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1.
Chem Commun (Camb) ; 55(89): 13362-13365, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31631195

RESUMO

Rule-of-five parameters and membrane permeabilities have been routinely used to guide development of orally bioavailabile drugs. Here we compare enantiomeric pairs of cyclic hexapeptides with identical rule-of-five parameters and membrane permeabilities. For each enantiomeric pair, the isomer with more l- than d-amino acids is much more orally bioavailable in rats, more metabolically stable to rat liver microsomes, and cleared more slowly in vivo.


Assuntos
Peptídeos Cíclicos/metabolismo , Peptídeos Cíclicos/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Conformação Molecular , Peptídeos Cíclicos/administração & dosagem , Ratos , Estereoisomerismo
2.
Pharm Res ; 36(10): 151, 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31451949

RESUMO

PURPOSE: In this study we evaluated the utility of in-vitro screening tools for predicting the in-vivo behavior of six cyclic peptides with different solubility and permeability properties (BCS class II and III), intended for oral delivery in presence of permeation enhancer Labrasol. METHODS: An in vitro flux assay was used to assess peptide permeation across a biomimetic, lipid-based membrane and in vivo studies in rats were used to determine oral peptide bioavailability in the presence of Labrasol. RESULTS: The in vitro flux was significantly increased for BCS class III peptides, while it significantly decreased or remained unchanged for BCS class II peptides with increasing Labrasol concentrations. The different flux responses were attributed to the combination of reduced effective free peptide concentration and increased membrane permeability in the presence of Labrasol. In vivo studies in male Wistar-Hans rats indicated improved oral bioavailability at different extents for all peptides in presence of Labrasol. On comparing the in vitro and in vivo data, a potential direct correlation for BCS class III peptides was seen but not for BCS class II peptides, due to lower free concentrations of peptides in this class. CONCLUSION: This study assessed the utility of in vitro screening tools for selecting peptides and permeation excipients early in drug product development. Graphical Abstract Graphical Abstract and Figure 1 contains small text.Graphical Abstract text is made larger. The Figure 1 text cannot be made larger.


Assuntos
Peptídeos Cíclicos/administração & dosagem , Peptídeos Cíclicos/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Permeabilidade da Membrana Celular , Química Farmacêutica , Excipientes/química , Glicerídeos/química , Bicamadas Lipídicas/metabolismo , Masculino , Modelos Biológicos , Peptídeos Cíclicos/química , Ratos Wistar , Solubilidade
3.
Int J Pharm ; 568: 118507, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31299336

RESUMO

Covering the surface of a nanoparticle with polyethylene glycol (PEG) is a common way to prevent non-specific interactions but how its presence impacts on the activity of targeting ligands is still poorly documented. We synthesized a set of 9 silica nanoparticles grafted with c[RGDfK]-, a peptide targeting integrin αvß3 (cRGD), and/or with ATWLPPR, an anti-neuropilin 1 peptide (ATW). We then added various PEGs, and studied NPs binding on primary endothelial cells, the downstream activated signaling pathways and the impact on apoptosis. Our results show that the presence of PEG2000 on cRGD/ATW nanoparticles moderately improves cell binding but induces a 6000 times augmentation of AKT-dependent cell response due to the recruitment of other Receptor Tyrosine Kinases. Augmenting the length of the spacer that separates the peptides from the silica (using PEG3000) mainly resulted in a loss of specificity. Finally, the PEG-mediated hyperactivation of AKT did not protect endothelial cell from dying in the absence of serum, while its moderate activation obtained without PEG did. Finally, PEGylation of cRGD/ATW-NPs can generate nanoparticles with potent capacities to activate the AKT-GSK3ß-eNOS cascade and to affect the resistance of endothelial cells to apoptosis. Thus, the impact of PEGylation should be precisely considered in order to avoid the apparition of counter-productive biological responses.


Assuntos
Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Nanopartículas/administração & dosagem , Oligopeptídeos/administração & dosagem , Peptídeos Cíclicos/administração & dosagem , Polietilenoglicóis/administração & dosagem , Dióxido de Silício/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Glicogênio Sintase Quinase 3 beta/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Nanopartículas/química , Óxido Nítrico Sintase Tipo III/metabolismo , Oligopeptídeos/química , Peptídeos Cíclicos/química , Polietilenoglicóis/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Dióxido de Silício/química
5.
Pan Afr Med J ; 32: 62, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31223354

RESUMO

Malignant paragangliomas pose a real challenge for the practitioners. They are rare complex tumors, very heterogeneous in their evolution and prognosis. Given the rarity of this tumor group, there is no consensus on therapeutic management. Through this illustrative case study, we report the case of a 29 year old female patient followed for malignant paraganglioma due to which she initially had surgery. After a six month interval, multifocal recurrence was detected on Octreoscan PET-CT (Positron Emission Tomography- Computer Tomography). The patient underwent monthly injection of Somatuline for one year and then discontinued therapy due to disease progression. Cytoreduction was then performed followed by radiotherapy. After a year, the patient had massive disease progression. Dacarbazine-based chemotherapy was initiated. The patient had an almost complete metabolic response after eight cycles. This study aims to highlight the different therapeutic options in the management of malignant paragangliomas.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Paraganglioma/terapia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Adulto , Terapia Combinada , Procedimentos Cirúrgicos de Citorredução/métodos , Dacarbazina/administração & dosagem , Feminino , Humanos , Recidiva Local de Neoplasia , Paraganglioma/diagnóstico por imagem , Peptídeos Cíclicos/administração & dosagem , Somatostatina/administração & dosagem , Somatostatina/análogos & derivados , Resultado do Tratamento
6.
Neuropeptides ; 76: 101935, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31146894

RESUMO

Childhood metabolic disorders are associated with insulin-like growth factor (IGF)-1 deficiency, which can adversely affect brain development and function. As a neuropeptide, cyclic glycine-proline (cGP) improves IGF-1 function in brain and regulates IGF-1 bioavailability in plasma. Whether such a regulatory process mediates the neurotrophic effects of cGP remains unknown. This study examined the effects cGP treatment on synaptic expression and their association with IGF-1, IGF binding protein (IGFBP)-2 and cGP concentrations in the brain of rats with high fat diet (HFD)-induced obesity. Male rats received either a HFD or a standard chow diet (STD) from weaning and were then treated with either saline or cGP from 11 to 15 weeks of age. The concentrations of cGP, IGF-1 and IGFBP-2 were measured in the brain tissues using ELISA and HPLC-MS. The expressions of synaptic markers were evaluated in the hippocampus, hypothalamus and striatum using immunohistochemical staining. Compared to the STD group, IGF-1 and IGFBP-2, but not cGP concentrations, were lower in the HFD groups. The expression of hippocampal synaptophysin, glutamate receptor-1, GFAP and striatal tyrosine-hydroxylase were also reduced in the HFD groups. While treatment did not alter tissue IGF-1, cGP administration that increased the concentration of cGP in brain tissues, normalized the expression of synaptophysin, GFAP and tyrosine-hydroxylase, but not glutamate receptor-1. IGF-1 concentration in brain tissues correlated with the expression of all synaptic markers. HFD feeding reduced synaptic expression and tissue IGF-1 in brains which were closely associated, thus suggesting IGF-1 in the brain is largely bioavailable. Without increasing IGF-1 in the brain, administration of cGP normalized synaptic expression, possibly be mediated through increasing bioavailable IGF-1, but further studies are required to confirm this.


Assuntos
Obesidade/metabolismo , Peptídeos Cíclicos/administração & dosagem , Sinaptofisina/metabolismo , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Ratos Sprague-Dawley
7.
Amino Acids ; 51(8): 1233-1240, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31197572

RESUMO

The aim of this study was to evaluate the effect of spreading the lipopeptide surfactin, for short time (10/20 s), on dentin wettability. Study groups were surfactin: 2.8; 1.4; 0.7; 0.35; and 0.175 mg/mL and a control group that received no treatment. Dentin discs (4 mm height) were prepared and polished with 600-grit SiC paper. Contact angle determinations were carried out after microbrush spreading of surfactin on dentin specimens for, respectively, 10 and 20 s. Excess liquid was removed, and after 60 s, the specimens were analyzed in a goniometer using the sessile drop method to measure the contact angle. Results were analyzed by two-way ANOVA (concentration × time) and t student, with α = 0.05. Lower contact angles were obtained for surfactin (0.7 mg/mL) spread for 10 s. However, no statistical difference was observed for surfactin (2.8 mg/mL) applied during 20 s. Higher contact angles were observed for surfactin (0.7 mg/mL) spread for 20 s. In conclusion, dentin wettability is dependent on spreading time and surfactin concentration.


Assuntos
Dentina/química , Lipopeptídeos/administração & dosagem , Peptídeos Cíclicos/administração & dosagem , Dente/química , Molhabilidade/efeitos dos fármacos , Dentina/efeitos dos fármacos , Humanos , Teste de Materiais , Propriedades de Superfície
8.
Endocrinol. diabetes nutr. (Ed. impr.) ; 66(5): 320-329, mayo 2019. graf, tab
Artigo em Inglês | IBECS | ID: ibc-182807

RESUMO

Objectives: The ACROSTART study was intended to determine the time to achieve normalization of GH and IGF-I levels in responding patients with acromegaly administered different dosage regimens of lanreotide Autogel (Somatuline(R) Autogel(R)). Methods: From March 2013 to October 2013, clinical data from 57 patients from 17 Spanish hospitals with active acromegaly treated with lanreotide for ≥4 months who achieved hormonal control (GH levels <2.5ng/ml and/or normalized IGF-I levels in ≥2 measurements) were analyzed. The primary objective was to determine the time from start of lanreotide treatment to hormonal normalization. Results: Median patient age was 64 years, 21 patients were male, 39 patients had undergone surgery, and 14 patients had received radiotherapy. Median hormonal values at start of lanreotide treatment were: GH, 2.6ng/ml; IGF-I, 1.6×ULN. The most common starting dose of lanreotide was 120mg (29 patients). The main initial regimens were 60mg/4 weeks (n=13), 90mg/4 weeks (n=6), 120mg/4 weeks (n=13), 120mg/6 weeks (n=6), and 120mg/8 weeks (n=9). An initial treatment regimen with a long interval (≥6 weeks) was administered in 25 patients. Mean duration of lanreotide treatment was 68 months (7-205). Median time to achieve hormonal control was 4.9 months. Injections were managed without healthcare assistance in 13 patients. Median number of visits to endocrinologists until hormonal control was achieved was 3. Fifty-one patients were "satisfied"/"very satisfied" with treatment and 49 patients did not miss any dose. Conclusions: Real-life treatment with lanreotide Autogel resulted in early hormonal control in responding patients, with high treatment adherence and satisfaction despite disparity in starting doses and dosing intervals


Objetivos: El objetivo del estudio ACROSTART era determinar el período de tiempo para lograr la normalización hormonal (GH e IGF-I) en pacientes con acromegalia respondedores al tratamiento considerando los regímenes de lanreótida Autogel (Somatuline(R) Autogel(R)) utilizados en la práctica clínica. Métodos: Desde marzo de 2013 hasta octubre de 2013, en 17 hospitales españoles se analizaron los datos clínicos de 57 pacientes con acromegalia activa tratados con lanreótida durante ≥4 meses que lograron control hormonal (niveles de GH <2,5ng/ml y/o IGF-I normalizado en ≥2 evaluaciones). El objetivo principal fue determinar el período de tiempo desde el inicio del tratamiento con lanreótida hasta la normalización hormonal. Resultados: La mediana de edad de los pacientes fue 64 años, 21 pacientes eran hombres, 39 pacientes habían recibido cirugía, 14 pacientes habían recibido radioterapia. Los valores hormonales medianos al inicio del tratamiento con lanreótida fueron GH: 2,6ng/ml, IGF-I: 1,6×LSN. La dosis inicial más frecuente de lanreótida fue de 120mg (29 pacientes). Los principales regímenes iniciales fueron 60mg/4 semanas (n=13), 90mg/4 semanas (n=6), 120mg/4 semanas (n=13), 120mg/6 semanas (n=6), 120mg/8 semanas (n=9). Se administró un régimen de intervalo prolongado (≥6 semanas) en 25 pacientes. La duración media del tratamiento con lanreótida fue de 68 meses (7-205). El tiempo medio hasta lograr el control hormonal fue de 4,9 meses. Las inyecciones se manejaron sin asistencia médica en 13 pacientes. La mediana del número de visitas al endocrinólogo hasta el control hormonal fue 3. Cincuenta y un pacientes estaban "satisfechos"/"muy satisfechos" con el tratamiento y 49 pacientes no olvidaron ninguna dosis. Conclusiones: El tratamiento en la vida real con lanreótida Autogel condujo a un control hormonal temprano en pacientes que respondieron, con una alta adherencia al tratamiento y satisfacción con el tratamiento, a pesar de la disparidad de las dosis iniciales y los intervalos de dosificación


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto Jovem , Adulto , Idoso , Idoso de 80 Anos ou mais , Acromegalia/tratamento farmacológico , Peptídeos Cíclicos/uso terapêutico , Hormônio do Crescimento Humano/metabolismo , Somatostatina/análogos & derivados , Acromegalia/sangue , Estudos Retrospectivos , Peptídeos Cíclicos/administração & dosagem , Acromegalia/metabolismo , Cooperação e Adesão ao Tratamento , Somatostatina/administração & dosagem
9.
Molecules ; 24(8)2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31022852

RESUMO

Determining chemokine receptor CXCR4 expression is significant in multiple diseases due to its role in promoting inflammation, cell migration and tumorigenesis. [68Ga]Pentixafor is a promising ligand for imaging CXCR4 expression in multiple tumor types, but its utility is limited by the physical properties of 68Ga. We screened a library of >200 fluorine-containing structural derivatives of AMD-3465 to identify promising candidates for in vivo imaging of CXCR4 expression by positron emission tomography (PET). Compounds containing fluoroethyltriazoles consistently achieved higher docking scores. Six of these higher scoring compounds were radiolabeled by click chemistry and evaluated in PC3-CXCR4 cells and BALB/c mice bearing bilateral PC3-WT and PC3-CXCR4 xenograft tumors. The apparent CXCR4 affinity of the ligands was relatively low, but tumor uptake was CXCR4-specific. The tumor uptake of [18F]RPS-534 (7.2 ± 0.3 %ID/g) and [18F]RPS-547 (3.1 ± 0.5 %ID/g) at 1 h p.i. was highest, leading to high tumor-to-blood, tumor-to-muscle, and tumor-to-lung ratios. Total cell-associated activity better predicted in vivo tumor uptake than did the docking score or apparent CXCR4 affinity. By this metric, and on the basis of their high yielding radiosynthesis, high tumor uptake, and good contrast to background, [18F]RPS-547, and especially [18F]RPS-534, are promising 18F-labeled candidates for imaging CXCR4 expression.


Assuntos
Complexos de Coordenação/administração & dosagem , Imagem Molecular , Peptídeos Cíclicos/administração & dosagem , Compostos Radiofarmacêuticos/administração & dosagem , Receptores CXCR4/genética , Animais , Linhagem Celular Tumoral , Complexos de Coordenação/química , Radioisótopos de Flúor/química , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Ligantes , Camundongos , Peptídeos Cíclicos/química , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/química , Receptores CXCR4/química , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Drug Deliv Transl Res ; 9(3): 679-693, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30972664

RESUMO

The development of an effective and safe treatment for glioblastoma (GBM) represents a significant challenge in oncology today. Downregulation of key mediators of cell signal transduction by RNA interference is considered a promising treatment strategy but requires efficient, intracellular delivery of siRNA into GBM tumor cells. Here, we describe novel polymeric siRNA nanocarriers functionalized with cRGD peptide that mediates targeted and efficient reporter gene silencing in U87R invasive human GBM cells. The polymer was synthesized via RAFT copolymerization of N-(2-hydroxypropyl)-methacrylamide (HPMA) and N-acryloxysuccinimide (NAS), followed by post-polymerization modification with cholesterol for stabilization, cationic amines for siRNA complexation, and azides for copper-free click chemistry. The novel resultant cationic polymer harboring a terminal cholesterol group, self-assembled with siRNA to yield nanosized polyplexes (~ 40 nm) with good colloidal stability at physiological ionic strength. Post-modification of the preformed polyplexes with PEG-cRGD end-functionalized with bicyclo[6.1.0]nonyne (BCN) group resulted in enhanced cell uptake and increased luciferase gene silencing in U87R cells, compared to polyplexes lacking cRGD-targeting groups.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Colesterol/administração & dosagem , Glioblastoma/tratamento farmacológico , Nanopartículas/administração & dosagem , Peptídeos Cíclicos/administração & dosagem , RNA Interferente Pequeno/administração & dosagem , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Colesterol/química , Humanos , Luciferases/genética , Nanopartículas/química , Peptídeos Cíclicos/química , Polímeros/administração & dosagem , Polímeros/química , RNA Interferente Pequeno/química
11.
Nat Commun ; 10(1): 1735, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988291

RESUMO

Injectable biopolymer hydrogels have gained attention for use as scaffolds to promote cardiac function and prevent negative left ventricular (LV) remodeling post-myocardial infarction (MI). However, most hydrogels tested in preclinical studies are not candidates for minimally invasive catheter delivery due to excess material viscosity, rapid gelation times, and/or concerns regarding hemocompatibility and potential for embolism. We describe a platform technology for progelator materials formulated as sterically constrained cyclic peptides which flow freely for low resistance injection, and rapidly assemble into hydrogels when linearized by disease-associated enzymes. Their utility in vivo is demonstrated by their ability to flow through a syringe and gel at the site of MI in rat models. Additionally, synthetic functionalization enables these materials to flow through a cardiac injection catheter without clogging, without compromising hemocompatibility or cytotoxicity. These studies set the stage for the development of structurally dynamic biomaterials for therapeutic hydrogel delivery to the MI.


Assuntos
Hidrogéis/química , Infarto do Miocárdio/terapia , Peptídeos Cíclicos/química , Animais , Cateteres Cardíacos , Hidrogéis/administração & dosagem , Hidrogéis/uso terapêutico , Miocárdio/patologia , Peptídeos Cíclicos/administração & dosagem , Peptídeos Cíclicos/uso terapêutico , Ratos
12.
Gastroenterology ; 157(2): 481-491.e7, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31022403

RESUMO

BACKGROUND & AIMS: Polycystic liver disease is the most common extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). There is need for robust long-term evidence for the volume-reducing effect of somatostatin analogues. We made use of data from an open-label, randomized trial to determine the effects of lanreotide on height-adjusted liver volume (hTLV) and combined height-adjusted liver and kidney volume (hTLKV) in patients with ADPKD. METHODS: We performed a 120-week study comparing the reno-protective effects of lanreotide vs standard care in 305 patients with ADPKD (the DIPAK-1 study). For this analysis, we studied the 175 patients with polycystic liver disease with hepatic cysts identified by magnetic resonance imaging and liver volume ≥2000 mL. Of these, 93 patients were assigned to a group that received lanreotide (120 mg subcutaneously every 4 weeks) and 82 to a group that received standard care (blood pressure control, a sodium-restricted diet, and antihypertensive agents). The primary endpoint was percent change in hTLV between baseline and end of treatment (week 120). A secondary endpoint was change in hTLKV. RESULTS: At 120 weeks, hTLV decreased by 1.99% in the lanreotide group (95% confidence interval [CI], -4.21 to 0.24) and increased by 3.92% in the control group (95% CI, 1.56-6.28). Compared with the control group, lanreotide reduced the growth of hTLV by 5.91% (95% CI, -9.18 to -2.63; P < .001). Growth of hTLV was still reduced by 3.87% at 4 months after the last injection of lanreotide compared with baseline (95% CI, -7.55 to -0.18; P = .04). Lanreotide reduced growth of hTLKV by 7.18% compared with the control group (95% CI, -10.25 to -4.12; P < .001). CONCLUSIONS: In this subanalysis of a randomized trial of patients with polycystic liver disease due to ADPKD, lanreotide for 120 weeks reduced the growth of liver and combined liver and kidney volume. This effect was still present 4 months after the last injection of lanreotide. ClinicalTrials.gov, Number: NCT01616927.


Assuntos
Cistos/tratamento farmacológico , Rim/patologia , Hepatopatias/tratamento farmacológico , Fígado/patologia , Peptídeos Cíclicos/administração & dosagem , Rim Policístico Autossômico Dominante/tratamento farmacológico , Somatostatina/análogos & derivados , Adulto , Cistos/diagnóstico por imagem , Cistos/etiologia , Cistos/patologia , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Rim/diagnóstico por imagem , Rim/efeitos dos fármacos , Fígado/diagnóstico por imagem , Fígado/efeitos dos fármacos , Hepatopatias/diagnóstico por imagem , Hepatopatias/etiologia , Hepatopatias/patologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão/efeitos dos fármacos , Rim Policístico Autossômico Dominante/complicações , Rim Policístico Autossômico Dominante/diagnóstico por imagem , Somatostatina/administração & dosagem , Resultado do Tratamento
13.
Theranostics ; 9(4): 1047-1065, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30867815

RESUMO

Background: Platinum (II) (Pt(II))-based anticancer drugs dominate the chemotherapy field of ovarian cancer. However, the patient's quality of life has severely limited owing to dose-limiting toxicities and the advanced disease at the time of diagnosis. Multifunctional tumor-targeted nanosized ultrasound contrast agents (glutathione (GSH)-sensitive platinum (IV) (Pt(IV)) prodrug-loaded phase-transitional nanoparticles, Pt(IV) NP-cRGD) were developed for precise theranostics against ovarian cancer. Methods: Pt(IV) NP-cRGD were composed of a perfluorohexane (PFH) liquid core, a hybrid lipid-polymer shell with PLGA12k-PEG2k and DSPE-PEG1k-Pt(IV), and an active targeting ligand, the cRGD peptide (PLGA: poly(lactic-co-glycolic acid), PEG: polyethylene glycol, DSPE: 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, cRGD: cyclic Arg-Gly-Asp). Pt(IV), a popular alternative to Pt(II), was covalently attached to DSPE-PEG1k to form the prodrug, which fine-tuned lipophilicity and improved cellular uptake. The potential of Pt(IV) NP-cRGD as contrast agents for ultrasound (US) imaging was assessed in vitro and in vivo. Moreover, studies on the antitumor efficiency and antitumor mechanism of Pt(IV) NP-cRGD assisted by US were carried out. Results: Pt(IV) NP-cRGD exhibited strong echogenic signals and excellent echo persistence under an US field. In addition, the GSH-sensitive and US-triggered drug delivery system maximized the therapeutic effect while reducing the toxicity of chemotherapy. The mechanistic studies confirmed that Pt(IV) NP-cRGD with US consumed GSH and enhanced reactive oxy gen species (ROS) levels, which further causes mitochondria-mediated apoptosis. Conclusion: A multifunctional nanoplatform based on phase-transitional Pt(IV) NP-cRGD with US exhibited excellent echogenic signals, brilliant therapeutic efficacy and limited side effect, suggesting precise theranostics against ovarian cancer.


Assuntos
Antineoplásicos/administração & dosagem , Terapia de Alvo Molecular/métodos , Nanocompostos/administração & dosagem , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/tratamento farmacológico , Compostos de Platina/administração & dosagem , Ultrassonografia/métodos , Animais , Meios de Contraste/administração & dosagem , Modelos Animais de Doenças , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Feminino , Lipídeos/administração & dosagem , Camundongos Nus , Nanocompostos/química , Transplante de Neoplasias , Peptídeos Cíclicos/administração & dosagem , Polímeros/administração & dosagem , Pró-Fármacos/administração & dosagem , Nanomedicina Teranóstica/métodos , Transplante Heterólogo , Resultado do Tratamento
14.
Endocrinol Diabetes Nutr ; 66(5): 320-329, 2019 May.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-30773338

RESUMO

OBJECTIVES: The ACROSTART study was intended to determine the time to achieve normalization of GH and IGF-I levels in responding patients with acromegaly administered different dosage regimens of lanreotide Autogel (Somatuline® Autogel®). METHODS: From March 2013 to October 2013, clinical data from 57 patients from 17 Spanish hospitals with active acromegaly treated with lanreotide for ≥4 months who achieved hormonal control (GH levels <2.5ng/ml and/or normalized IGF-I levels in ≥2 measurements) were analyzed. The primary objective was to determine the time from start of lanreotide treatment to hormonal normalization. RESULTS: Median patient age was 64 years, 21 patients were male, 39 patients had undergone surgery, and 14 patients had received radiotherapy. Median hormonal values at start of lanreotide treatment were: GH, 2.6ng/ml; IGF-I, 1.6×ULN. The most common starting dose of lanreotide was 120mg (29 patients). The main initial regimens were 60mg/4 weeks (n=13), 90mg/4 weeks (n=6), 120mg/4 weeks (n=13), 120mg/6 weeks (n=6), and 120mg/8 weeks (n=9). An initial treatment regimen with a long interval (≥6 weeks) was administered in 25 patients. Mean duration of lanreotide treatment was 68 months (7-205). Median time to achieve hormonal control was 4.9 months. Injections were managed without healthcare assistance in 13 patients. Median number of visits to endocrinologists until hormonal control was achieved was 3. Fifty-one patients were "satisfied"/"very satisfied" with treatment and 49 patients did not miss any dose. CONCLUSIONS: Real-life treatment with lanreotide Autogel resulted in early hormonal control in responding patients, with high treatment adherence and satisfaction despite disparity in starting doses and dosing intervals.


Assuntos
Acromegalia/sangue , Acromegalia/tratamento farmacológico , Hormônio do Crescimento Humano/sangue , Fator de Crescimento Insulin-Like I/análise , Peptídeos Cíclicos/administração & dosagem , Somatostatina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Esquema de Medicação , Feminino , Géis , Humanos , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Valores de Referência , Estudos Retrospectivos , Somatostatina/administração & dosagem , Fatores de Tempo , Adulto Jovem
15.
Eur J Pharm Biopharm ; 136: 138-146, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30660694

RESUMO

An ideal cancer therapy targets the tumor cells selectively without damaging healthy tissues. Even though the tumor-specific markers are limited, these molecules can be used for the delivery of anti-cancer drugs as an active targeting strategy. Since the lymphatic system plays a critical role in the dissemination of cancer cells, the drugs directed through lymphatics can feasibly reach to the sites of metastasis. LyP-1 is a peptide that binds to the p32 receptor which is highly expressed not only on the lymphatic endothelium but also on the malignant cells; thus, making this peptide ligand a preferable candidate to mediate active targeting of lymphatics and cancer cells. In this study, different formulations of LyP-1 containing lipid-based nanopharmaceutics so-called self-microemulsifying drug delivery systems (SMEDDS) were developed and tested for their efficacy in targeting breast cancer. Following the selection of non-toxic formulation, doxorubicin hydrochloride and LyP-1 were co-administered in the SMEDDS, which resulted in a significant increase in in vitro cytotoxicity in p32-expressing breast cancer cells, 4T1 and MDA-MB-231. Accordingly, the uptake of LyP-1 in the SMEDDS by the cancer cells was demonstrated. The expression of p32 was detected in the 4T1 tumor tissues which were efficiently targeted with LyP-1 in the SMEDDS. When doxorubicin was co-administrated with LyP-1 in SMEDDS via intraperitonial administration, tumor growth and metastasis were significantly reduced. In conclusion, a novel and efficacious SMEDDS formulation containing LyP-1 with a droplet size less than 100 nm was developed for the lymphatic targeting of breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Emulsificantes/farmacocinética , Microesferas , Peptídeos Cíclicos/farmacocinética , Animais , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Emulsificantes/administração & dosagem , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Peptídeos Cíclicos/administração & dosagem
16.
Invest New Drugs ; 37(3): 573-578, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30267338

RESUMO

Neuroendocrine tumors (NET) are rare tumors for which somatostatin analogs (SSA) are used not only for symptom control due to a functioning tumor, but also for the disease control of unresectable NET. The efficacy of SSA for midgut NET has been verified by previous studies, but insufficient evidence exists for SSA treatment of NET in the foregut and hindgut (F/H-NET). The aim of this retrospective study was to evaluate the efficacy of SSA for unresectable F/H-NET. Patients with unresectable F/H-NET treated with SSA between February 2011 and August 2017 at our hospital were retrospectively reviewed. Parameters of efficacy were progression-free survival (PFS), overall survival, objective response rate (ORR), and adverse events. Twelve cases with unresectable F/H-NET were extracted from our database. With a median follow-up time of 25.9 months, the median PFS was 13.6 months. Two- and 3-year survival rates were 87.5 and 62.5%, respectively. The ORR was 8.3%, and the disease control rate was 75%. Serious adverse events were not observed. Subgroup analysis, including G1/G2, and hepatic tumor load, which is the volume of NET liver metastases, did not reveal a difference in PFS. The efficacy and safety of SSA for F/H-NET seemed similar to that found in the PROMID study, highlighting its relevance for the treatment of this disease.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/mortalidade , Neoplasias Gastrointestinais/mortalidade , Neoplasias Hepáticas/mortalidade , Neoplasias Pulmonares/mortalidade , Tumores Neuroendócrinos/mortalidade , Idoso , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Feminino , Seguimentos , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/patologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Masculino , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/patologia , Octreotida/administração & dosagem , Peptídeos Cíclicos/administração & dosagem , Prognóstico , Estudos Retrospectivos , Somatostatina/administração & dosagem , Somatostatina/análogos & derivados , Taxa de Sobrevida
17.
Horm Res Paediatr ; 91(1): 56-61, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30114684

RESUMO

BACKGROUND: A long-acting somatostatin analogue (lanreotide) is used in the management of a diazoxide-unresponsive diffuse form of congenital hyperinsulinism (CHI). However, no reports of its use in patients with the focal form of CHI exist. Case 1: A 1-month-old boy diagnosed with diazoxide-unresponsive CHI due to a paternal heterozygous ABCC8 gene mutation showed partial response to octreotide. 18F-DOPA-PET/CT scan revealed a focal lesion in the pancreatic head. Surgical removal of the lesion was unsuccessful. He was switched to monthly lanreotide treatment at the age of 11 months, which stabilised his blood glucose over a 12-month period. Case 2: A 1-month-old boy with diazoxide-unresponsive CHI due to a paternal heterozygous KCNJ11 gene mutation was partially responsive to octreotide. 18F-DOPA-PET/CT scan confirmed a focal pancreatic head lesion. Over 6 months, he underwent 3 lesionectomies and afterwards responded to octreotide. At the age of 9 months, treatment was switched to monthly lanreotide. Currently, he is aged 3, with stable glycaemia, and improved fasting tolerance. Case 3: A 3-week-old girl with a paternal heterozygous ABCC8 gene mutation was unresponsive to diazoxide. 18F-DOPA-PET/CT scan confirmed a focal pancreatic head lesion. She responded to octreotide, and her parents preferred to avoid pancreatic surgery. At the age of 20 months, treatment was switched to monthly lanreotide, resulting in euglycaemia over the last 7 months. CONCLUSION: CHI patients with focal pancreatic head lesions are challenging, especially if not surgically amenable. Conservative treatment is preferable, and lanreotide might be an option. The therapeutic impact of lanreotide treatment in patients with the focal forms of CHI should be confirmed in prospective studies with close monitoring of the side effects.


Assuntos
Hiperinsulinismo Congênito/diagnóstico por imagem , Hiperinsulinismo Congênito/tratamento farmacológico , Peptídeos Cíclicos/administração & dosagem , Tomografia por Emissão de Pósitrons , Somatostatina/análogos & derivados , Tomografia Computadorizada por Raios X , Hiperinsulinismo Congênito/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pancreatopatias/induzido quimicamente , Pancreatopatias/diagnóstico por imagem , Pancreatopatias/terapia , Peptídeos Cíclicos/efeitos adversos , Canais de Potássio Corretores do Fluxo de Internalização/genética , Somatostatina/administração & dosagem , Somatostatina/efeitos adversos , Receptores Sulfonilureia/genética
18.
Drug Dev Ind Pharm ; 45(1): 88-95, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30198790

RESUMO

Lumbrokinase (LK) has strong fibrinolytic and thrombolytic activities, but it has a short half-life, can be easily inactivated, and may cause hemorrhage as a side effect. This study develops a potential thrombolytic therapy by fabricating N,N,N-Trimethyl Chitosan (TMC) nanoparticles modified with the cyclic Arg-Gly-Asp-Phe-Lys peptide (c-RGD) and loaded with LK (i.e. c-RGD-LK-NPs). The binding of c-RGD to platelet membrane GPIIb/IIIa receptors is expected to enable targeted delivery of the c-RGD-conjugated TMC to the thrombus. The synthesized c-RGD-LK-NPs had a mean particle size of 232.0 nm, zeta potential of 19.8 mV, entrapment efficiency of 52.7% ± 2.5%, and loading efficiency of 17.4% ± 0.65%. Transmission electron microscopy showed that they were generally spherical. The c-RGD-LK-NPs gave a cumulative in vitro LK release of 80.6% over 8 h, and the activity of LK was close to 80%, indicating that the nanoparticles protected the activity of LK. In vitro blood clot lysis assays were carried out and in vivo thrombolysis effect was tested in Sprague-Dawley rats carotid artery thrombus model. In all cases, the c-RGD-LK-NPs showed superior performance compared with the free LK and the unmodified TMC nanoparticles loaded with LK. The c-RGD-LK-NPs reagent is expected to be potentially useful in treating thromboembolic diseases.


Assuntos
Quitosana/administração & dosagem , Portadores de Fármacos/administração & dosagem , Endopeptidases/administração & dosagem , Nanopartículas/administração & dosagem , Peptídeos Cíclicos/administração & dosagem , Animais , Trombose das Artérias Carótidas/tratamento farmacológico , Trombose das Artérias Carótidas/metabolismo , Quitosana/síntese química , Quitosana/metabolismo , Portadores de Fármacos/síntese química , Portadores de Fármacos/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Endopeptidases/síntese química , Endopeptidases/metabolismo , Fibrinolíticos/administração & dosagem , Fibrinolíticos/síntese química , Fibrinolíticos/metabolismo , Nanopartículas/química , Nanopartículas/metabolismo , Peptídeos Cíclicos/química , Peptídeos Cíclicos/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
19.
Expert Opin Drug Saf ; 18(1): 1-10, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30582380

RESUMO

INTRODUCTION: Lanreotide autogel is a synthetic somatostatin analogue which has been FDA and EMA approved for unresectable, well to moderately differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumor. Its action is mediated by its affinity to somatostatin receptors, especially sst2 and sst5 receptors. Its longer half-life offers the convenience of 4-week dosing over the need for frequent injections of short-acting somatostatin analogues. Areas covered: Lanreotide ATG offers progression-free survival benefit in locally advanced or metastatic neuroendocrine tumor (NET) compared to placebo, reflecting a strong antiproliferative signal. As lanreotide is commonly used for management of NET, it is imperative to recognize and appropriately manage any drug-related toxicities. In this review, we will provide an overview of the toxicity with lanreotide and its management. Expert opinion: Lanreotide is highly effective in managing carcinoid symptoms and has a robust anti-tumor effect in NET. Overall, it is well tolerated with low rates of treatment discontinuation due to toxicity. It's toxicity profile is mostly predictable, and patients should be informed of the transient nature of some of the upfront toxicities.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Intestinais/tratamento farmacológico , Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Peptídeos Cíclicos/administração & dosagem , Somatostatina/análogos & derivados , Neoplasias Gástricas/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Intervalo Livre de Doença , Humanos , Neoplasias Intestinais/patologia , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Peptídeos Cíclicos/efeitos adversos , Peptídeos Cíclicos/farmacologia , Somatostatina/administração & dosagem , Somatostatina/efeitos adversos , Somatostatina/farmacologia , Neoplasias Gástricas/patologia
20.
Res Microbiol ; 170(2): 74-79, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30447257

RESUMO

Abnormal blood vessels and hypoxic and necrotic regions are common features of solid tumors and related to the malignant phenotype and therapy resistance. Certain obligate or facultative anaerobic bacteria exhibit inherent ability to colonize and proliferate within solid tumors in vivo. Escherichia coli Nissle 1917 (EcN), a non-pathogenic probiotic in European markets, has been known to proliferate selectively in the interface between the viable and necrotic regions of solid tumors. The objective of this study was to establish a tumor-targeting therapy system using the genetically engineered EcN for targeted delivery of cytotoxic compounds, including colibactin, glidobactin and luminmide. Biosynthetic gene clusters of these cytotoxic compounds were introduced into EcN and the corresponding compounds were detected in the resultant recombinant EcN strains. The recombinant EcN showed significant cytotoxic activity in vitro and in vivo as well, and significantly suppressed the tumor growth. Together, this study confirmed efficient tumor-targeting colonization of EcN and demonstrated its potentiality in the tumor-specific delivery of cytotoxic compounds as a new tumor-targeting therapy system.


Assuntos
Sistemas de Liberação de Medicamentos , Proteínas de Escherichia coli/farmacologia , Escherichia coli/genética , Engenharia Genética/métodos , Neoplasias/terapia , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Nus , Família Multigênica , Peptídeos/administração & dosagem , Peptídeos Cíclicos/administração & dosagem , Policetídeos/administração & dosagem , Probióticos , Proteínas Recombinantes/administração & dosagem
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