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2.
Respir Physiol Neurobiol ; 288: 103645, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33657448

RESUMO

Several pre-clinical and clinical trials show that exogenous pulmonary surfactant has clinical efficacy in inflammatory lung diseases, especially ARDS. By infecting type II alveolar cells, COVID-19 interferes with the production and secretion of the pulmonary surfactant and therefore causes an increase in surface tension, which in turn can lead to alveolar collapse. The use of the pulmonary surfactant seems to be promising as an additional therapy for the treatment of ARDS. COVID-19 causes lung damage and ARDS, so beneficial effects of surfactant therapy in COVID-19-associated ARDS patients are conceivable, especially when applied early in the treatment strategy against pulmonary failure. Because of the robust anti-inflammatory and lung protective efficacy and the current urgent need for lung-supportive therapy, the exogenous pulmonary surfactant could be a valid supportive treatment of COVID-19 pneumonia patients in intensive care units in addition to the current standard of ARDS treatment.


Assuntos
/tratamento farmacológico , Surfactantes Pulmonares/uso terapêutico , /tratamento farmacológico , Administração por Inalação , Produtos Biológicos/uso terapêutico , Humanos , Peptídeos Cíclicos/uso terapêutico , Fosfolipídeos/uso terapêutico , /fisiopatologia
3.
J Med Chem ; 64(4): 2110-2124, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33538583

RESUMO

Neurotensin (NT) receptor type 2 (NTS2) represents an attractive target for the development of new NT-based analgesics. Here, we report the synthesis and functional in vivo characterization of the first constrained NTS2-selective macrocyclic NT analog. While most chemical optimization studies rely on the NT(8-13) fragment, we focused on NT(7-12) as a scaffold to design NTS2-selective macrocyclic peptides. Replacement of Ile12 by Leu, and Pro7/Pro10 by allylglycine residues followed by cyclization via ring-closing metathesis led to macrocycle 4, which exhibits good affinity for NTS2 (50 nM), high selectivity over NTS1 (>100 µM), and improved stability compared to NT(8-13). In vivo profiling in rats reveals that macrocycle 4 produces potent analgesia in three distinct rodent pain models, without causing the undesired effects associated with NTS1 activation. We further provide evidence of its non-opioid antinociceptive activity, therefore highlighting the strong therapeutic potential of NTS2-selective analogs for the management of acute and chronic pain.


Assuntos
Analgésicos/uso terapêutico , Neurotensina/análogos & derivados , Neurotensina/uso terapêutico , Dor/tratamento farmacológico , Peptídeos Cíclicos/uso terapêutico , Receptores de Neurotensina/metabolismo , Analgésicos/síntese química , Animais , Desenho de Fármacos , Masculino , Estrutura Molecular , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/uso terapêutico , Peptídeos Cíclicos/síntese química , Ratos Sprague-Dawley , Relação Estrutura-Atividade
4.
J Med Chem ; 64(4): 2064-2076, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33577327

RESUMO

A facile procedure for in situ peptide cyclization and phthalocyanine conjugation was developed by utilizing a bifunctional linker incorporated with a bis(bromomethyl)benzene unit and a cyclopentadiene moiety. These functional groups facilitated the nucleophilic substitution with the two cysteine residues of the linear peptides followed by the Diels-Alder reaction with the maleimide moiety attached to a zinc(II) phthalocyanine. With this approach, three cyclic peptide-phthalocyanine conjugates were prepared in 20-26% isolated yield via a one-pot procedure. One of the conjugates containing a cyclic form of the epidermal growth factor receptor (EGFR)-binding peptide sequence CMYIEALDKYAC displayed superior features as an advanced photosensitizer. It showed preferential uptake by two EGFR-positive cancer cell lines (HT29 and HCT116) compared with two EGFR-negative counterparts (HeLa and HEK293), resulting in significantly higher photocytotoxicity. Intravenous administration of this conjugate into HT29 tumor-bearing nude mice resulted in selective localization in tumor and effective inhibition of tumor growth upon photodynamic treatment.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Receptores ErbB/metabolismo , Indóis/uso terapêutico , Peptídeos Cíclicos/uso terapêutico , Fármacos Fotossensibilizantes/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/efeitos da radiação , Linhagem Celular Tumoral , Neoplasias do Colo/metabolismo , Feminino , Células HEK293 , Humanos , Indóis/síntese química , Indóis/metabolismo , Indóis/efeitos da radiação , Luz , Camundongos Endogâmicos BALB C , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/metabolismo , Peptídeos Cíclicos/efeitos da radiação , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/metabolismo , Fármacos Fotossensibilizantes/efeitos da radiação , Medicina de Precisão
5.
Cancer Imaging ; 21(1): 22, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33579381

RESUMO

BACKGROUND: Expression of CXCR4, a chemokine (C-X-C motif) receptor that plays a central role in tumor growth and metastasis of circulating tumor cells, has been described in a variety of solid tumors. A high expression of CXCR4 has a prognostic significance with regard to overall and progression-free survival and offers a starting point for targeted therapies. In this context, [68]Ga-Pentixafor-Positron Emission Tomography/Computer Tomography (PET/CT) offers promising possibility of imaging the CXCR4 expression profile. We set out to compare a [18F] fluorodeoxyglucose (FDG)-PET/CT and a [68Ga]Pentixafor-PET/CT in (re-)staging and radiation planning of patients with localized esophageal cancer. MATERIALS AND METHODS: In this retrospective analysis, ten patients, with adeno- or squamous cell carcinoma of the esophagus (n = 3 and n = 7, respectively), which were scheduled for radio (chemo) therapy, were imaged using both Pentixafor and FDG PET/CT examinations. All lesions were visually rated as Pentixafor and FDG positive or negative. For both tracers, SUVmax was measured all lesions and compared to background. Additionally, immunohistochemistry of CXCR4 was obtained in patients undergoing surgery. RESULTS: FDG-positive tumor-suspicious lesions were detected in all patients and a total of 26 lesions were counted. The lesion-based analysis brought equal status in 14 lesions which were positive for both tracers while five lesions were FDG positive and Pentixafor negative and seven lesions were FDG negative, but Pentixafor positive. Histopathologic correlation was available in seven patients. The CXCR4 expression of four non-pretreated tumour lesion samples was confirmed immunohistochemically. CONCLUSION: Our data shows that additional PET/CT imaging with Pentixafor for imaging the CXCR4 chemokine receptor is feasible but heterogeneous in both newly diagnosed and pretreated recurrent esophageal cancer. In addition, the Pentixafor PET/CT may serve as complementary tool for radiation field expansion in radiooncology.


Assuntos
Complexos de Coordenação/uso terapêutico , Neoplasias Esofágicas/diagnóstico por imagem , Fluordesoxiglucose F18/uso terapêutico , Imagem Molecular/métodos , Peptídeos Cíclicos/uso terapêutico , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Receptores CXCR4/metabolismo , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
6.
Artigo em Inglês | MEDLINE | ID: mdl-33558296

RESUMO

Finding antivirals to reduce coronavirus disease 2019 (COVID-19) morbidity and mortality has been challenging. Large randomized clinical trials that aimed to test four repurposed drugs, hydroxychloroquine, lopinavir-ritonavir, interferon beta 1a, and remdesivir, have shown that these compounds lack an impact on the COVID-19 course. Although the phase III COVID-19 vaccine trial results are encouraging, the search for effective COVID-19 therapeutics should not stop. Recently, plitidepsin (aplidin) demonstrated highly effective preclinical activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Its antiviral activity was 27.5-fold more potent than that of remdesivir (K. M. White, R. Rosales, S. Yildiz, T. Kehrer, et al., Science, 2021, https://science.sciencemag.org/content/early/2021/01/22/science.abf4058). Plitidepsin, a repurposed drug developed for the treatment of multiple myeloma, targets the host translation cofactor eEF1A. Plitidepsin has shown efficacy in animal models and phase I/II human trials. Although plitidepsin is administered intravenously and its toxicity profile remains to be fully characterized, this compound may be a promising alternative COVID-19 therapeutic.


Assuntos
Antivirais/uso terapêutico , Depsipeptídeos/uso terapêutico , Peptídeos Cíclicos/uso terapêutico , Animais , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Humanos , /efeitos dos fármacos
7.
Arch Biochem Biophys ; 701: 108776, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33515532

RESUMO

Cancer is a global health issue that origins thousands of deaths annually worldwide. Cyclic peptides are polypeptide chains which are formed by cyclic sequence of amide bonds between proteinogenic or non-proteinogenic amino acids. Numerous evidences indicate that cyclic peptides are implicated with the occurrence and development of cancer. This review presents the current knowledge about the role of cyclic peptides in cancer, such as liver cancer, colorectal cancer, ovarian cancer, breast cancer as well as prostate cancer. Specifically, the precise molecular mechanisms between cyclic peptides and cancer are elaborated. Some cyclic peptides from nature and synthesis prevent the occurrence and development of cancer. However, some other cyclic peptides including endothelin-1, urotensinⅡand melanin-concentrating hormone deteriorate the pathogenesis of cancer. Given the pleiotropic actions of cyclic peptides, the identification and development of cyclic peptides and their derivates as drug may be a potent therapeutic strategy for cancer.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Peptídeos Cíclicos/uso terapêutico , Antineoplásicos/química , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Peptídeos Cíclicos/química
8.
Clin Immunol ; 220: 108598, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32961333

RESUMO

Growing clinical evidence has implicated complement as a pivotal driver of COVID-19 immunopathology. Deregulated complement activation may fuel cytokine-driven hyper-inflammation, thrombotic microangiopathy and NET-driven immunothrombosis, thereby leading to multi-organ failure. Complement therapeutics have gained traction as candidate drugs for countering the detrimental consequences of SARS-CoV-2 infection. Whether blockade of terminal complement effectors (C5, C5a, or C5aR1) may elicit similar outcomes to upstream intervention at the level of C3 remains debated. Here we compare the efficacy of the C5-targeting monoclonal antibody eculizumab with that of the compstatin-based C3-targeted drug candidate AMY-101 in small independent cohorts of severe COVID-19 patients. Our exploratory study indicates that therapeutic complement inhibition abrogates COVID-19 hyper-inflammation. Both C3 and C5 inhibitors elicit a robust anti-inflammatory response, reflected by a steep decline in C-reactive protein and IL-6 levels, marked lung function improvement, and resolution of SARS-CoV-2-associated acute respiratory distress syndrome (ARDS). C3 inhibition afforded broader therapeutic control in COVID-19 patients by attenuating both C3a and sC5b-9 generation and preventing FB consumption. This broader inhibitory profile was associated with a more robust decline of neutrophil counts, attenuated neutrophil extracellular trap (NET) release, faster serum LDH decline, and more prominent lymphocyte recovery. These early clinical results offer important insights into the differential mechanistic basis and underlying biology of C3 and C5 inhibition in COVID-19 and point to a broader pathogenic involvement of C3-mediated pathways in thromboinflammation. They also support the evaluation of these complement-targeting agents as COVID-19 therapeutics in large prospective trials.


Assuntos
Betacoronavirus/patogenicidade , Complemento C3/antagonistas & inibidores , Complemento C5/antagonistas & inibidores , Inativadores do Complemento/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Pneumonia Viral/tratamento farmacológico , /tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Estudos de Coortes , Ativação do Complemento/efeitos dos fármacos , Complemento C3/genética , Complemento C3/imunologia , Complemento C5/genética , Complemento C5/imunologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Armadilhas Extracelulares/efeitos dos fármacos , Feminino , Expressão Gênica , Humanos , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/virologia , Pandemias , Peptídeos Cíclicos/uso terapêutico , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , /imunologia , Índice de Gravidade de Doença
9.
Clin Immunol ; 215: 108450, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32360516

RESUMO

Acute respiratory distress syndrome (ARDS) is a devastating clinical manifestation of COVID-19 pneumonia and is mainly based on an immune-driven pathology. Mounting evidence suggests that COVID-19 is fueled by a maladaptive host inflammatory response that involves excessive activation of innate immune pathways. While a "cytokine storm" involving IL-6 and other cytokines has been documented, complement C3 activation has been implicated as an initial effector mechanism that exacerbates lung injury in preclinical models of SARS-CoV infection. C3-targeted intervention may provide broader therapeutic control of complement-mediated inflammatory damage in COVID-19 patients. Herein, we report the clinical course of a patient with severe ARDS due to COVID-19 pneumonia who was safely and successfully treated with the compstatin-based complement C3 inhibitor AMY-101.


Assuntos
Betacoronavirus/efeitos dos fármacos , Ativação do Complemento/efeitos dos fármacos , Complemento C3/antagonistas & inibidores , Inativadores do Complemento/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Peptídeos Cíclicos/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Idoso , Antivirais/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/imunologia , Fibrilação Atrial/patologia , Fibrilação Atrial/virologia , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Humanos , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/imunologia , Hipercolesterolemia/patologia , Hipercolesterolemia/virologia , Hipertensão/tratamento farmacológico , Hipertensão/imunologia , Hipertensão/patologia , Hipertensão/virologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Masculino , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Resultado do Tratamento
10.
Eur J Endocrinol ; 183(1): G17-G23, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32369770

RESUMO

Patients with pituitary tumours, ensuing hormonal abnormalities and mass effects are usually followed in multidisciplinary pituitary clinics and can represent a management challenge even during the times of non-pandemic. The COVID-19 pandemic has put on hold routine medical care for hundreds of millions of patients around the globe, while many pituitary patients' evaluations cannot be delayed for too long. Furthermore, the majority of patients with pituitary tumours have co-morbidities potentially impacting the course and management of COVID-19 (e.g. hypopituitarism, diabetes mellitus, hypertension, obesity and cardiovascular disease). Here, we summarize some of the diagnostic and management dilemmas encountered, and provide guidance on safe and as effective as possible delivery of care in the COVID-19 era. We also attempt to address how pituitary services should be remodelled in the event of similar crises, while maintaining or even improving patient outcomes. Regular review of these recommendations and further adjustments are needed, depending on the evolution of the COVID-19 pandemic status. We consider that the utilization of successful models of pituitary multidisciplinary care implemented during the COVID-19 pandemic should continue after the crisis is over by using the valuable and exceptional experience gained during these challenging times.


Assuntos
Adenoma/terapia , Antineoplásicos Hormonais/uso terapêutico , Infecções por Coronavirus , Agonistas de Dopamina/uso terapêutico , Procedimentos Neurocirúrgicos , Pandemias , Apoplexia Hipofisária/terapia , Neoplasias Hipofisárias/terapia , Pneumonia Viral , Adenoma/diagnóstico , Cabergolina/uso terapêutico , Gerenciamento Clínico , Terapia de Reposição Hormonal , Hormônio do Crescimento Humano/análogos & derivados , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Octreotida/uso terapêutico , Peptídeos Cíclicos/uso terapêutico , Apoplexia Hipofisária/diagnóstico , Neoplasias Hipofisárias/diagnóstico , Guias de Prática Clínica como Assunto , Radioterapia , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Telemedicina , Fatores de Tempo , Testes de Campo Visual
12.
Eur J Endocrinol ; 182(6): 583, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32217809

RESUMO

Objective: In the Phase III PAOLA study (clinicaltrials.gov: NCT01137682), enrolled patients had uncontrolled acromegaly despite ≥6 months of octreotide/lanreotide treatment before study start. More patients achieved biochemical control with long-acting pasireotide versus continued treatment with octreotide/lanreotide (active control) at month 6. The current work assessed the extent of comorbidities at baseline and outcomes during a long-term extension. Design/methods: Patients receiving pasireotide 40 or 60 mg at core study end could continue on the same dose in an extension phase if biochemically controlled or receive pasireotide 60 mg if uncontrolled. Uncontrolled patients on active control were switched to pasireotide 40 mg, with the dose increased at week 16 of the extension if still uncontrolled (crossover group). Efficacy and safety are reported to 304 weeks (~5.8 years) for patients randomized to pasireotide (core + extension), and 268 weeks for patients in the crossover group (extension only). Results: Almost half (49.5%; 98/198) of patients had ≥3 comorbidities at core baseline. During the extension, 173 patients received pasireotide. Pasireotide effectively and consistently reduced GH and IGF-I levels for up to 5.8 years' treatment; 37.0% of patients achieved GH <1.0 µg/L and normal IGF-I at some point during the core or extension. Improvements were observed in key symptoms. The long-term safety profile was similar to that in the core study; 23/173 patients discontinued treatment because of adverse events. Conclusions: In this patient population with a high burden of comorbid illness, pasireotide was well tolerated and efficacious, providing prolonged maintenance of biochemical control and improving symptoms.


Assuntos
Acromegalia/tratamento farmacológico , Hormônios/administração & dosagem , Somatostatina/análogos & derivados , Fatores de Tempo , Acromegalia/sangue , Adulto , Estudos Cross-Over , Esquema de Medicação , Feminino , Hormônio do Crescimento Humano/sangue , Humanos , Fator de Crescimento Insulin-Like I/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Octreotida/uso terapêutico , Peptídeos Cíclicos/uso terapêutico , Estudos Prospectivos , Somatostatina/administração & dosagem , Somatostatina/uso terapêutico , Resultado do Tratamento
13.
Molecules ; 25(3)2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31979296

RESUMO

Pantoea dispersa W18, isolated from contaminated soil, was found to exert antimicrobial activity against Mycobacterium species, including Mycobacterium tuberculosis, an important human pathogen. Here, the anti-mycobacterial compound produced by Pantoea dispersa W18 was purified by a combination of hydrophobic interaction chromatography, cation exchange chromatography, and reverse phase HPLC. Active compounds from Pantoea dispersa W18 were identified as a natural peptide named pantocin wh-1 with a 1927 Da molecular weight. The primary structure of this compound was detected by N-terminal amino acid sequencing. The amino acid sequence of pantocin wh-1 consisted of 16 amino acid residues with a cyclic structure. The pantocin wh-1 could be inactivated by protease K, but was heat stable and unaffected by pH (2-12). However, the activity was not completely inactivated by trypsin and pepsin. This is the first report of a cyclic polypeptide purified from a strain of Pantoea dispersa.


Assuntos
Antituberculosos/isolamento & purificação , Antituberculosos/uso terapêutico , Mycobacterium tuberculosis/efeitos dos fármacos , Pantoea/química , Tuberculose/tratamento farmacológico , Sequência de Aminoácidos , Animais , Antituberculosos/química , Antituberculosos/metabolismo , Cromatografia Líquida de Alta Pressão , Cromatografia por Troca Iônica , Feminino , Temperatura Alta , Concentração de Íons de Hidrogênio , Klebsiella/efeitos dos fármacos , Listeria monocytogenes/efeitos dos fármacos , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos BALB C , Peso Molecular , Mycobacterium smegmatis/efeitos dos fármacos , Pantoea/metabolismo , Peptídeos Cíclicos/química , Peptídeos Cíclicos/isolamento & purificação , Peptídeos Cíclicos/metabolismo , Peptídeos Cíclicos/uso terapêutico , Streptococcus suis/efeitos dos fármacos
14.
Ann Pharmacother ; 54(7): 684-690, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31893927

RESUMO

Objective: To review data regarding bremelanotide, a recently approved therapy for hypoactive sexual desire disorder (HSDD). Data Sources: Literature search of Medline, SCOPUS, and EMBASE was performed using the search terms bremelanotide, bremelanotide injection, Vyleesi, and melanocortin 4 receptor agonist between January 1, 1996, and December 15, 2019. Reference lists from included articles were also reviewed for pertinent citations. Study Selection/Data Extraction: We included phase 2 and 3 trials of bremelanotide. There were 2 reports of phase 3 trials and 2 reports of phase 2 trials. Additional information from supplementary analyses was also referenced. Data Synthesis: Bremelanotide demonstrates significant improvement in desire and a significant decrease in distress related to lack of desire. The most common adverse effects include nausea (39.9%), facial flushing (20.4%), and headache (11%). Relevance to Patient Care and Clinical Practice: Bremelanotide is the second Food and Drug Administration-approved medication for the treatment of HSDD. Bremelanotide's place in therapy is unknown, as the HSDD guidelines were last updated in 2017. Although the trials met statistical significance for change in sexual desire elements and distress related to sexual desire, the clinical benefit may only be modest. Conclusion: Bremelanotide is a subcutaneous injection that can be administered as needed approximately 45 minutes prior to sexual activity. Bremelanotide is safe and has limited drug-drug interactions, including no clinically significant interactions with ethanol. Prescribing guidelines recommend no more than 1 dose in 24 hours and no more than 8 doses per month. Individuals should discontinue use after 8 weeks without benefit.


Assuntos
Libido/efeitos dos fármacos , Peptídeos Cíclicos/uso terapêutico , Disfunções Sexuais Psicogênicas/tratamento farmacológico , alfa-MSH/uso terapêutico , Ensaios Clínicos como Assunto , Interações Medicamentosas , Feminino , Humanos , Injeções Subcutâneas , Náusea/induzido quimicamente , Peptídeos Cíclicos/administração & dosagem , Peptídeos Cíclicos/efeitos adversos , Peptídeos Cíclicos/farmacocinética , Receptor Tipo 3 de Melanocortina/agonistas , Receptor Tipo 4 de Melanocortina/agonistas , Resultado do Tratamento , alfa-MSH/administração & dosagem , alfa-MSH/efeitos adversos , alfa-MSH/farmacocinética
15.
J Med Chem ; 63(5): 2673-2687, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-31834798

RESUMO

Four novel fluorinated cyclic analogues of biphalin with excellent to modest binding affinity for µ-, δ-, and κ-receptors were synthesized. The cyclic peptides have a combination of piperazine or hydrazine linker with or without a xylene bridge. Among the ligands, MACE3 demonstrated a better activity than biphalin after intravenous administration, and its corresponding analogue incorporating the hydrazine linker (MACE2) was able to induce longer lasting analgesia following subcutaneous administration. An analogue of MACE2 containing 2,6-dimethyl-l-tyrosine (MACE4) showed the best potency and in vivo antinociceptive activity of this series.


Assuntos
Analgésicos Opioides/uso terapêutico , Peptídeos Opioides/uso terapêutico , Dor/tratamento farmacológico , Peptídeos Cíclicos/uso terapêutico , Administração Intravenosa , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/farmacologia , Animais , Células CHO , Cricetulus , Feminino , Humanos , Infusões Subcutâneas , Masculino , Camundongos , Modelos Moleculares , Peptídeos Opioides/administração & dosagem , Peptídeos Opioides/farmacocinética , Peptídeos Opioides/farmacologia , Dor/metabolismo , Peptídeos Cíclicos/administração & dosagem , Peptídeos Cíclicos/farmacocinética , Peptídeos Cíclicos/farmacologia , Receptores Opioides/metabolismo
16.
Eur J Pharm Sci ; 143: 105201, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31866565

RESUMO

The YSNSG peptide is a synthetic cyclopeptide targeting αvß3 integrin with antitumor activity. Previous study has determined main pharmacokinetic parameters in plasma and in tissue in healthy animals using microdialysis. First we aim to assess the impact of a 20 mg/kg dosage instead of 10 mg/kg in tumor growth inhibition. Secondly we aim to investigate the YSNSG peptide distribution in two different tumor regions in animals with melanoma. C57BL/6 mice were exposed at Days 8, 10 and 12 after melanoma cells implantation (B16F1) to different dosage of YSNSG peptide or control, respectively (n = 10 per group). Data analysis was performed at D16, 20 and 24 with a Nonlinear Mixed-Effects (NLME) approach. For pharmacokinetic study n = 8 mice (same disease condition) received YSNSG peptide by intravenous after insertion of two microdialysis probes in central peripheral region of tumor, respectively. Plasma and tissue samples were collected during 2 h. A non-compartmental analysis was performed to determine main pharmacokinetic parameters. There was a significant tumor growth inhibition in mice receiving 20 mg/kg vs Control (p < 0.02). Main plasma parameters were half-life elimination 25.8 ± 8.2 min, volume of distribution 11.9 ± 0.4 mL, clearance 19.8 ± 9.4 mL/h and area under the curve 1,173.6 µg.min/mL. Penetration rate of the YSNSG peptide from plasma to tumor tissue were 3.3 ± 2.1% and 3.4 ± 2.7% in central and peripheral, respectively. Contrary to subcutaneous distribution in healthy animals the distribution of the YSNSG peptide into tumoral tissue is low but seems non-heterogeneous between central and peripheral tumor region.


Assuntos
Antineoplásicos/farmacocinética , Melanoma/metabolismo , Peptídeos Cíclicos/farmacocinética , Administração Intravenosa , Animais , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Modelos Animais de Doenças , Feminino , Melanoma/sangue , Melanoma/tratamento farmacológico , Melanoma/patologia , Camundongos Endogâmicos C57BL , Microdiálise , Peptídeos Cíclicos/sangue , Peptídeos Cíclicos/uso terapêutico , Carga Tumoral/efeitos dos fármacos
17.
J Clin Endocrinol Metab ; 105(1)2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31586182

RESUMO

PURPOSE: Pancreatic neuroendocrine tumors (pNETs) are frequent in multiple endocrine neoplasia type 1 (MEN1) syndrome. They are usually not surgically treated unless larger than 1 to 2 cm or a growth rate > 0.5 cm per year. Somatostatin analogues represent one of the main therapeutic options in pNETs, but they have never been prospectively investigated in MEN1-related pNETs. The aim of this study was to prospectively evaluate the effectiveness of lanreotide in patients with MEN1-related pNETs < 2 cm. METHODS: MEN1 patients with 1 or more pNETs < 2 cm of maximal diameter were considered. Study design was prospective observational, comparing patients treated with lanreotide autogel 120 mg every 28 days (LAN group) and patients in active surveillance, not receiving any therapy (AS group). RESULTS: Forty-two patients were enrolled: 23 in LAN and 19 in AS group. Median follow-up was 73 months. Initial imaging identified a total of 91 pNETs. The median progression-free survival was significantly longer in the LAN than in the AS group (median not reached vs 40 months, P < 0.001). In the LAN group, 4 patients had an objective tumor response, 15 patients had stable disease, while 4 had tumor progression. In the AS group, 13 patients had pNET progression, while 6 were stable. CONCLUSIONS: This is the first prospective study evaluating the efficacy of somatostatin analogues in MEN1-related pNETs. These findings highlight that lanreotide autogel is effective as antiproliferative therapy in MEN1-related pNETs < 2cm, suggesting the utility of somatostatin analogues to arrest the development of tumor lesions as well as to delay or avoid pancreatic surgery.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasia Endócrina Múltipla Tipo 1/complicações , Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Peptídeos Cíclicos/uso terapêutico , Somatostatina/análogos & derivados , Conduta Expectante/estatística & dados numéricos , Adulto , Idoso , Estudos de Casos e Controles , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/etiologia , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/patologia , Prognóstico , Estudos Prospectivos , Somatostatina/uso terapêutico , Carga Tumoral , Adulto Jovem
18.
Physiol Genomics ; 51(12): 657-667, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31762409

RESUMO

Rhesus theta defensin-1 (RTD-1), a macrocyclic immunomodulatory host defense peptide from Old World monkeys, is therapeutic in pristane-induced arthritis (PIA) in rats, a model of rheumatoid arthritis (RA). RNA-sequence (RNA-Seq) analysis was used to interrogate the changes in gene expression in PIA rats, which identified 617 differentially expressed genes (DEGs) in PIA synovial tissue of diseased rats. Upstream regulator analysis showed upregulation of gene expression pathways regulated by TNF, IL1B, IL6, proinflammatory cytokines, and matrix metalloproteases (MMPs) involved in RA. In contrast, ligand-dependent nuclear receptors like the liver X-receptors NR1H2 and NR1H3 and peroxisome proliferator-activated receptor gamma (PPARG) were downregulated in arthritic synovia. Daily RTD-1 treatment of PIA rats for 1-5 days following disease presentation modulated 340 of the 617 disease genes, and synovial gene expression in PIA rats treated 5 days with RTD-1 closely resembled the gene signature of naive synovium. Systemic RTD-1 inhibited proinflammatory upstream regulators such as TNF, IL1, and IL6 and activated antiarthritic ligand-dependent nuclear receptor pathways, including PPARG, NR1H2, and NR1H3, that were suppressed in untreated PIA rats. RTD-1 also inhibited proinflammatory responses in IL-1ß-stimulated human RA fibroblast-like synoviocytes (FLS) in vitro and diminished expression of human orthologs of disease genes that are induced in rat PIA synovium. Thus, the antiarthritic mechanisms of systemic RTD-1 include homeostatic regulation of arthritogenic gene networks in a manner that correlates temporally with clinical resolution of rat PIA.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Fibroblastos/metabolismo , Mediadores da Inflamação/antagonistas & inibidores , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/uso terapêutico , Membrana Sinovial/metabolismo , Transcriptoma/efeitos dos fármacos , alfa-Defensinas/farmacologia , alfa-Defensinas/uso terapêutico , Animais , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/metabolismo , Linhagem Celular , Cercopithecidae , Citocinas/genética , Modelos Animais de Doenças , Feminino , Humanos , Imunossupressores/farmacologia , RNA-Seq , Ratos , Sinoviócitos/metabolismo , Terpenos/farmacologia , Regulação para Cima
19.
Am J Nephrol ; 50(5): 375-385, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31600749

RESUMO

BACKGROUND: Markers currently used to predict the likelihood of rapid disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD) are expensive and time consuming to assess and often have limited sensitivity. New, easy-to-measure markers are therefore needed that alone or in combination with conventional risk markers can predict the rate of disease progression. In the present study, we investigated the ability of tubular damage and inflammation markers to predict kidney function decline. METHODS: At baseline, albumin, immunoglobulin G, kidney injury molecule 1, ß2 microglobulin (ß2MG), heart-type fatty acid-binding protein, neutrophil gelatinase-associated lipocalin, and monocyte chemotactic protein-1 -(MCP-1) were measured in 24-h urine samples of patients participating in a study investigating the therapeutic efficacy of lanreotide in ADPKD. Individual change in estimated glomerular filtration rate (eGFR) during follow-up was calculated using mixed-model analysis taking into account 13 -eGFRs (chronic kidney disease EPIdemiology) per patient. Logistic regression analysis was used to select urinary biomarkers that had the best association with rapidly progressive disease. The predictive value of these selected urinary biomarkers was compared to other risk scores using C-statistics. RESULTS: Included were 302 patients of whom 53.3% were female, with an average age of 48 ± 7 years, eGFR of 52 ± 12 mL/min/1.73 m2, and a height-adjusted total kidney volume (htTKV) of 1,082 (736-1,669) mL/m. At baseline, all urinary damage and inflammation markers were associated with baseline eGFR, also after adjustment for age, sex and baseline htTKV. For longitudinal analyses only patients randomized to standard care were considered (n = 152). A stepwise backward analysis revealed that ß2MG and MCP-1 showed the strongest association with rapidly progressive disease. A urinary biomarker score was created by summing the ranking of tertiles of ß2MG and MCP-1 excretion. The predictive value of this urinary biomarker score was higher compared to that of the Mayo htTKV classification (area under the curve [AUC] 0.73 [0.64-0.82] vs. 0.61 [0.51-0.71], p = 0.04) and comparable to that of the predicting renal outcomes in -ADPKD score (AUC 0.73 [0.64-0.82] vs. 0.65 [0.55-0.75], p = 0.18). In a second independent cohort with better kidney function, similar results were found for the urinary biomarker score. CONCLUSION: Measurement of urinary ß2MG and MCP-1 excretion allows selection of ADPKD patients with rapidly progressive disease, with a predictive value comparable to or even higher than that of TKV or PKD mutation. Easy and inexpensive to measure urinary markers therefore hold promise to help predict prognosis in ADPKD.


Assuntos
Falência Renal Crônica/diagnóstico , Peptídeos Cíclicos/uso terapêutico , Rim Policístico Autossômico Dominante/complicações , Somatostatina/análogos & derivados , Adulto , Biomarcadores/urina , Quimiocina CCL2/urina , Progressão da Doença , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/etiologia , Falência Renal Crônica/prevenção & controle , Túbulos Renais/imunologia , Túbulos Renais/patologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Rim Policístico Autossômico Dominante/tratamento farmacológico , Rim Policístico Autossômico Dominante/patologia , Rim Policístico Autossômico Dominante/urina , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Somatostatina/uso terapêutico , Fatores de Tempo , Microglobulina beta-2/urina
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