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1.
Onco Targets Ther ; 14: 3037-3049, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33994796

RESUMO

BACKGROUND: Crizotinib inhibits ALK, MET and ROS1 tyrosine kinases but the development of resistance to monotherapy is an issue. The anti-angiogenic properties of pazopanib could overcome crizotinib drug resistance. Additionally, the anti-angiogenic properties of crizotinib could augment the clinical efficacy of pazopanib. METHODS: We evaluated the safety and responses in patients with advanced solid tumors treated with crizotinib and pazopanib. RESULTS: Eighty-two patients (median age 53 years, range 18-78 years) were enrolled. The median number of prior systemic therapies was 3 (range, 0-8). We were able to dose escalate to dose level 8 (crizotinib 250 mg twice daily and pazopanib 800 mg daily) with no MTD identified. Grade 3 or 4 toxicities were seen in 32% of patients with the highest prevalence being fatigue (n=9, 11%), diarrhea (n=6, 7%), vomiting (n=3, 4%), anemia (n=2, 2%) and ALT increased (n=2, 2%). Of the 82 patients, 61 (74%) had measurable disease by RECISTv1.1 and reached first restaging (6 weeks). Partial response (PR) was observed in 6/61 (10%) patients, and stable disease (SD) lasting ≥6 months was observed in 10/61 patients (16%) (total = 16/61 (26%) of patients with SD ≥6 months/PR). CONCLUSION: Dose level 6 (crizotinib 200 mg twice daily and pazopanib 600 mg daily) was the most tolerable dosing of the combination and can be used in future studies. We also observed moderate clinical activity in patients with advanced solid tumors that had received numerous prior therapies.

2.
Bone ; 145: 115040, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-31437568

RESUMO

Hip fractures at the femoral neck are a major cause of morbidity and mortality, but aside from biomechanical strength testing, little is known about femoral neck architecture in mice. Procedures were optimized to analyze high-resolution (6 µm voxel size) microCT scans of the mouse femoral neck to provide bone mass and architectural information. Similar to histomorphometric observations in rats, the boundary between cortical and trabecular bone is difficult to identify in the mouse femoral mid-neck and these compartments were not analyzed separately. Analyses included total area, mineralized bone area, and bone volume fraction (BV/TV). Femoral neck architecture varies in C57BL/6J, 129/SvEv and BALB/c mouse strains. Bone cross sectional area and BV/TV were low in Lrp5 but elevated in Sost gene knockout mice. Sfrp4 gene knockout resulted in high total area, normal bone area, low BV/TV and, as indicated by BS/BV values, greater trabecularization. Femoral neck BV/TV declined with age and ovariectomy, but increased with teriparatide treatment. These findings demonstrate that the architecture of the mouse femoral neck mimics phenotypes and treatment effects observed at other skeletal sites and is a relevant bone site for translational studies examining osteoporosis therapies.


Assuntos
Densidade Óssea , Colo do Fêmur , Animais , Feminino , Colo do Fêmur/diagnóstico por imagem , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas , Ratos , Microtomografia por Raio-X
3.
J Pharmacol Exp Ther ; 362(1): 85-97, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28442582

RESUMO

LX2761 is a potent sodium/glucose cotransporter 1 inhibitor restricted to the intestinal lumen after oral administration. Studies presented here evaluated the effect of orally administered LX2761 on glycemic control in preclinical models. In healthy mice and rats treated with LX2761, blood glucose excursions were lower and plasma total glucagon-like peptide-1 (GLP-1) levels higher after an oral glucose challenge; these decreased glucose excursions persisted even when the glucose challenge occurred 15 hours after LX2761 dosing in ad lib-fed mice. Further, treating mice with LX2761 and the dipeptidyl-peptidase 4 inhibitor sitagliptin synergistically increased active GLP-1 levels, suggesting increased LX2761-mediated release of GLP-1 into the portal circulation. LX2761 also lowered postprandial glucose, fasting glucose, and hemoglobin A1C, and increased plasma total GLP-1, during long-term treatment of mice with either early- or late-onset streptozotocin-diabetes; in the late-onset cohort, LX2761 treatment improved survival. Mice and rats treated with LX2761 occasionally had diarrhea; this dose-dependent side effect decreased in severity and frequency over time, and LX2761 doses were identified that decreased postprandial glucose excursions without causing diarrhea. Further, the frequency of LX2761-associated diarrhea was greatly decreased in mice either by gradual dose escalation or by pretreatment with resistant starch 4, which is slowly digested to glucose in the colon, a process that primes the colon for glucose metabolism by selecting for glucose-fermenting bacterial species. These data suggest that clinical trials are warranted to determine if LX2761 doses and dosing strategies exist that provide improved glycemic control combined with adequate gastrointestinal tolerability in people living with diabetes.


Assuntos
Compostos Benzidrílicos/farmacologia , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Peptídeo 1 Semelhante ao Glucagon/antagonistas & inibidores , Peptídeo 1 Semelhante ao Glucagon/sangue , Hipoglicemiantes/farmacologia , Tioglicosídeos/farmacologia , Animais , Compostos Benzidrílicos/química , Relação Dose-Resposta a Droga , Índice Glicêmico/efeitos dos fármacos , Índice Glicêmico/fisiologia , Hipoglicemiantes/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Tioglicosídeos/química
4.
J Med Chem ; 60(2): 710-721, 2017 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-28045524

RESUMO

The increasing number of people afflicted with diabetes throughout the world is a major health issue. Inhibitors of the sodium-dependent glucose cotransporters (SGLT) have appeared as viable therapeutics to control blood glucose levels in diabetic patents. Herein we report the discovery of LX2761, a locally acting SGLT1 inhibitor that is highly potent in vitro and delays intestinal glucose absorption in vivo to improve glycemic control.


Assuntos
Compostos Benzidrílicos/farmacologia , Hipoglicemiantes/farmacologia , Fenilbutiratos/farmacologia , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Tioglicosídeos/farmacologia , Animais , Compostos Benzidrílicos/administração & dosagem , Compostos Benzidrílicos/síntese química , Compostos Benzidrílicos/química , Glucose/metabolismo , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Absorção Intestinal/efeitos dos fármacos , Masculino , Camundongos Knockout , Fenilbutiratos/administração & dosagem , Fenilbutiratos/síntese química , Fenilbutiratos/química , Relação Estrutura-Atividade , Tioglicosídeos/administração & dosagem , Tioglicosídeos/síntese química , Tioglicosídeos/química
5.
Pharmacol Res Perspect ; 3(2): e00129, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26038705

RESUMO

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of oral anti-diabetic agents that improve glycemic control by inhibiting SGLT2-mediated renal glucose reabsorption. Currently available agents increase urinary glucose excretion (UGE) to <50% of maximal values because they do not inhibit SGLT1, which reabsorbs >50% of filtered glucose when SGLT2 is completely inhibited. This led us to test whether LP-925219, a small molecule dual SGLT1/SGLT2 inhibitor, increases UGE to maximal values in wild-type (WT) mice. We first tested LP-925219 inhibition of glucose transport by HEK293 cells expressing SGLT1 or SGLT2, and then characterized LP-925219 pharmacokinetics. We found that LP-925219 was a potent inhibitor of mouse SGLT1 (IC50 = 22.6 nmol/L) and SGLT2 (IC50 = 0.5 nmol/L), and that a 10 mg/kg oral dose was bioavailable (87%) with a long half-life (7 h). We next delivered LP-925219 by oral gavage to WT, SGLT1 knockout (KO), SGLT2 KO, and SGLT1/SGLT2 double KO (DKO) mice and measured their 24-h UGE. We found that, in vehicle-treated mice, DKO UGE was maximal and SGLT2 KO, SGLT1 KO, and WT UGEs were 30%, 2%, and 0.2% of maximal, respectively; we also found that LP-925219 dosed at 60 mg/kg twice daily increased UGE of SGLT1 KO, SGLT2 KO, and WT mice to DKO UGE levels. These findings show that orally available dual SGLT1/SGLT2 inhibitors can maximize 24-h UGE in mammals, and suggest that such agents merit further evaluation for their potential, in diabetic patients, to achieve better glycemic control than is achieved using selective SGLT2 inhibitors.

6.
J Pharmacol Exp Ther ; 350(2): 232-42, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24849925

RESUMO

Treatments that lower blood glucose levels and body weight should benefit patients with type 2 diabetes mellitus (T2DM). We developed LX4211 [(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol], an orally available small molecule that decreases postprandial glucose excursions by inhibiting intestinal sodium/glucose cotransporter 1 (SGLT1) and increases urinary glucose excretion (UGE) by inhibiting renal SGLT2. In clinical studies of patients with T2DM, LX4211 appears to act through dual SGLT1/SGLT2 inhibition to improve glycemic control and promote weight loss. Here, we present preclinical studies that explored the ability of LX4211 to improve glycemic control and promote weight loss. We found that 1) LX4211 inhibited in vitro glucose transport mediated by mouse, rat, and dog SGLT1 and SGLT2; 2) a single daily LX4211 dose markedly increased UGE for >24 hours in mice, rats, and dogs; and 3) in the KK.Cg-Ay/J heterozygous (KKA(y)) mouse model of T2DM, LX4211 lowered A1C and postprandial glucose concentrations while increasing postprandial glucagon-like peptide 1 concentrations. Also, long-term LX4211 treatment 1) decreased oral glucose tolerance test (OGTT) glucose excursions, increased OGTT 30-minute insulin concentrations and increased pancreatic insulin content in KKA(y) mice; and 2) decreased weight gain in dogs and rats but not in KKA(y) mice while increasing food consumption in dogs, rats, and KKA(y) mice; in these KKA(y) mice, calories lost through UGE were completely offset by calories gained through hyperphagia. These findings suggest that LX4211 improves glycemic control by dual SGLT1/SGLT2 inhibition in mice as in humans, and that the LX4211-mediated weight loss observed in patients with T2DM may be attenuated by LX4211-mediated hyperphagia in some of these individuals.


Assuntos
Composição Corporal/efeitos dos fármacos , Glucose/metabolismo , Glicosídeos/farmacologia , Homeostase/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Cães , Glicosídeos/farmacocinética , Glicosúria/tratamento farmacológico , Humanos , Absorção Intestinal/efeitos dos fármacos , Camundongos , Ratos , Ratos Sprague-Dawley
7.
J Steroid Biochem Mol Biol ; 108(1-2): 137-48, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17942302

RESUMO

Using a luciferase reporter assay we found that human serum transactivated the ileal apical sodium-dependent bile acid transporter (ASBT) promoter three to fourfold. Confirming this effect, addition of human serum to both Caco-2 cells and fresh human ileal biopsies caused an approximate 2.0-fold increase in endogenous ASBT mRNA production. Alteration of non-esterified fatty acid (NEFA) content and cortisol content did not affect the transactivation potential of serum. Site-directed mutagenesis of response elements for corticosteroid, peroxisome proliferation-activated alpha (PPARalpha), hepatocyte nuclear factor 1alpha (HNF1alpha), and retinoic acid (RAR/RXR) did not affect transactivation potential of serum. Three putative serum response elements (SRE) were identified on the promoter, but all were determined inactive using site-directed mutagenesis and electrophoretic mobility shift assay. Promoter deletion analysis demonstrated that >80% of the response to serum was located within the last 273 bp of the 5'-UTR, an area containing one of two activate protein 1 (AP-1) response elements. Site-directed mutagenesis of this downstream AP-1 response element reduced the effect of serum on the promoter by about 50% while full deletion of the response element completely eliminated the effect of serum. These studies demonstrate that one or more constituents of human stimulate ASBT gene expression largely via the down-stream AP-1 response element.


Assuntos
Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Soro/fisiologia , Simportadores/genética , Ativação Transcricional , Animais , Células CACO-2 , Proteínas de Transporte/farmacologia , Galinhas , Corticosterona , Ácidos Graxos não Esterificados/farmacologia , Genes Reporter/efeitos dos fármacos , Humanos , Hidrocortisona/farmacologia , Íleo/metabolismo , Luciferases/genética , Mifepristona/farmacologia , Mutagênese Sítio-Dirigida , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , RNA Mensageiro/metabolismo , Receptores do Ácido Retinoico/metabolismo , Elemento de Resposta Sérica/efeitos dos fármacos , Elemento de Resposta Sérica/fisiologia , Simportadores/metabolismo , Fator de Transcrição AP-1/metabolismo , Ativação Transcricional/efeitos dos fármacos , Transfecção , Células Tumorais Cultivadas
8.
Biochim Biophys Acta ; 1771(11): 1380-8, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17964214

RESUMO

Using a luciferase reporter assay in both LMH cells and Caco2 cells we found that certain bile acids including unconjugated deoxycholic and others transactivated the ileal apical sodium-dependent bile acid transporter (ASBT) at concentrations ranging from 20 to 300 microM. Confirming this effect, addition of deoxycholic acid to fresh human ileal biopsies caused an approximate 40% increase in endogenous ASBT mRNA production. Promoter deletion analysis indicated the effect of bile acids was mediated by a response element located in the downstream half of the 5'-UTR, a region known to contain a retinoic acid (RXR/RAR) response element and an activated protein-1 (AP-1) response element. Site-directed mutagenesis of the RAR/RXR response element actually enhanced response to deoxycholic acid. Site-directed mutagenesis of the downstream AP-1 response element reduced activation by deoxycholic acid while deletion of this response element completely eliminated this response. The epidermal growth factor (EGF) receptor inhibitor, AG1478, completely eliminated the response to bile acid while the mitogen-activated protein extracellular signal-regulated kinase cascade (MEK) inhibitor, U0126, partially inhibited the response to bile acid. These studies demonstrate that certain bile acids stimulate ASBT gene expression acting on the down-stream AP-1 response element via the EGF receptor and MEK cascade.


Assuntos
Ácidos e Sais Biliares/farmacologia , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Simportadores/genética , Regiões 5' não Traduzidas , Animais , Sequência de Bases , Linhagem Celular , Primers do DNA/genética , Expressão Gênica/efeitos dos fármacos , Humanos , Íleo/efeitos dos fármacos , Íleo/metabolismo , Técnicas In Vitro , Mutagênese Sítio-Dirigida , Regiões Promotoras Genéticas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores do Ácido Retinoico/genética , Receptores X de Retinoides/genética , Deleção de Sequência , Fator de Transcrição AP-1/genética , Transfecção
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