or a random-effects model. We also assessed the quality of the evidence for each outcome. MAIN RESULTS: We included 20 trials in the review and used 14 studies (on approximately 1400 participants) with published results in the analyses. Six published studies compared fibroblast growth factors (FGF), four studies hepatocyte growth factors (HGF) and another four studies vascular endothelial growth factors (VEGF), versus placebo or no therapy. Six of these studies exclusively or mainly investigated participants with intermittent claudication and eight studies exclusively participants with critical limb ischaemia. Follow-up generally ranged from three months to one year. Two small studies provided some data at 2 years and one of them also at 10 years.The direction and size of effects for growth factors on major limb amputations (OR 0.99, 95% CI 0.71 to 1.38; 10 studies, N = 1075) and death (OR 0.99, 95% CI 0.69 to 1.41; 12 studies, N = 1371) at up to two years are uncertain. The quality of the evidence is low due to risk of bias and imprecision (at one year, moderate-quality evidence due to imprecision). However, growth factors may decrease the rate of any limb amputations (OR 0.56, 95% CI 0.31 to 0.99; 6 studies, N = 415). The quality of the evidence is low due to risk of bias and selective reporting.The direction and size of effects for growth factors on serious adverse events (OR 1.09, 95% CI 0.79 to 1.50; 13 studies, N = 1411) and on any adverse events (OR 1.10, 95% CI 0.73 to 1.64; 4 studies, N = 709) at up to two years are also uncertain. The quality of the evidence is low due to risk of bias and imprecision (for serious adverse events at one year, moderate-quality evidence due to imprecision).Growth factors may improve haemodynamic measures (low-quality evidence), ulceration (very low-quality evidence) and rest pain (very low-quality evidence) up to one year, but they have little or no effect on walking ability (low-quality evidence). We did not identify any relevant differences in effects between growth factors (FGF, HGF and VEGF). AUTHORS' CONCLUSIONS: The results of this review do not support the use of therapy with the growth factors FGF, HGF or VEGF in people with PAD of the lower extremities to prevent death or major limb amputation or to improve walking ability. However, the use of these growth factors may improve haemodynamic measures and decrease the rate of any limb amputations (probably due to preventing minor amputations) with an uncertain effect on adverse events; an improvement of ulceration and rest pain is very uncertain. New trials at low risk of bias are needed to generate evidence with more certainty.


Assuntos
Fatores de Crescimento de Fibroblastos/uso terapêutico , Fator de Crescimento de Hepatócito/uso terapêutico , Claudicação Intermitente/tratamento farmacológico , Doença Arterial Periférica/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Amputação/estatística & dados numéricos , Fatores de Crescimento de Fibroblastos/efeitos adversos , Fator de Crescimento de Hepatócito/efeitos adversos , Humanos , Claudicação Intermitente/mortalidade , Perna (Membro)/irrigação sanguínea , Perna (Membro)/cirurgia , Úlcera da Perna/tratamento farmacológico , Doença Arterial Periférica/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Fator A de Crescimento do Endotélio Vascular/efeitos adversos
4.
J Diabetes Complications ; 31(4): 726-734, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28143735

RESUMO

Fibroblast growth factor 21 (FGF21) is a promising regulator of glucose and lipid metabolism with multiple beneficial effects including hypoglycemic and lipid-lowering. Previous studies have reported that FGF21 is expected to become a new drug for treatment of diabetes. Liraglutide and insulin glargine are the two representative anti-diabetic biological drugs. In the current study, we aim to compare the long-term pharmacological efficacy of mFGF21 (an FGF21 analogue), liraglutide and insulin glargine in type 2 diabetic db/db mice. Db/db mice were initially treated with three kinds of proteins (25nmol/kg/day) by subcutaneous injection once a day for 4weeks, then subsequently be treated with once every two days for next 4weeks. After 8weeks of treatments, the blood glucose levels, body weights, glycosylated hemoglobin levels, fasting insulin levels, serum lipid profiles, hepatic biochemical parameters, oral glucose tolerance tests and hepatic mRNA expression levels of several proteins (GK, G6P, GLUT-1 and GLUT-4) associated with glucose metabolism of the experimental mice were detected. Results demonstrated that three proteins could significantly decrease the fed blood glucose levels of db/db mice. After treatment for 1week, the fed blood glucose levels of db/db mice in liraglutide group were significantly lower than those in mFGF21 and insulin glargine groups. However, after 2weeks of administration, the long-lasting hypoglycemic effect of mFGF21 was superior to liraglutide and insulin glargine up to the end of the experiments. Compared with liraglutide and insulin glargine, mFGF21 significantly reduced the glycosylated hemoglobin levels and improved the ability on glycemic control, insulin resistance, serum lipid and liver function states in db/db mice after 8weeks treatments. In addition, mFGF21 regulated glucose metabolism through increasing the mRNA expression levels of GK and GLUT-1, and decreasing the mRNA expression level of G6P. But liraglutide and insulin glargine could only up-regulate the mRNA expression of GLUT-4. In summary, as a hypoglycemic drug for long-term treatment, mFGF21 has the potential to be an ideal drug candidate for the therapy of type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Drogas em Investigação/uso terapêutico , Fatores de Crescimento de Fibroblastos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Insulina Glargina/uso terapêutico , Liraglutida/uso terapêutico , Proteínas Mutantes/uso terapêutico , Animais , Biomarcadores/sangue , Glicemia/análise , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Drogas em Investigação/efeitos adversos , Drogas em Investigação/metabolismo , Drogas em Investigação/farmacologia , Endopeptidases/metabolismo , Feminino , Fatores de Crescimento de Fibroblastos/efeitos adversos , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Hiperglicemia/prevenção & controle , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Insulina Glargina/efeitos adversos , Insulina Glargina/farmacologia , Resistência à Insulina , Liraglutida/efeitos adversos , Liraglutida/farmacologia , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Proteínas Mutantes/efeitos adversos , Proteínas Mutantes/genética , Proteínas Mutantes/farmacologia , Distribuição Aleatória , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico
5.
PLoS One ; 12(2): e0171703, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28207794

RESUMO

We evaluated the mitigating effects of fibroblast growth factor 4 and 7 (FGF4 and FGF7, respectively) in comparison with long acting protected graft copolymer (PGC)-formulated FGF4 and 7 (PF4 and PF7, respectively) administered to C57BL/6J mice a day after exposure to LD50/30 (15.7 Gy) partial body irradiation (PBI) which targeted the gastrointestinal (GI) system. The PGC that we developed increased the bioavailability of FGF4 and FGF7 by 5- and 250-fold compared to without PGC, respectively, and also sustained a 24 hr presence in the blood after a single subcutaneous administration. The dose levels tested for mitigating effects on radiation injury were 3 mg/kg for the PF4 and PF7 and 1.5 mg each for their combination (PF4/7). Amifostine administered prior to PBI was used as a positive control. The PF4, PF7, or PF4/7 mitigated the radiation lethality in mice. The mitigating effect of PF4 and PF7 was similar to the positive control and PF7 was better than other mitigators tested. The plasma citrulline levels and hematology parameters were early markers of recovery and survival. GI permeability function appeared to be a late or full recovery indicator. The villus length and crypt number correlated with plasma citrulline level, indicating that it can act as a surrogate marker for these histology evaluations. The IL-18 concentrations in jejunum as early as day 4 and TPO levels in colon on day 10 following PBI showed statistically significant changes in irradiated versus non-irradiated mice which makes them potential biomarkers of radiation exposure. Other colon and jejunum cytokine levels are potentially useful but require larger numbers of samples than in the present study before their full utility can be realized.


Assuntos
Síndrome Aguda da Radiação/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/uso terapêutico , Trato Gastrointestinal/efeitos dos fármacos , Lesões Experimentais por Radiação/terapia , Animais , Proliferação de Células/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Feminino , Fator 4 de Crescimento de Fibroblastos/efeitos adversos , Fator 4 de Crescimento de Fibroblastos/uso terapêutico , Fator 7 de Crescimento de Fibroblastos/efeitos adversos , Fator 7 de Crescimento de Fibroblastos/uso terapêutico , Fatores de Crescimento de Fibroblastos/efeitos adversos , Fibroblastos/efeitos dos fármacos , Trato Gastrointestinal/patologia , Trato Gastrointestinal/efeitos da radiação , Estimativa de Kaplan-Meier , Dose Letal Mediana , Masculino , Camundongos Endogâmicos C57BL , Polilisina/química , Polímeros/química
6.
J Intern Med ; 281(3): 233-246, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27878865

RESUMO

Fibroblast growth factor (FGF) 21 belongs to a hormone-like subgroup within the FGF superfamily. The members of this subfamily, FGF19, FGF21 and FGF23, are characterized by their reduced binding affinity for heparin that enables them to be transported in the circulation and function in an endocrine manner. It is likely that FGF21 also acts in an autocrine and paracrine fashion, as multiple organs can produce this protein and its plasma concentration seems to be below the level necessary to induce a pharmacological effect. FGF21 signals via FGF receptors, but for efficient receptor engagement it requires a cofactor, membrane-spanning ßKlotho (KLB). The regulation of glucose uptake in adipocytes was the initial biological activity ascribed to FGF21, but this hormone is now recognized to stimulate many other pathways in vitro and display multiple pharmacological effects in metabolically compromised animals and humans. Understanding of the precise physiology of FGF21 and its potential medicinal role has evolved exponentially over the last decade, yet numerous aspects remain to be defined and others are a source of debate. Here we provide a historical overview of the advances in FGF21 biology focusing on the uncertainties in the mechanism of action as well as the differing viewpoints relating to this intriguing protein.


Assuntos
Fatores de Crescimento de Fibroblastos/fisiologia , Adipócitos/metabolismo , Animais , Glicemia/metabolismo , Fatores de Crescimento de Fibroblastos/efeitos adversos , Fatores de Crescimento de Fibroblastos/farmacologia , Glucose/metabolismo , Humanos , Lipólise , Obesidade/fisiopatologia , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais
7.
Clin Exp Rheumatol ; 34(3): 445-50, 2016 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27050139

RESUMO

OBJECTIVES: To evaluate the safety of intra-articular sprifermin (primary), and to evaluate systemic exposure, biomarkers, histology, and other cartilage parameters in patients with advanced osteoarthritis (OA). METHODS: This was a first-in-human, double-blind, randomised, placebo-controlled trial of single and multiple ascending doses of sprifermin from 3-300 µg in knee OA patients scheduled for total knee replacement. Patients were randomised 3:1 to sprifermin or placebo, injected into the target knee once or once weekly for 3 weeks, and followed-up for 24 weeks. RESULTS: Fifty-five patients were treated with sprifermin, 25 with single and 30 with multiple doses, 18 received placebo. There was no clear difference between the active and placebo groups in incidence, severity, and nature of reported treatment emergent adverse events. Acute inflammatory reactions were slightly more common with sprifermin 300 µg, but none led to discontinuation. No clear difference was seen between placebo and sprifermin in physician-assessed local tolerability, pain, or swelling in the knee. No meaningful changes over time, or differences between treatment groups, were observed for safety laboratory parameters or ECG. Although individual abnormalities were observed, no patterns were evident suggesting a relation to treatment or potential safety concern. No systemic sprifermin exposure, anti-FGF18 antibodies, or clear-cut effects on systemic biomarkers were detected. CONCLUSIONS: This first clinical trial of sprifermin revealed no serious safety concerns, although larger studies are needed. The possibility of positive effects of intra-articular sprifermin on histological and other cartilage parameters in knee OA also warrant further investigation.


Assuntos
Cartilagem Articular , Fatores de Crescimento de Fibroblastos , Osteoartrite do Joelho , Adulto , Idoso , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Monitoramento de Medicamentos/métodos , Feminino , Fatores de Crescimento de Fibroblastos/administração & dosagem , Fatores de Crescimento de Fibroblastos/efeitos adversos , Substâncias de Crescimento , Humanos , Injeções Intra-Articulares , Articulação do Joelho/patologia , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/diagnóstico , Osteoartrite do Joelho/tratamento farmacológico , Osteoartrite do Joelho/fisiopatologia , Gravidade do Paciente , Resultado do Tratamento
8.
Br J Clin Pharmacol ; 80(5): 1051-63, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25940675

RESUMO

AIMS: The aim of the present study was to evaluate the pharmacokinetics/pharmacodynamics (PK/PD), safety and tolerability of single intravenous (IV) doses of PF-05231023, a long acting fibroblast growth factor 21 (FGF21) analogue being developed for the treatment of type 2 diabetes mellitus (T2DM). METHODS: T2DM subjects (glycosylated haemoglobin: 7.0-10.5%; on stable metformin therapy and/or diet and exercise) were randomized to receive a single dose of placebo or PF-05231023 (0.5-200 mg). Safety evaluations were performed up to 14 days after dosing. PK and PD endpoints were measured and a PK/PD model was developed for triglyceride - an early marker of drug activity. RESULTS: No antidrug antibody or serious adverse events (AEs) were observed. The most frequent AEs were gastrointestinal but were generally mild. Plasma PF-05231023 levels peaked immediately post-IV dosing, with mean terminal half-lives of 6.5-7.7 h and 66.5- 96.6 h for intact C- and N-termini, respectively. Intact C-terminus exposures increased proportionally with increasing dose, whereas N-terminus exposures appeared to trend higher than dose-proportionally. Although no apparent effect on plasma glucose was seen, dose-dependent decreases in triglyceride were observed, with a maximum reduction of 48.5 ± 10.0% (mean ± standard deviation) for the 200 mg dose compared with a reduction of 19.1 ± 26.4% for placebo, demonstrating proof of pharmacology. Moreover, a reduction in total cholesterol and low-density lipoprotein cholesterol and an increase in high-density lipoprotein cholesterol were observed in the high-dose groups. CONCLUSIONS: Single IV doses of PF-05231023 up to 200 mg were generally safe and well tolerated by subjects with T2DM. The observed early sign of pharmacology supports further clinical testing of PF-05231023 upon repeated administration.


Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Diabetes Mellitus Tipo 2/sangue , Fatores de Crescimento de Fibroblastos/agonistas , Fatores de Crescimento de Fibroblastos/farmacocinética , Administração Intravenosa , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacologia , Relação Dose-Resposta a Droga , Feminino , Fatores de Crescimento de Fibroblastos/administração & dosagem , Fatores de Crescimento de Fibroblastos/efeitos adversos , Fatores de Crescimento de Fibroblastos/farmacologia , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangue
9.
Int Immunopharmacol ; 25(1): 74-82, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25601498

RESUMO

It has been demonstrated that circulating FGF21 levels are elevated in the serum and synovial fluid of patients with rheumatoid arthritis (RA). The aim of this study is to investigate efficacy of FGF21 for treatment of RA and the molecular mechanisms of the therapeutic effect on collagen-induced arthritis (CIA). Mice with CIA were subcutaneously administered with FGF21 (5, 2 or 1mg·kg(-1)·d(-1)), IL-1ß antibody (5mg·kg(-1)·d(-1)), IL-17A antibody (5mg·kg(-1)·d(-1)) and dexamethasone (DEX) (1mg·kg(-1)·d(-1)), respectively. The effects of treatment were determined by arthritis severity score, histological damage and cytokine production. The activation of NF-κB was analyzed by Western blotting. We also detected the levels of oxidative stress parameters. Our results showed that FGF21 had beneficial effects on clinical symptom and histological lesion of CIA mice. Similar to antibody and DEX, FGF21 treatment alleviated the severity of arthritis by reducing humoral and cellular immune responses and down-regulating the expression of pro-inflammatory cytokines. FGF21 treatment also reduced the expression of TNF-α, IL-1ß, IL-6, IFN-γ and MMP-3 and increased level of IL-10 in the spleen tissue or the plasma of CIA mice in a dose-dependent manner. Furthermore, FGF21 inhibited IκBα degradation and NF-κB p65 nuclear translocation and induced significant changes of oxidative stress parameters (MDA, SOD, CAT, GSH-PX and GSH) in the plasma. FGF21 exerts therapeutic efficacy for RA through antioxidant reaction and inhibiting NF-κB inflammatory pathway. This study provides evidence that FGF21 may be a promising therapeutic agent for RA patients.


Assuntos
Antioxidantes/administração & dosagem , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/administração & dosagem , NF-kappa B/metabolismo , Animais , Anticorpos Bloqueadores/administração & dosagem , Anticorpos Bloqueadores/efeitos adversos , Antioxidantes/efeitos adversos , Células Cultivadas , Citocinas/imunologia , Citocinas/metabolismo , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Progressão da Doença , Fatores de Crescimento de Fibroblastos/efeitos adversos , Humanos , Imunossupressão , Mediadores da Inflamação/metabolismo , Masculino , Metaloproteinase 3 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos DBA , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
10.
Sci Transl Med ; 6(247): 247ra100, 2014 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-25080475

RESUMO

Hepatic accumulation of bile acids is central to the pathogenesis of cholestatic liver diseases. Endocrine hormone fibroblast growth factor 19 (FGF19) may reduce hepatic bile acid levels through modulation of bile acid synthesis and prevent subsequent liver damage. However, FGF19 has also been implicated in hepatocellular carcinogenesis, and consequently, the potential risk from prolonged exposure to supraphysiological levels of the hormone represents a major hurdle for developing an FGF19-based therapy. We describe a nontumorigenic FGF19 variant, M70, which regulates bile acid metabolism and, through inhibition of bile acid synthesis and reduction of excess hepatic bile acid accumulation, protects mice from liver injury induced by either extrahepatic or intrahepatic cholestasis. Administration of M70 in healthy human volunteers potently reduces serum levels of 7α-hydroxy-4-cholesten-3-one, a surrogate marker for the hepatic activity of cholesterol 7α-hydroxylase (CYP7A1), the enzyme responsible for catalyzing the first and rate-limiting step in the classical bile acid synthetic pathway. This study provides direct evidence for the regulation of bile acid metabolism by FGF19 pathway in humans. On the basis of these results, the development of nontumorigenic FGF19 variants capable of modulating CYP7A1 expression represents an effective approach for the prevention and treatment of cholestatic liver diseases as well as potentially for other disorders associated with bile acid dysregulation.


Assuntos
Ácidos e Sais Biliares/metabolismo , Colagogos e Coleréticos/uso terapêutico , Colestase Extra-Hepática/tratamento farmacológico , Colestase Intra-Hepática/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/uso terapêutico , Fígado/efeitos dos fármacos , Adulto , Animais , Austrália , Biomarcadores/sangue , Colagogos e Coleréticos/efeitos adversos , Colagogos e Coleréticos/farmacocinética , Colestase Extra-Hepática/genética , Colestase Extra-Hepática/metabolismo , Colestase Extra-Hepática/patologia , Colestase Intra-Hepática/genética , Colestase Intra-Hepática/metabolismo , Colestase Intra-Hepática/patologia , Colestenonas/sangue , Colesterol 7-alfa-Hidroxilase/genética , Colesterol 7-alfa-Hidroxilase/metabolismo , Modelos Animais de Doenças , Método Duplo-Cego , Regulação para Baixo , Fatores de Crescimento de Fibroblastos/efeitos adversos , Fatores de Crescimento de Fibroblastos/biossíntese , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/farmacocinética , Regulação Enzimológica da Expressão Gênica , Técnicas de Transferência de Genes , Variação Genética , Voluntários Saudáveis , Humanos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Proteínas Recombinantes/uso terapêutico , Medição de Risco , Adulto Jovem
11.
Biol Pharm Bull ; 37(7): 1149-57, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24989006

RESUMO

Disabilities triggered by neurodegeneration mainly result in mortality in the elderly, and patients with neurodegenerative disease also display deficits in olfactory function. Therefore drug distribution to the brain through intranasal administration has become one of the most difficult challenges in the treatment of central nervous system (CNS) diseases. TAT-human acidic fibroblast growth factor (HaFGF) is a new fused protein retaining the neuroprotective activities of HaFGF, and is a promising prospect in the treatment of neurodegenerative diseases. TAT (a cell-penetrating peptide) contains a high relative abundance of positively charged amino acids such as lysine and arginine, which have a powerful attraction to the negatively charge on the nasal epithelial membrane. The present study focused on the evaluation of the safety and absorption characteristics of TAT-HaFGF following intranasal administration. After TAT-HaFGF intranasal administration (100, 300, 600 µg/kg) for 5 weeks, hematoxylin-eosin (HE) staining showed no pathology in any of the investigated tissues and organs. The expression of olfactory marker protein (OMP) was observed with immunohistochemical staining, which showed no altered expression in the sensory neurons of the nasal epithelium. Nasal ciliotoxicity studies carried out using an in situ palate model and optical microscope showed that TAT-HaFGF had no nasal ciliotoxicity. The distribution of the TAT-HaFGF following intranasal administration was assessed using a radioisotopic tracing method. Radioactivity was observed in the brain after 15 min. This became stronger at 30 min and weaker at 1 h. All of the results confirmed the in vivo safety of TAT-HaFGF via intranasal administration.


Assuntos
Encéfalo/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/administração & dosagem , Produtos do Gene tat/administração & dosagem , Absorção Nasal/efeitos dos fármacos , Mucosa Nasal/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Administração Intranasal , Animais , Encéfalo/metabolismo , Bufo bufo , Cílios/efeitos dos fármacos , Feminino , Fatores de Crescimento de Fibroblastos/efeitos adversos , Fatores de Crescimento de Fibroblastos/farmacocinética , Produtos do Gene tat/efeitos adversos , Produtos do Gene tat/farmacocinética , Masculino , Mucosa Nasal/metabolismo , Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/farmacocinética , Bulbo Olfatório/efeitos dos fármacos , Bulbo Olfatório/metabolismo , Ratos Sprague-Dawley , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/farmacocinética , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo , Distribuição Tecidual
12.
Arthritis Rheumatol ; 66(7): 1820-31, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24740822

RESUMO

OBJECTIVE: To evaluate the efficacy and safety of intraarticular sprifermin (recombinant human fibroblast growth factor 18) in the treatment of symptomatic knee osteoarthritis (OA). METHODS: The study was a randomized, double-blind, placebo-controlled, proof-of-concept trial. Intraarticular sprifermin was evaluated at doses of 10 µg, 30 µg, and 100 µg. The primary efficacy end point was change in central medial femorotibial compartment cartilage thickness at 6 months and 12 months as determined using quantitative magnetic resonance imaging (qMRI). The primary safety end points were nature, incidence, and severity of local and systemic treatment-emergent adverse events (AEs) and acute inflammatory reactions, as well as results of laboratory assessments. Secondary end points included changes in total and compartment femorotibial cartilage thickness and volume as assessed by qMRI, changes in joint space width (JSW) seen on radiographs, and pain scores on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). RESULTS: One hundred ninety-two patients were randomized and evaluated for safety, 180 completed the trial, and 168 were evaluated for the primary efficacy end point. We found no statistically significant dose response in change in central medial femorotibial compartment cartilage thickness. Sprifermin was associated with statistically significant, dose-dependent reductions in loss of total and lateral femorotibial cartilage thickness and volume and in JSW narrowing in the lateral femorotibial compartment. All groups had improved WOMAC pain scores, with statistically significantly less improvement at 12 months in patients receiving the 100-µg dose of sprifermin as compared with those receiving placebo. There was no significant difference in serious AEs, treatment-emergent AEs, or acute inflammatory reactions between sprifermin and placebo groups. CONCLUSION: No statistically significant relationship between treatment group and reduction in central medial femorotibial compartment cartilage thickness was observed; however, prespecified structural secondary end points showed statistically significant dose-dependent reductions after sprifermin treatment. Sprifermin was not associated with any local or systemic safety concerns.


Assuntos
Fatores de Crescimento de Fibroblastos/administração & dosagem , Osteoartrite do Joelho/tratamento farmacológico , Osteoartrite do Joelho/imunologia , Idoso , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Método Duplo-Cego , Feminino , Fatores de Crescimento de Fibroblastos/efeitos adversos , Humanos , Injeções Intra-Articulares , Articulação do Joelho/efeitos dos fármacos , Articulação do Joelho/patologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/patologia , Placebos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Resultado do Tratamento
13.
Endocrinology ; 155(5): 2031-40, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24564398

RESUMO

Thyroid hormone (TH) regulates fibroblast growth factor 21 (FGF21) levels in the liver and in the adipose tissue. In contrast, peripheral FGF21 administration leads to decreased circulating levels of TH. These data suggest that FGF21 and TH could interact to regulate metabolism. In the present study, we confirmed that TH regulates adipose and hepatic FGF21 expression and serum levels in mice. We next investigated the influence of TH administration on key serum metabolites, gene expression in the liver and brown adipose tissue, and energy expenditure in FGF21 knockout mice. Surprisingly, we did not observe any significant differences in the effects of TH on FGF21 knockout mice compared with those in wild-type animals, indicating that TH acts independently of FGF21 for the specific outcomes studied. Furthermore, exogenous FGF21 administration to hypothyroid mice led to similar changes in serum and liver lipid metabolites and gene expression in both hypothyroid and euthyroid mice. Thus, it appears that FGF21 and TH have similar actions to decrease serum and liver lipids despite having some divergent regulatory effects. Whereas TH leads to up-regulation in the liver and down-regulation in brown adipose tissue of genes involved in the lipid synthesis pathway (eg, fatty acid synthase (FASN) and SPOT14), FGF21 leads to the opposite changes in expression of these genes. In conclusion, TH and FGF21 act independently on the outcomes studied, despite their ability to regulate each other's circulating levels. Thus, TH and FGF21 may modulate the availability of each other in critical metabolic states.


Assuntos
Fatores de Crescimento de Fibroblastos/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Hipotireoidismo/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipotrópicos/uso terapêutico , Tiroxina/uso terapêutico , Tri-Iodotironina/uso terapêutico , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Animais , Metabolismo Energético/efeitos dos fármacos , Feminino , Fatores de Crescimento de Fibroblastos/efeitos adversos , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Terapia de Reposição Hormonal/efeitos adversos , Hiperlipidemias/etiologia , Hiperlipidemias/prevenção & controle , Hipertireoidismo/sangue , Hipertireoidismo/induzido quimicamente , Hipertireoidismo/metabolismo , Hipotireoidismo/sangue , Hipotireoidismo/metabolismo , Hipotireoidismo/fisiopatologia , Lipotrópicos/efeitos adversos , Lipotrópicos/sangue , Lipotrópicos/envenenamento , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/uso terapêutico , Tiroxina/efeitos adversos , Tiroxina/sangue , Tiroxina/envenenamento , Tri-Iodotironina/efeitos adversos , Tri-Iodotironina/sangue
14.
Support Care Cancer ; 21(1): 343-55, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22987094

RESUMO

PURPOSE: The aim of this project was to review the literature and define clinical practice guidelines for the use of cytokines and growth factor agents for the prevention or treatment of oral mucositis induced by cancer chemotherapy or radiotherapy. METHODS: A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO). The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: Recommendation, Suggestion, No guideline possible. RESULTS: Sixty-four clinical studies across 11 interventions were evaluated. A recommendation was made for the use of recombinant human KGF-1 (palifermin) at a dose of 60 µg/kg per day for 3 days prior to conditioning treatment and for 3 days post-transplant for prevention of oral mucositis in patients receiving high-dose chemotherapy and total body irradiation followed by autologous stem cell transplantation for hematological malignancies. A suggestion was made against using granulocyte macrophage colony-stimulating factor mouthwash for the prevention of oral mucositis in the setting of high-dose chemotherapy followed by autologous or allogeneic stem cell transplantation. No guideline was possible for any other cytokine or growth factor agents due to inconclusive evidence. CONCLUSIONS: Of the cytokine and growth factor agents studied for oral mucositis, the evidence only supports use of palifermin in the specific population listed above. Additional well-designed research is needed on other cytokine and growth factor interventions and in other cancer treatment settings.


Assuntos
Citocinas/uso terapêutico , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Neoplasias/complicações , Estomatite/terapia , Citocinas/efeitos adversos , Medicina Baseada em Evidências , Fator 7 de Crescimento de Fibroblastos/efeitos adversos , Fator 7 de Crescimento de Fibroblastos/uso terapêutico , Fatores de Crescimento de Fibroblastos/efeitos adversos , Fatores de Crescimento de Fibroblastos/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/efeitos adversos , Antissépticos Bucais , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Guias de Prática Clínica como Assunto , Estomatite/etiologia , Estomatite/prevenção & controle
16.
Expert Opin Biol Ther ; 11(11): 1533-41, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21883031

RESUMO

INTRODUCTION: Basic fibroblast growth factor (bFGF) has been shown to reduce volume in acute ischemic stroke models, and to promote functional recovery as well as new synapse formation when given to animals with completed cerebral infarction. A recombinant native form of human bFGF, trafermin, has been tested in Phase III clinical trials in patients with stroke. AREAS COVERED: The role of trafermin in stroke. Data were identified by searching PubMed for single or combined terms including: trafermin, basic fibroblast growth factors, neuroprotection, neuroprotective drugs, stroke therapy, stroke rehabilitation and acute stroke. Original research papers, clinical series and reviews are included. Our research covered all relevant data up until 1 April 2011. EXPERT OPINION: To date, all Phase III trials have failed to demonstrate the superiority of trafermin over placebo when given within 6 h from stroke onset because trafermin causes a dose-dependent hypotension and an increased mortality rate in treated patients. However, a 24-h intravenous infusion seems to be safe for stroke patients and may result in an improved outcome when given 5 - 6 h after infarct. This finding may open renewed interest in restorative treatment for stroke, which could enhance recovery mechanisms rather than immediate neuroprotection. Studies suggest that growth factors can produce improvement in animal models of stroke, even when administered at postischemic intervals from many hours to days, when conventional neuroprotective approaches are typically ineffective. Because of the number of side effects and increased mortality reported in the first clinical studies with high dose of FGF, further experimental studies are necessary to asses whether it is possible to achieve a pharmacologically significant therapeutic level in the brain, by minimizing peripheral side effects. Another randomized clinical trial is needed to test trafermin in stroke patients but to enhance functional recovery.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Isquemia Encefálica/mortalidade , Medicina Baseada em Evidências , Fatores de Crescimento de Fibroblastos/administração & dosagem , Fatores de Crescimento de Fibroblastos/efeitos adversos , Humanos , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/efeitos adversos , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/efeitos adversos , Acidente Vascular Cerebral/mortalidade , Fatores de Tempo , Resultado do Tratamento
17.
Exp Clin Endocrinol Diabetes ; 119(8): 472-9, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21811960

RESUMO

AIMS: Assessment of the safety, efficacy and effectiveness of growth factors alone or in combination with other technologies in the treatment of DFU including medical, economical, social, ethical and juridical aspects. METHODS: We systematically searched relevant data bases limited to English and German language and publications since 1990. Review and assessment of the quality of publications followed methods conforming to widely accepted standards for evidence-based medicine and health economics. RESULTS: We identified 25 studies comparing becaplermin, rhEGF, bFGF and the metabolically active skin grafts Dermagraft and Apligraf with standard wound care (SWC) alone or extracellular wound matrix. Study duration ranged from 12 to 20 weeks and the study population comprised between 17 and 382 patients. Treatment with becaplermin, rhEGF, Dermagraft and Apligraf resulted in a higher incidence of complete wound closure and shorter time to complete wound healing with statistically significant differences. Regarding the proportion of adverse events there was no difference between treatment groups. The methodological quality of the studies was affected by significant deficiencies. Economic evaluations showed becaplermin being cost-effective. CONCLUSIONS: Add-on therapy with growth factors and active skin substitutes for treating uncomplicated DFU could be an alternative to SWC alone. For explicit recommendations further studies with stronger evidence are necessary.


Assuntos
Pé Diabético/tratamento farmacológico , Pé Diabético/terapia , Fator de Crescimento Epidérmico/uso terapêutico , Medicina Baseada em Evidências , Fatores de Crescimento de Fibroblastos/uso terapêutico , Fator de Crescimento Derivado de Plaquetas/uso terapêutico , Pele Artificial , Terapia Combinada , Pé Diabético/economia , Fator de Crescimento Epidérmico/efeitos adversos , Fator de Crescimento Epidérmico/economia , Fatores de Crescimento de Fibroblastos/efeitos adversos , Fatores de Crescimento de Fibroblastos/economia , Humanos , Fator de Crescimento Derivado de Plaquetas/efeitos adversos , Fator de Crescimento Derivado de Plaquetas/economia , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/economia , Proteínas Recombinantes/uso terapêutico , Pele Artificial/efeitos adversos , Pele Artificial/economia , Avaliação da Tecnologia Biomédica
18.
Artigo em Inglês | MEDLINE | ID: mdl-20219587

RESUMO

Tumor-induced osteomalacia (TIO) is a rare acquired paraneoplastic disease characterized by renal phosphate wasting and hypophosphatemia. Recently, it was reported that tumors associated with TIO produce fibroblast growth factor (FGF) 23, identified as the last member of the FGF family and of which excessive action causes several hypophosphatemic diseases whereas deficient FGF23 activity results in hyperphosphatemic tumoral calcinosis. In this case, although it was difficult to locate the associated tumor, an abnormal mass in the left maxilla was detected by imaging. The tumor was removed by partial resection of the left maxillary alveolar region. Thereafter, serum level of FGF23 rapidly decreased, hypophosphatemia improved, and the clinical symptoms greatly improved. Histopathologic diagnosis of the tumor was phosphaturic mesenchymal tumor, mixed connective tissue variant. Immunohistochemical findings confirmed that the removed tumor produced FGF23. These results indicate that development of osteomalacia in this patient was related to the maxillary tumor, which overexpressed FGF23.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Neoplasias Maxilares/metabolismo , Mesenquimoma/metabolismo , Proteínas de Neoplasias/metabolismo , Osteomalacia/etiologia , Síndromes Paraneoplásicas/etiologia , Adulto , Fatores de Crescimento de Fibroblastos/efeitos adversos , Seguimentos , Humanos , Hipofosfatemia/sangue , Hipofosfatemia/etiologia , Hipofosfatemia/patologia , Masculino , Neoplasias Maxilares/complicações , Neoplasias Maxilares/patologia , Neoplasias Maxilares/cirurgia , Mesenquimoma/complicações , Mesenquimoma/patologia , Mesenquimoma/cirurgia , Proteínas de Neoplasias/efeitos adversos , Osteomalacia/sangue , Osteomalacia/patologia , Síndromes Paraneoplásicas/patologia , Resultado do Tratamento
19.
Physiol Res ; 58(1): 1-7, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19331512

RESUMO

Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator produced primarily by the liver that exerts potent antidiabetic and lipid-lowering effects in animal models of obesity and type 2 diabetes mellitus. This hormone contributes to body weight regulation and is strongly involved in the response to nutritional deprivation and ketogenic state in mice. The principal sites of metabolic actions of FGF21 are adipose tissue, liver and pancreas. Experimental studies have shown marked improvements in diabetes compensation and dyslipidemia after FGF21 administration in diabetic mice and primates. Positive metabolic actions of FGF21 without the presence of apparent side effects make this factor a hot candidate to treat type 2 diabetes and accompanying metabolic diseases. The aim of this review is to summarize the current knowledge about the metabolic effects of FGF21 including some preliminary data on changes of its levels in humans with a special emphasis on its therapeutic potential in type 2 diabetes mellitus.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Metabolismo Energético/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Obesidade/tratamento farmacológico , Animais , Fármacos Antiobesidade/efeitos adversos , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Fatores de Crescimento de Fibroblastos/efeitos adversos , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Hipoglicemiantes/efeitos adversos , Obesidade/metabolismo , Transdução de Sinais/efeitos dos fármacos
20.
Support Care Cancer ; 16(5): 477-83, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-17710442

RESUMO

GOALS OF WORK: The objective of this study was to evaluate the safety and tolerability of velafermin in patients at risk of developing severe oral mucositis (OM) from chemotherapy. MATERIALS AND METHODS: This study was a single-center, open-label, single-dose escalation, phase I trial in patients undergoing high-dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplant (PBSCT). Velafermin was administered 24 h after stem cell infusion as a single intravenous dose infused over 15 min. Clinical safety variables were assessed and OM status scored daily for 30 days using the World Health Organization (WHO) grading scale. MAIN RESULTS: Thirty patients were treated with velafermin at doses of 0.03 (n = 10), 0.1 (n = 10), 0.2 (n = 8), or 0.33 mg/kg (n = 2). Patients were diagnosed with multiple myeloma (n = 16), non-Hodgkin's lymphoma (n = 12), acute myelogenous leukemia (n = 1), or desmoplasmic round cell tumor (n = 1). Velafermin was well tolerated at doses up to 0.2 mg/kg. There were no drug-related serious adverse events. No patient discontinued because of adverse events; however, two patients administered 0.33 mg/kg developed adverse reactions immediately after infusion of the study drug. No other patients were treated at this dose level. The most frequent (>35% of patients) treatment-emergent adverse events were diarrhea, fatigue, pyrexia, vomiting, and nausea. Most adverse events were mild or moderate and resolved the same day without sequelae. Eight (27%) patients developed WHO grade 3 or 4 OM during the study; seven of these patients received high-dose melphalan as a conditioning regimen. CONCLUSION: Velafermin was well tolerated by autologous PBSCT patients at doses up to 0.2 mg/kg.


Assuntos
Fatores de Crescimento de Fibroblastos/efeitos adversos , Estomatite/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Fatores de Crescimento de Fibroblastos/uso terapêutico , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco de Sangue Periférico , Estomatite/induzido quimicamente , Resultado do Tratamento
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