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1.
Neurosci Lett ; 751: 135809, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33713748

RESUMO

Migraineurs experience increased oxidative stress which drives the initiation and maintenance of migraine-related pain in animal models and, by extension, migraine in humans. Oxidative stress augments calcitonin gene-related peptide (CGRP) levels, a mediator of migraine pain. Insulin-like growth factor-1 (IGF-1), a neuroprotective growth factor, reduces susceptibility to spreading depression, a preclinical model of migraine, in cultured brain slices by blocking oxidative stress and neuroinflammation from microglia. Similarly, nasal delivery of IGF-1 inhibits spreading depression in vivo. After recurrent cortical spreading depression, nasal administration of IGF-1 also significantly reduces trigeminal ganglion oxidative stress and CGRP levels as well as trigeminocervical c-Fos activation. Here, we probed for the impact of nasal IGF-1 pretreatment on trigeminal system activation using a second well-established preclinical model of migraine, systemic nitroglycerin injection. Adult male rats were treated with one of three doses of IGF-1 (37.5, 75 or 150 µg) and the optimal dose found in males was subsequently used for treatment of female rats. One day later, animals received an intraperitoneal injection of nitroglycerin. Measurements taken two hours later after nitroglycerin alone showed increased surrogate markers of trigeminal activation - oxidative stress and CGRP in the trigeminal ganglion and c-Fos in the trigeminocervical complex compared to vehicle control. These effects were significantly reduced at all doses of IGF-1 for trigeminal ganglion metrics of oxidative stress and CGRP and only at the lowest dose in both males and females for c-Fos. The latter inverted U-shaped or hormetic response is seen in enzyme-targeting drugs. While the specific mechanisms remain to be explored, our data here supports the ability of IGF-1 to preserve mitochondrial and antioxidant pathway homeostasis as means to prevent nociceptive activation in the trigeminal system produced by an experimental migraine model.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Fator de Crescimento Insulin-Like I/farmacologia , Transtornos de Enxaqueca/tratamento farmacológico , Nitroglicerina/farmacologia , Estresse Oxidativo , Gânglio Trigeminal/metabolismo , Administração Intranasal , Animais , Feminino , Fator de Crescimento Insulin-Like I/administração & dosagem , Fator de Crescimento Insulin-Like I/uso terapêutico , Masculino , Transtornos de Enxaqueca/etiologia , Transtornos de Enxaqueca/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Gânglio Trigeminal/efeitos dos fármacos , Gânglio Trigeminal/fisiologia
2.
Eur J Endocrinol ; 184(2): 267-276, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33434161

RESUMO

Objective: The European Increlex® Growth Forum Database Registry monitors the effectiveness and safety of recombinant human insulin-like growth factor-1 (rhIGF1; mecasermin, Increlex®) therapy in patients with severe primary IGF1 deficiency (SPIGFD). We present data from patients with and without a reported genetic diagnosis of Laron syndrome (LS). Design: Ongoing, open-label, observational registry (NCT00903110). Methods: Children and adolescents receiving rhIGF1 therapy from 10 European countries were enrolled in 2008-2017 (n = 242). The treatment-naïve/prepubertal (NPP) cohort (n = 138) was divided into subgroups based on reported genetic diagnosis of LS (n = 21) or non-LS (n = 117). Multivariate analysis of the NPP-non-LS subgroup was conducted to identify factors predictive of growth response (first-year-height standard deviation score (SDS) gain ≥ 0.3). Assessments included change in height and weight over 5 years and adverse events (AEs). Results: Height SDS gain from baseline was greater in the NPP-LS than the NPP-non-LS subgroup after 1 years' treatment (P < 0.05). In the NPP-non-LS subgroup, 56% were responders; young age at baseline was a positive independent predictive factor (P < 0.001). NPP-non-LS-responders and the NPP-LS subgroup had a similar mean age (6.07 years vs 7.00 years) at baseline and height SDS gain in year 1 (0.64 vs 0.70), although NPP-non-LS-responders were taller (P < 0.001) at baseline. BMI SDS changes did not differ across subgroups. Treatment-emergent AEs were experienced by 65.3% of patients; hypoglycaemia was most common. Conclusions: In most NPP children with SPIGFD, with or without LS, rhIGF1 therapy promotes linear growth. The safety profile was consistent with previous studies.


Assuntos
Transtornos do Crescimento/tratamento farmacológico , Perda Auditiva Neurossensorial/tratamento farmacológico , Fator de Crescimento Insulin-Like I/deficiência , Fator de Crescimento Insulin-Like I/uso terapêutico , Síndrome de Laron/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Adolescente , Estatura , Peso Corporal/efeitos dos fármacos , Criança , Feminino , Crescimento/efeitos dos fármacos , Humanos , Hipoglicemia/sangue , Hipoglicemia/induzido quimicamente , Síndrome de Laron/genética , Estudos Longitudinais , Masculino , Segurança do Paciente , Puberdade , Resultado do Tratamento , Adulto Jovem
4.
Wiad Lek ; 73(1): 63-67, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32124808

RESUMO

OBJECTIVE: The aim: To study the dynamics of markers of angiogenesis based on insulin-like growth factor-1 (IGF-1) and endostatin, as well as to determine 6-month survival in patients taking zofenopril from the first day of AMI with and without obesity. PATIENTS AND METHODS: Materials and methods: using enzyme immunoassay, we determined the level of endostatin and IGF-1 in serum on days 1 and 12 in patients with AMI with the presence and absence of obesity, and a statistical processing of the data obtained. RESULTS: Results: The relationship between obesity and angiogenesis indicators, both activators and inhibitors, was determined, and a significant relationship was found between zofenopril therapy and angiogenesis activator IGF-1. Differences in the survival of patients with complicated AMI were determined depending on the choice of ACE inhibitor in favor of a higher survival rate of patients who took zofenopril. CONCLUSION: Conclusions: patients who underwent complicated AMI, taking zofenopril, have a higher survival rate during the 6-month follow-up period. Zofenopril stimulated angiogenesis in the examined patients, which was expressed in patients with and without obesity.


Assuntos
Captopril/análogos & derivados , Endostatinas/uso terapêutico , Fator de Crescimento Insulin-Like I/uso terapêutico , Infarto do Miocárdio , Obesidade/tratamento farmacológico , Captopril/uso terapêutico , Humanos , Infarto do Miocárdio/tratamento farmacológico
5.
Biomed Res Int ; 2020: 2308124, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32149088

RESUMO

It has been recognized that people with obesity are more likely to have low growth hormone secretion. Recent studies have also confirmed that the abnormalities of the growth hormone/insulin-like growth factor 1 axis were associated with cardiovascular complications in people with obesity. However, little is known about whether recombinant human growth hormone therapy could improve cardiovascular and metabolic risks in obese children. This study aims to evaluate the effect of one-year growth hormone therapy on obesity-related comorbidities and to assess the safety in Chinese boys with obesity. Eighteen boys with obesity were treated with recombinant human growth hormone for one year. Anthropometric measurements, endocrine testing, and cardiovascular risk markers were performed in all obese boys in baseline, and follow-up visits were performed at 3 months, 6 months, 9 months, and one year, respectively. After one year of recombinant human growth hormone treatment, the body mass index standard deviation scores decreased (P < 0.001) and insulin-like growth factor 1 levels increased (P < 0.001). GH treatment also reduced low density lipoprotein cholesterol (P < 0.001), total cholesterol (P < 0.001), triglycerides (P=0.042), and alanine aminotransferase (P=0.027) when compared with the baseline. One-year of recombinant human growth hormone treatment could improve cardiometabolic risk markers, without adverse effects on glucose homeostasis in boys with obesity.


Assuntos
Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Obesidade/complicações , Adolescente , Alanina Transaminase , Índice de Massa Corporal , Criança , Colesterol , Glucose/metabolismo , Hormônio do Crescimento Humano/efeitos adversos , Humanos , Fator de Crescimento Insulin-Like I/uso terapêutico , Lipoproteínas , Masculino , Proteínas Recombinantes/uso terapêutico , Fatores de Risco , Triglicerídeos
7.
Am J Physiol Endocrinol Metab ; 318(4): E568-E578, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32101029

RESUMO

Fetal growth restriction (FGR) is associated with compromised growth and metabolic function throughout life. Intrauterine therapy of FGR with intra-amniotic insulin-like growth factor-1 (IGF1) enhances fetal growth and alters perinatal metabolism and growth in a sex-specific manner, but the adult effects are unknown. We investigated the effects of intra-amniotic IGF1 treatment of FGR on adult growth and body composition, adrenergic sensitivity, and glucose-insulin axis regulation. Placental embolization-induced FGR was treated with four weekly doses of 360 µg intra-amniotic IGF1 (FGRI) or saline (FGRS). Offspring were raised to adulthood (18 mo: FGRI, n = 12 females, 12 males; FGRS, n = 13 females, 10 males) alongside offspring from unembolized and untreated sheep (CON; n = 12 females, 21 males). FGRI females had increased relative lean mass compared with CON but not FGRS (P < 0.05; 70.6 ± 8.2% vs. 61.4 ± 8.2% vs. 67.6 ± 8.2%), decreased abdominal adipose compared with CON and FGRS (P < 0.05; 43.7 ± 1.2% vs. 49.3 ± 0.9% vs. 48.5 ± 1.0%), increased glucose utilization compared with FGRS but not CON (P < 0.05; 9.6 ± 1.0 vs. 6.0 ± 0.9 vs. 7.6 ± 0.9 mg·kg-1·min-1), and increased ß-hydroxybutyric acid:nonesterified fatty acid ratio in response to adrenaline compared with CON and FGRS (P < 0.05; 3.9 ± 1.4 vs. 1.1 ± 1.4 vs. 1.8 ± 1.4). FGRS males were smaller and lighter compared with CON but not FGRI (P < 0.05; 86.8 ± 6.3 vs. 93.5 ± 6.1 vs. 90.7 ± 6.3 kg), with increased peak glucose concentration (10%) in response to a glucose load but few other differences. These effects of intra-amniotic IGF1 therapy on adult body composition, glucose-insulin axis function, and adrenergic sensitivity could indicate improved metabolic regulation during young adulthood in female FGR sheep.


Assuntos
Composição Corporal/efeitos dos fármacos , Retardo do Crescimento Fetal/tratamento farmacológico , Fator de Crescimento Insulin-Like I/uso terapêutico , Metabolismo/efeitos dos fármacos , Ácido 3-Hidroxibutírico/metabolismo , Absorciometria de Fóton , Animais , Epinefrina/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Glucose/metabolismo , Injeções , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/administração & dosagem , Gravidez , Caracteres Sexuais , Ovinos , Embolização da Artéria Uterina , Útero
8.
Muscle Nerve ; 61(5): 623-631, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32108355

RESUMO

INTRODUCTION: Recombinant human insulin-like growth factor-1 (rhIGF-1) is a growth factor and has anabolic effects on muscle. We investigated whether rhIGF-1 therapy: 1) improves or preserves muscle function; and 2) improves growth in boys with Duchenne muscular dystrophy (DMD). METHODS: In this study we compared prepubescent, ambulatory, glucocorticoid-treated boys with DMD (n = 17) vs controls (glucocorticoid therapy only, n = 21) in a 6-month-long, prospective, randomized, controlled trial of subcutaneous rhIGF-1 therapy. The primary outcome was 6-minute walk distance (6MWD). Secondary outcomes included height velocity (HV), change in height standard deviation score (ΔHtSDS), motor function, cardiopulmonary function, body composition, insulin sensitivity, quality of life, and safety. RESULTS: Change in 6MWD was similar between groups (rhIGF-1 vs controls [mean ± SD]: 3.4 ± 32.4 vs -5.1 ± 50.2 meters, P = .53). Treated subjects grew more than controls (HV: 6.5 ± 1.7 vs 3.3 ± 1.3 cm/year, P < .0001; 6-month ΔHtSDS: 0.25, P < .0001). Lean mass and insulin sensitivity increased in treated subjects. DISCUSSION: In boys with DMD, 6 months of rhIGF-1 therapy did not change motor function, but it improved linear growth.


Assuntos
Estatura , Substâncias de Crescimento/uso terapêutico , Resistência à Insulina , Fator de Crescimento Insulin-Like I/uso terapêutico , Força Muscular , Distrofia Muscular de Duchenne/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Absorciometria de Fóton , Glicemia/metabolismo , Automonitorização da Glicemia , Composição Corporal , Criança , Quimioterapia Combinada , Glucocorticoides/uso terapêutico , Humanos , Imagem por Ressonância Magnética , Masculino , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/fisiopatologia , Qualidade de Vida , Resultado do Tratamento , Teste de Caminhada
9.
Am J Respir Crit Care Med ; 201(9): 1120-1134, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32101461

RESUMO

Rationale: Antenatal factors, such as chorioamnionitis, preeclampsia, and postnatal injury, are associated with an increased risk for bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) after preterm birth. IGF-1 (insulin-like growth factor-1) is markedly decreased in normal preterm infants, but whether IGF-1 treatment can prevent BPD or PH is unknown.Objectives: To evaluate whether postnatal treatment with rhIGF-1 (recombinant human IGF-1)/BP3 (binding peptide 3) improves lung growth and prevents PH in two antenatal models of BPD induced by intraamniotic exposure to endotoxin (ETX) or sFlt-1 (soluble fms-like tyrosine kinase 1), and in a postnatal model due to prolonged hyperoxia.Methods: ETX or sFlt-1 were administered into the amniotic sac of pregnant rats at Embryonic Day 20 to simulate antenatal models of chorioamnionitis and preeclampsia, respectively. Pups were delivered by cesarean section at Embryonic Day 22 and treated with rhIGF-1/BP3 (0.02-20 mg/kg/d intraperitoneal) or buffer for 2 weeks. Study endpoints included radial alveolar counts (RACs), vessel density, and right ventricular hypertrophy (RVH). Direct effects of rhIGF-1/BP3 (250 ng/ml) on fetal lung endothelial cell proliferation and tube formation and alveolar type 2 cell proliferation were studied by standard methods in vitro.Measurements and Main Results: Antenatal ETX and antenatal sFlt-1 reduced RAC and decreased RVH in infant rats. In both models, postnatal rhIGF-1/BP3 treatment restored RAC and RVH to normal values when compared with placebo injections. rhIGF-1/BP3 treatment also preserved lung structure and prevented RVH after postnatal hyperoxia. In vitro studies showed that rhIGF-1/BP3 treatment increased lung endothelial cell and alveolar type 2 cell proliferation.Conclusions: Postnatal rhIGF-1/BP3 treatment preserved lung structure and prevented RVH in antenatal and postnatal BPD models. rhIGF-1/BP3 treatment may provide a novel strategy for the prevention of BPD in preterm infants.


Assuntos
Displasia Broncopulmonar/tratamento farmacológico , Hipertensão Pulmonar/prevenção & controle , Recém-Nascido Prematuro/crescimento & desenvolvimento , Fator de Crescimento Insulin-Like I/uso terapêutico , Pulmão/efeitos dos fármacos , Pulmão/crescimento & desenvolvimento , Cuidado Pós-Natal/métodos , Animais , Animais Recém-Nascidos/crescimento & desenvolvimento , Displasia Broncopulmonar/fisiopatologia , Feminino , Humanos , Hipertensão Pulmonar/fisiopatologia , Lactente , Recém-Nascido , Masculino , Modelos Animais , Gravidez , Ratos , Ratos Sprague-Dawley
10.
Burns ; 46(1): 19-32, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31852612

RESUMO

Major thermal injury induces profound metabolic derangements secondary to an inflammatory "stress-induced" hormonal environment. Several pharmacological interventions have been tested in an effort to halt the hypermetabolic response to severe burns. Insulin, insulin growth factor 1, insulin growth factor binding protein 3, metformin, human growth hormone, thyroid hormones, testosterone, oxandrolone, and propranolol, among others, have been proposed to have anabolic or anticatabolic effects. The aim of this broad analysis of pharmacological interventions was to raise awareness of treatment options and to help establishing directions for future clinical research efforts. A PubMed search was conducted on the anabolic and anticatabolic agents used in burn care. One hundred and thirty-five human studies published between 1999 and 2017 were included in this review. The pharmacological properties, rationale for the treatments, efficacy considerations and side effect profiles are summarized in the article. Many of the drugs tested for investigational purposes in the severely thermally injured are not yet gold-standard therapies in spite of their potential benefit. Propranolol and oxandrolone have shown great promise but further evidence is still needed to clarify their potential use for anabolic and anticatabolic purposes.


Assuntos
Anabolizantes/uso terapêutico , Queimaduras/tratamento farmacológico , Hormônios/uso terapêutico , Queimaduras/imunologia , Queimaduras/metabolismo , Clonidina/uso terapêutico , Hormônio Liberador de Hormônio do Crescimento/uso terapêutico , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Inflamação , Insulina/uso terapêutico , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina , Fator de Crescimento Insulin-Like I/uso terapêutico , Metformina/uso terapêutico , Oxandrolona/uso terapêutico , Propranolol/uso terapêutico , Testosterona/uso terapêutico , Hormônios Tireóideos/uso terapêutico
11.
Curr Opin Endocrinol Diabetes Obes ; 27(1): 82-86, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31789832

RESUMO

PURPOSE OF REVIEW: To discuss treatments used to enhance growth in pediatric patients with short stature. RECENT FINDINGS: New data confirm the known efficacy of recombinant human growth hormone (rhGH) in growth hormone deficiency (GHD) and idiopathic short stature. The latest data from the Safety and Appropriateness of Growth hormone Treatment in Europe cohort did not indicate a long-term risk of malignancy in those treated for isolated GHD, but possibly increased risk in those with other diagnoses. Recombinant human insulin-like growth factor 1 is effective in treating patients with pregnancy-associated plasma protein A2 deficiency. Gonadotropin-releasing hormone agonists or aromatase inhibitor treatment to delay puberty remains controversial. They are more likely to augment adult height if combined with rhGH treatment in children already receiving rhGH. Preliminary data indicate that recombinant C-type natriuretic peptide (CNP) is safe in children and increases growth velocity upon 42 months of treatment in achondroplasia. SUMMARY: Recent data confirms previous data on rhGH efficacy and safety. Therapies to delay growth plate closure have greatest efficacy to augment height if combined with GH in select diagnoses. Recombinant CNP holds promise as a medical treatment for short stature associated with achondroplasia.


Assuntos
Endocrinologia , Transtornos do Crescimento/prevenção & controle , Transtornos do Crescimento/terapia , Hormônio do Crescimento Humano/deficiência , Adulto , Estatura/efeitos dos fármacos , Criança , Nanismo Hipofisário/tratamento farmacológico , Nanismo Hipofisário/epidemiologia , Endocrinologia/métodos , Endocrinologia/tendências , Europa (Continente)/epidemiologia , Transtornos do Crescimento/epidemiologia , Terapia de Reposição Hormonal/métodos , Terapia de Reposição Hormonal/tendências , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Fator de Crescimento Insulin-Like I/uso terapêutico , Puberdade/efeitos dos fármacos , Puberdade/fisiologia , Proteínas Recombinantes/uso terapêutico
12.
Pediatr Hematol Oncol ; 37(2): 99-108, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31747806

RESUMO

Imatinib results in growth retardation in children with chronic myeloid leukemia (CML). The study was planned to assess the GHRH-GH-IGF1 axis in children with CML, receiving Imatinib and to evaluate the efficacy of human growth hormone (hGH) therapy. Twenty children with CML, receiving Imatinib for a period exceeding 6 months, with resultant growth retardation were included. The GHRH-GH-IGF1 axis was assessed using growth hormone stimulation tests. IGF-1 generation test was performed for the evaluation of GH insensitivity. The mean age at inclusion was 15.2 years. The mean duration of treatment with Imatinib was 5.7 years. The mean decrease in height SDS since the start of Imatinib was -0.95 (p = 0.008). IGF-1 SDS was <-2 in all the patients. 71.4% of patients had a suboptimal GH response following stimulation with GHRH-Arginine. All patients had stimulable, although a delayed GH response with glucagon stimulation. 20% of patients had GH insensitivity. Four patients were treated with hGH for a mean duration of 5.75 months, achieved normalization of IGF-1 levels and improvement in growth velocity improved from 0.21 to 0.86 cm/month. Imatinib results in an acquired neurosecretory defect in GH secretion. Treatment with growth hormone leads to an improvement in growth velocity and normalization of IGF-1.


Assuntos
Antineoplásicos/efeitos adversos , Transtornos do Crescimento/induzido quimicamente , Hormônio do Crescimento Humano/sangue , Mesilato de Imatinib/efeitos adversos , Fator de Crescimento Insulin-Like I/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Criança , Pré-Escolar , Feminino , Humanos , Fator de Crescimento Insulin-Like I/farmacologia , Masculino
14.
Biomaterials ; 216: 119246, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31203034

RESUMO

Microvascular muscle transfer is the gold standard for reanimation following chronic facial nerve paralysis, however, despite the regenerative capacity of peripheral motor axons, poor reinnervation often results in sub-optimal function. We hypothesized that injection of alginate hydrogels releasing growth factors directly into donor tissue would promote reinnervation, muscle regeneration, and function. A murine model of sciatic nerve ligation and neurorrhaphy was first used to assess the ability of gel delivery of vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) to promote functional reinnervation. VEGF + IGF-1 gel delivery to aged mice resulted in prolonged ability to control toe movement, increased toe spreading, and improved static sciatic index score, indicative of improved sciatic nerve and neuromuscular junction function. Further, a 26% increase in muscle fiber area, and 2.8 and 3.0-fold increases in muscle contraction force and velocity, respectively, were found compared to blank alginate in the murine model. This strategy was subsequently tested in a rabbit model of craniofacial gracilis muscle transplantation. Electromyography demonstrated a 71% increase in compound muscle action potential 9 weeks after transplantation following treatment with VEGF + IGF-1 alginate, compared to blank alginate in the rabbit model. Improving functional innervation in transplanted muscle via a hydrogel source of growth factors may enhance the therapeutic outcomes of facial palsy treatments and, more broadly, muscle transplantations.


Assuntos
Sistemas de Liberação de Medicamentos , Fator de Crescimento Insulin-Like I/administração & dosagem , Músculo Esquelético/inervação , Músculo Esquelético/transplante , Fator A de Crescimento do Endotélio Vascular/administração & dosagem , Alginatos/química , Animais , Feminino , Géis/química , Fator de Crescimento Insulin-Like I/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacos , Junção Neuromuscular/efeitos dos fármacos , Junção Neuromuscular/fisiologia , Coelhos , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/lesões , Nervo Isquiático/fisiologia , Fator A de Crescimento do Endotélio Vascular/uso terapêutico
15.
Tissue Eng Part A ; 25(17-18): 1191-1201, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31237484

RESUMO

IMPACT STATEMENT: A critical attribute for the long-term success of cartilage defect repair is the strong integration between the repair tissue and the surrounding native tissue. Current approaches utilized by physicians fail to achieve this attribute, leading to eventual relapse of the defect. This article demonstrates the concept of a simple, clinically viable approach for enhancing tissue integration via the combination of a safe, transient enzymatic treatment with a locally delivered, retained growth factor through an in vitro hydrogel/cartilage explant model.


Assuntos
Cartilagem/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/uso terapêutico , Tripsina/uso terapêutico , Animais , Cartilagem Articular/citologia , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/metabolismo , Bovinos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Condrócitos/citologia , Condrócitos/efeitos dos fármacos , Glicosaminoglicanos/metabolismo , Humanos , Microscopia Confocal , Engenharia Tecidual
16.
Clin Perinatol ; 46(2): 291-310, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31010561

RESUMO

Rates of bronchopulmonary dysplasia (BPD) are increasing. After preterm birth, there are important developmental periods in which neonates are more vulnerable to stressful events. These periods are opportunities for pharmacologic interventions. Many drugs remain inadequately tested and no new drugs have been approved in more than 25 years for BPD prevention or therapy. More progress is needed in defining appropriate end points based on the pathophysiology of BPD and postdischarge chronic pulmonary insufficiency of prematurity and to develop effective new drugs. In addition, much work is needed to better define perinatal factors, early postnatal findings, and physiologic phenotypes or endotypes.


Assuntos
Displasia Broncopulmonar/tratamento farmacológico , Displasia Broncopulmonar/prevenção & controle , Administração por Inalação , Corticosteroides/uso terapêutico , Broncodilatadores/uso terapêutico , Cafeína/uso terapêutico , Diuréticos/uso terapêutico , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Fator de Crescimento Insulin-Like I/uso terapêutico , Transplante de Células-Tronco Mesenquimais , Óxido Nítrico/uso terapêutico , Oxigenoterapia , Inibidores da Fosfodiesterase 5/uso terapêutico , Inibidores de Fosfodiesterase/uso terapêutico , Gravidez , Cuidado Pré-Natal , Progesterona/uso terapêutico , Progestinas/uso terapêutico , Surfactantes Pulmonares/uso terapêutico , Citrato de Sildenafila/uso terapêutico , Vitamina A/uso terapêutico , Vitaminas/uso terapêutico
17.
Int J Urol ; 26(5): 572-577, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30806004

RESUMO

OBJECTIVES: To evaluate the preventive effect of an insulin-like growth factor 1 sustained-release collagen urethral catheter on urethral stricture after urethral injury in a rabbit model. METHODS: We made urethral catheters coated either with insulin-like growth factor 1 impregnated collagen or with only collagen, and we divided 19 male Japanese white rabbits into three groups according to the kind of catheter inserted immediately after the rabbit's urethra was injured by electrocoagulation. Group 1 (n = 7) had a catheter coated with insulin-like growth factor 1 impregnated collagen inserted; group 2 (n = 7) had a catheter coated with only collagen inserted; and group 3 (n = 5) had an uncoated catheter inserted. A total of 14 days later, the injured urethras were evaluated by urethrography and urethroscopy, and were also histologically examined. RESULTS: Urethrography showed that the ratio of the urethral lumen diameter in injured urethra to that in normal urethra was the largest in group 1 (P < 0.0001). In addition, five of the seven rabbits in group 1 (71.4%) had a urethral lumen large enough for passage of a urethroscope, a fraction larger than the corresponding fractions in groups 2 (57.1%) and 3 (20%). On histological analysis, the injured area not covered with regenerated urethral epithelium tended to be smaller in group 1 than the other two groups, but the mean difference was not significant (P = 0.19). CONCLUSIONS: An insulin-like growth factor 1 sustained-release collagen urethral catheter significantly improves wound healing and prevents urethral stricture after urethral injury.


Assuntos
Fator de Crescimento Insulin-Like I/uso terapêutico , Estreitamento Uretral/prevenção & controle , Cateteres Urinários , Animais , Preparações de Ação Retardada , Modelos Animais de Doenças , Masculino , Coelhos , Uretra/lesões , Estreitamento Uretral/etiologia
18.
Exp Neurol ; 311: 162-172, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30287160

RESUMO

Our previous studies showed that Insulin-like Growth Factor (IGF)-1 reduced blood brain barrier permeability and decreased infarct volume caused by middle cerebral artery occlusion (MCAo) in middle aged female rats. Similarly, cultures of primary brain microvessel endothelial cells from middle-aged female rats and exposed to stroke-like conditions (oxygen glucose deprivation; OGD) confirmed that IGF-1 reduced dye transfer across this cell monolayer. Surprisingly, IGF-1 did not attenuate endothelial cell death caused by OGD. To reconcile these findings, the present study tested the hypothesis that, at the earliest phase of ischemia, IGF-1 promotes barrier function by increasing anchorage and stabilizing cell geometry of surviving endothelial cells. Cultures of human brain microvessel endothelial cells were subject to oxygen-glucose deprivation (OGD) in the presence of IGF-1, IGF-1 + JB-1 (IGFR inhibitor) or vehicle. OGD disrupted the cell monolayer and reduced cell-cell interactions, which was preserved in IGF-1-treated cultures and reversed by concurrent treatment with JB-1. IGF-1-mediated preservation of the endothelial monolayer was reversed with LY294002 treatment, but not by Rapamycin, indicating that IGF-1 s actions on cell-cell contacts are likely mediated via the PI3K pathway. In vivo, microvessel morphology was evaluated in middle-aged female rats that were subjected to ischemia by MCAo, and treated ICV with IGFI, IGF-1 + JB-1, or artificial CSF (aCSF; vehicle) after reperfusion. Compared to vehicle controls, IGF-1 treated animals displayed larger microvessel diameters in the peri-infarct area and increased staining density for vinculin, an anchorage protein. Both these measures were reversed by concurrent IGF-1 + JB-1 treatment. Moreover these effects were restricted to 24 h after ischemia-reperfusion and no treatment effects were seen at 5d post stroke. Collectively, these data suggest that in the earliest hours during ischemia, IGF-1 promotes receptor-mediated anchorage of endothelial cells, and its actions may be accurately characterized as vasculoprotective.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Citoesqueleto/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/uso terapêutico , Microvasos/efeitos dos fármacos , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Isquemia Encefálica/metabolismo , Linhagem Celular , Citoesqueleto/metabolismo , Endotélio Vascular/metabolismo , Feminino , Humanos , Fator de Crescimento Insulin-Like I/farmacologia , Microvasos/metabolismo , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento
19.
Mol Ther ; 27(1): 46-58, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30528085

RESUMO

Insulin-like growth factor 1 (IGF1) is an anabolic hormone that controls the growth and metabolism of many cell types. However, IGF1 also mediates cardio-protective effects after acute myocardial infarction (AMI), but the underlying mechanisms and cellular targets are not fully understood. Here we demonstrate that short-term IGF1 treatment for 3 days after AMI improved cardiac function after 1 and 4 weeks. Regional wall motion was improved in ischemic segments, scar size was reduced, and capillary density increased in the infarcted area and the border zone. Unexpectedly, inducible inactivation of the IGF1 receptor (IGF1R) in cardiomyocytes did not attenuate the protective effect of IGF1. Sequential cardiac transcriptomic analysis indicated an altered myeloid cell response in the acute phase after AMI, and, notably, myeloid-cell Igf1r-/- mice lost the protective IGF1 function after I/R. In addition, IGF1 induced an M2-like anti-inflammatory phenotype in bone marrow-derived macrophages and enhanced the number of anti-inflammatory macrophages in heart tissue on day 3 after AMI in vivo. In summary, modulation of the acute inflammatory phase after AMI by IGF1 represents an effective mechanism to preserve cardiac function after I/R.


Assuntos
Fator de Crescimento Insulin-Like I/uso terapêutico , Células Mieloides/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Animais , Ecocardiografia , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo
20.
J Pediatr ; 206: 56-65.e8, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30471715

RESUMO

OBJECTIVE: To investigate recombinant human insulin-like growth factor 1 complexed with its binding protein (rhIGF-1/rhIGFBP-3) for the prevention of retinopathy of prematurity (ROP) and other complications of prematurity among extremely preterm infants. STUDY DESIGN: This phase 2 trial was conducted from September 2014 to March 2016. Infants born at a gestational age of 230/7 weeks to 276/7 weeks were randomly allocated to rhIGF-1/rhIGFBP-3 (250 µg/kg/ 24 hours, continuous intravenous infusion from <24 hours of birth to postmenstrual age 296/7 weeks) or standard neonatal care, with follow-up to a postmenstrual age of 404/7 weeks. Target exposure was ≥70% IGF-1 measurements within 28-109 µg/L and ≥70% intended therapy duration. The primary endpoint was maximum severity of ROP. Secondary endpoints included time to discharge from neonatal care, bronchopulmonary dysplasia, intraventricular hemorrhage, and growth measures. RESULTS: Overall, 61 infants were allocated to rhIGF-1/rhIGFBP-3, 60 to standard care (full analysis set); 24 of 61 treated infants achieved target exposure (evaluable set). rhIGF-1/rhIGFBP-3 did not decrease ROP severity or ROP occurrence. There was, however, a 53% decrease in severe bronchopulmonary dysplasia in the full analysis set (21.3% treated vs 44.9% standard care), and an 89% decrease in the evaluable set (4.8% vs 44.9%; P = .04 and P = .02, respectively) for severity distribution between groups. There was also a nonsignificant trend toward decrease in grades 3-4 intraventricular hemorrhage in the full analysis set (13.1% vs 23.3%) and in the evaluable set (8.3% vs 23.3%). Fatal serious adverse events were reported in 19.7% of treated infants (12/61) and 11.7% of control infants (7/60). No effect was observed on time to discharge from neonatal care/growth measures. CONCLUSIONS: rhIGF-1/rhIGFBP-3 did not affect development of ROP, but decreased the occurrence of severe bronchopulmonary dysplasia, with a nonsignificant decrease in grades 3-4 intraventricular hemorrhage. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01096784.


Assuntos
Hemorragia Cerebral/prevenção & controle , Fator de Crescimento Insulin-Like I/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Retinopatia da Prematuridade/prevenção & controle , Displasia Broncopulmonar/prevenção & controle , Hemorragia Cerebral/terapia , Feminino , Idade Gestacional , Humanos , Lactente Extremamente Prematuro , Recém-Nascido , Recém-Nascido Prematuro , Infusões Intravenosas , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/uso terapêutico , Masculino , Retinopatia da Prematuridade/mortalidade , Retinopatia da Prematuridade/terapia , Índice de Gravidade de Doença , Resultado do Tratamento
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