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1.
Nat Commun ; 10(1): 3546, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391464

RESUMO

Polyamines are essential for the growth of eukaryotic cells and can be dysregulated in tumors. Here we describe a strategy to deplete polyamines through host-guest encapsulation using a peptide-pillar[5]arene conjugate (P1P5A, P1 = RGDSK(N3)EEEE) as a supramolecular trap. The RGD in the peptide sequence allows the molecule to bind to integrin αvß3-overexpressing tumor cells. The negative charged glutamic acid residues enhance the inclusion affinities between the pillar[5]arene and cationic polyamines via electrostatic interactions and facilitate the solubility of the conjugate in aqueous media. The trap P1P5A efficiently encapsulates polyamines with association constants of 105-106 M-1. We show that P1P5A has a wide spectrum of antitumor activities, and induces apoptosis via affecting the polyamine biosynthetic pathway. Experiments in vivo show that P1P5A effectively inhibits the growth of breast adenocarcinoma xenografts in female nude mice. This work reveals an approach for suppressing tumor growth by using supramolecular macrocycles to trap polyamines in tumor cells.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Poliaminas/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Vias Biossintéticas/efeitos dos fármacos , Neoplasias da Mama/patologia , Calixarenos/química , Calixarenos/farmacologia , Calixarenos/uso terapêutico , Cátions/química , Cátions/metabolismo , Feminino , Humanos , Integrina alfaVbeta3/metabolismo , Células MCF-7 , Camundongos , Camundongos Nus , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/uso terapêutico , Poliaminas/química , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Drugs ; 79(14): 1599-1606, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31429064

RESUMO

Bremelanotide (Vyleesi™) is a melanocortin receptor agonist recently approved in the USA for the treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder (HSDD), as characterized by low sexual desire that causes marked distress or interpersonal difficulty. It is a self-administered, on-demand subcutaneous therapy. Initially developed by Palatin Technologies who sponsored the Phase 3 clinical trials, bremelanotide was subsequently out-licensed to AMAG Pharmaceuticals Inc. for exclusive North American rights to develop and commercialize the drug, including submitting the New Drug Application to the US FDA. Bremelanotide is a synthetic peptide analogue of the neuropeptide hormone alpha melanocyte-stimulating hormone (α-MSH) with high affinity for the melanocortin type 4 receptor (thought to be important for sexual function), giving it the potential to modulate brain pathways involved in sexual response. This article summarizes the milestones in the development of bremelanotide leading to this first regulatory approval.


Assuntos
Peptídeos Cíclicos/uso terapêutico , alfa-MSH/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Ensaios Clínicos Fase III como Assunto , Humanos , Disfunções Sexuais Psicogênicas/tratamento farmacológico , Disfunções Sexuais Psicogênicas/metabolismo , alfa-MSH/metabolismo
4.
Saudi Med J ; 40(7): 669-674, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31287126

RESUMO

OBJECTIVES: To report the genotype-phenotype characteristics, demographic features and clinical outcome of Omani patients with congenital hyperinsulinism (CHI). Methods: We retrospectively analyzed the clinical, biochemical, genotypical, phenotypical characteristics and outcomes of  children with CHI who were presented to the pediatric endocrine team in the Royal Hospital, Muscat, Oman between January 2007 and December 2016. Results: Analysis of 25 patients with CHI genetically revealed homozygous mutation in ABCC8 in 23 (92%) patients and 2 patients (8%) with compound heterozygous mutation in ABCC8. Fifteen (60%) patients underwent subtotal pancreatectomy as medical therapy failed and 2 (8%) patients showed response to medical therapy. Three patients expired during the neonatal period, 2 had cardiomyopathy and sepsis, and one had sepsis and severe metabolic acidosis. Out of the 15 patients who underwent pancreatectomy, 6 developed diabetes mellitus, 6 continued to have hypoglycemia and required medical therapy and one had pancreatic exocrine dysfunction post-pancreatectomy, following up with gastroenterology clinic and was placed on pancreatic enzyme supplements, while 2 patients continued to have hypoglycemia and both had abdominal MRI and 18-F-fluoro-L-DOPA positron emission tomography scan (PET-scan), that showed  persistent of the disease and started on medical therapy. Conclusion:  Mutation in ABCC8 is the most common cause of CHI and reflects the early age of presentation. There is a need for early diagnosis and appropriate therapeutic strategy.


Assuntos
Hiperinsulinismo Congênito/metabolismo , Hipoglicemia/metabolismo , Apneia/etiologia , Apneia/fisiopatologia , Pré-Escolar , Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/fisiopatologia , Hiperinsulinismo Congênito/terapia , Diabetes Mellitus/tratamento farmacológico , Terapia de Reposição de Enzimas , Insuficiência Pancreática Exócrina/tratamento farmacológico , Feminino , Fármacos Gastrointestinais/uso terapêutico , Heterozigoto , Homozigoto , Humanos , Hipoglicemia/complicações , Hipoglicemia/fisiopatologia , Lactente , Recém-Nascido , Letargia/etiologia , Letargia/fisiopatologia , Masculino , Mutação , Octreotida/uso terapêutico , Omã , Pancreatectomia , Peptídeos Cíclicos/uso terapêutico , Complicações Pós-Operatórias/tratamento farmacológico , Estudos Retrospectivos , Convulsões/etiologia , Convulsões/fisiopatologia , Sirolimo/uso terapêutico , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Receptores Sulfonilureia/genética , Resultado do Tratamento
5.
Nat Commun ; 10(1): 2992, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278250

RESUMO

Lysocin E, a 37-membered natural depsipeptide, induces rapid bacteriolysis in methicillin-resistant Staphylococcus aureus via a unique menaquinone-dependent mechanism, presenting a promising therapeutic lead. Despite the great medical importance, exploring the potential utility of its derivatives as new platform structures for antibiotic development has remained a significant challenge. Here, we report a high-throughput strategy that enabled the preparation of thousands of analogues of lysocin E and large-scale structure-activity relationship analyses. We integrate 26-step total synthesis of 2401 cyclic peptides, tandem mass spectrometry-sequencing, and two microscale activity assays to identify 23 candidate compounds. Re-synthesis of these candidates shows that 11 of them (A1-A11) exhibit antimicrobial activity superior or comparable to that of lysocin E, and that lysocin E and A1-A11 share L-Leu-6 and L-Ile-11. Therefore, the present strategy allows us to efficiently decipher biologically crucial residues and identify potentially useful agents for the treatment of infectious diseases.


Assuntos
Antibacterianos/farmacologia , Descoberta de Drogas/métodos , Ensaios de Triagem em Larga Escala/métodos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Antibacterianos/química , Antibacterianos/uso terapêutico , Química Farmacêutica/métodos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Peptídeos Cíclicos/química , Peptídeos Cíclicos/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Relação Estrutura-Atividade , Espectrometria de Massas em Tandem/métodos
6.
Nat Commun ; 10(1): 2730, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227691

RESUMO

Recently our groups discovered lugdunin, a new cyclic peptide antibiotic that inhibits Staphylococcus aureus epithelial colonization in humans and rodents. In this work, we analyzed its immuno-modulatory and antimicrobial potential as a single agent or in combination with other microbiota- or host-derived factors. We show that pretreatment of primary human keratinocytes or mouse skin with lugdunin in combination with microbiota-derived factors results in a significant reduction of S. aureus colonization. Moreover, lugdunin increases expression and release of LL-37 and CXCL8/MIP-2 in human keratinocytes and mouse skin, and results in the recruitment of monocytes and neutrophils in vivo, both by a TLR/MyD88-dependent mechanism. Interestingly, S. aureus elimination by lugdunin is additionally achieved by synergistic antimicrobial activity with LL-37 and dermcidin-derived peptides. In summary, our results indicate that lugdunin provides multi-level protection against S. aureus and may thus become a promising treatment option for S. aureus skin infections in the future.


Assuntos
Antibacterianos/farmacologia , Imunidade Inata/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Tiazolidinas/farmacologia , Animais , Antibacterianos/uso terapêutico , Peptídeos Catiônicos Antimicrobianos/imunologia , Células Cultivadas , Modelos Animais de Doenças , Feminino , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/imunologia , Queratinócitos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microbiota/efeitos dos fármacos , Microbiota/imunologia , Peptídeos/imunologia , Peptídeos Cíclicos/uso terapêutico , Cultura Primária de Células , Pele/efeitos dos fármacos , Pele/imunologia , Pele/microbiologia , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Tiazolidinas/uso terapêutico
7.
Int J Mol Sci ; 20(12)2019 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-31234481

RESUMO

In recent decades, the incidence of neuroendocrine tumors (NETs) has steadily increased. Due to the slow-growing nature of these tumors and the lack of early symptoms, most cases are diagnosed at advanced stages, when curative treatment options are no longer available. Prognosis and survival of patients with NETs are determined by the location of the primary lesion, biochemical functional status, differentiation, initial staging, and response to treatment. Somatostatin analogue (SSA) therapy has been a mainstay of antisecretory therapy in functioning neuroendocrine tumors, which cause various clinical symptoms depending on hormonal hypersecretion. Beyond symptomatic management, recent research demonstrates that SSAs exert antiproliferative effects and inhibit tumor growth via the somatostatin receptor 2 (SSTR2). Both the PROMID (placebo-controlled, prospective, randomized study in patients with metastatic neuroendocrine midgut tumors) and the CLARINET (controlled study of lanreotide antiproliferative response in neuroendocrine tumors) trial showed a statistically significant prolongation of time to progression/progression-free survival (TTP/PFS) upon SSA treatment, compared to placebo. Moreover, the combination of SSA with peptide receptor radionuclide therapy (PRRT) in small intestinal NETs has proven efficacy in the phase 3 neuroendocrine tumours therapy (NETTER 1) trial. PRRT is currently being tested for enteropancreatic NETs versus everolimus in the COMPETE trial, and the potential of SSTR-antagonists in PRRT is now being evaluated in early phase I/II clinical trials. This review provides a synopsis on the pharmacological development of SSAs and their use as antisecretory drugs. Moreover, this review highlights the clinical evidence of SSAs in monotherapy, and in combination with other treatment modalities, as applied to the antiproliferative management of neuroendocrine tumors with special attention to recent high-quality phase III trials.


Assuntos
Tumores Neuroendócrinos/tratamento farmacológico , Octreotida/uso terapêutico , Peptídeos Cíclicos/uso terapêutico , Somatostatina/análogos & derivados , Animais , Antineoplásicos Hormonais/uso terapêutico , Ensaios Clínicos como Assunto , Intervalo Livre de Doença , Humanos , Tumores Neuroendócrinos/metabolismo , Octreotida/metabolismo , Octreotida/farmacologia , Peptídeos Cíclicos/metabolismo , Peptídeos Cíclicos/farmacologia , Receptores de Somatostatina/metabolismo , Transdução de Sinais , Somatostatina/metabolismo , Somatostatina/farmacologia , Somatostatina/uso terapêutico
8.
Mol Med Rep ; 20(2): 1157-1166, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173215

RESUMO

Osteonecrosis of the femoral head (ONFH) is a common osteological disease. Treatment of ONFH prior to the collapse of the femoral head is critical for increasing therapeutic efficiency. Tissue engineering therapy using bone mesenchymal stem cells (BMSCs) combined with a scaffold is a promising strategy. However, it is currently unclear how to improve the efficiency of BMSC recruitment under such conditions. In the present study, a specific cyclic peptide for Sprague­Dawley rat BMSCs, CTTNPFSLC (known as C7), was used, which was identified via phage display technology. Its high affinity for BMSCs was demonstrated using flow cytometry and fluorescence staining. Subsequently, the cyclic peptide was placed on ß­tricalcium phosphate (ß­TCP) scaffolds using absorption and freeze­drying processes. Adhesion, expansion and proliferation of BMSCs was investigated in vitro on the C7­treated ß­TCP scaffolds and compared with pure ß­TCP scaffolds. The results revealed that C7 had a promoting effect on the adhesion, expansion and proliferation of BMSCs on ß­TCP scaffolds. Therefore, C7 may be effective in future tissue engineering therapy for ONFH.


Assuntos
Fosfatos de Cálcio , Adesão Celular , Células-Tronco Mesenquimais/efeitos dos fármacos , Osteogênese , Peptídeos Cíclicos/farmacologia , Tecidos Suporte/química , Animais , Proliferação de Células , Necrose da Cabeça do Fêmur/terapia , Células-Tronco Mesenquimais/fisiologia , Peptídeos Cíclicos/uso terapêutico , Ratos , Ratos Sprague-Dawley
9.
Int Immunopharmacol ; 73: 395-404, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31151077

RESUMO

Study on the constituents of bioactive culture broth extract (CBE) of Pseudomonas sp. (ABS-36) explored the secretion of an array of cyclic dipeptides (CDPs) and twenty of them had been isolated and reported in the present paper. Six major CDPs [(cyclo(Leu-Pro) (1), cyclo(Val-Pro) (2), cyclo(Leu-hydroxy-Pro) (9), cyclo(Pro-Tyr) (10), cyclo(Pro-Ala) (11) and cyclo(Gly-Pro) (12)] exhibited pan cytokine inhibition effect by inhibiting key pro-inflammatory cytokines IL-1ß, TNF-α and IL-6 tested under various cell based assays. With this background, the effect of these six CDPs in treating renal inflammation was screened using crystal-induced nephropathy model in mice at 50 mg/kg body weight through oral administration. cis-Cyclo(Val-Pro) (2) exhibited 57% inhibition of plasma IL-1ß protein expression and 35.2% inhibition of elevated blood urea nitrogen. Further, cis-cyclo(Val-Pro) (2) attenuated renal injury as demonstrated by significant reduction of mRNA expressions of IL-1ß (P < 0.01) and kidney injury marker-1 (P < 0.001). Furthermore, evaluation of tubular-necrosis, -dilation and -cast in the histological sections exhibited moderate protection of renal tissues by cis-cyclo(Val-Pro) (2). All the tested CDPs reduced the nitrite production and were interestingly non-cytotoxic.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Dipeptídeos/uso terapêutico , Peptídeos Cíclicos/uso terapêutico , Prolina , Pseudomonas , Lesão Renal Aguda/patologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Camundongos , Camundongos Endogâmicos C57BL , Ácido Oxálico , Células RAW 264.7
10.
Molecules ; 24(9)2019 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-31083642

RESUMO

Lipogenesis plays a critical role in the growth and metastasis of tumors, which is becoming an attractive target for anti-tumor drugs. RA-XII, one of the cyclopeptide glycosides isolated from Rubia yunnanensis, exerts anti-tumor effects on liver cancer. However, the underlying mechanisms are not clear. In the present study, the effects of RA-XII on lipogenesis were evaluated and the underlying mechanisms were investigated. The results indicated that RA-XII strongly inhibited tumor growth and lipogenesis (triglycerides and lipid droplets) in HepG2 cells, and the expression of key factors involved in lipogenesis (SREBP, SCD, FASN) was also obviously downregulated. Further investigation showed that the anti-tumor effects of RA-XII were attenuated by SREBP knockdown. Moreover, RA-XII downregulated the expression of SREBP cleavage-activating protein (SCAP), an upstream regulator of SREBP, and siRNA of SCAP prevented its restrained effects on tumor growth and lipogenesis. In addition, the in vivo experiment showed that RA-XII strongly restrained the lipogenesis and growth of liver tumor in nude mice xenograft model. Taken together, these results indicate that RA-XII suppresses the liver cancer growth by inhibition of lipogenesis via SCAP-dependent SREBP suppression. The findings reveal the potentials of RA-XII to be used in a novel therapeutic approach for treating liver cancer.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipogênese/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Proteínas de Membrana/metabolismo , Peptídeos Cíclicos/uso terapêutico , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Células Hep G2 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Peptídeos Cíclicos/farmacologia
11.
J Neuroinflammation ; 16(1): 100, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31109346

RESUMO

BACKGROUND: Numerous studies have identified the proinflammatory, pronociceptive effects of morphine which ultimately exacerbate pain. Our novel endomorphin analog ZH853 does not produce proinflammatory effects on its own and gives potent, long-lasting analgesia. This study investigates whether ZH853's lack of interaction with the neuroimmune system reduces the risk of prolonged pain. METHODS: Adult male Sprague-Dawley rats were subjected to one of two treatment paradigms. Either (1) chronic pain followed by chronic treatment with morphine, ZH853 or vehicle, or (2) chronic drug administered prior to pain induction. Complete Freund's adjuvant (CFA) was injected or paw incision surgery was performed on the left hind plantar foot pad. Drugs were administered through Alzet osmotic minipumps at a rate of 1 µl/h for 5 days at appropriate doses based on prior experiments. Animals were tested for mechanical allodynia and thermal hyperalgesia using von Frey filaments and the Hargreaves apparatus, respectively. Additionally, several gait parameters were measured using the CatWalk XT. When all animals had recovered from pain, 1 mg/kg of naltrexone was administered to test for development of latent sensitization (LS). A second set of animals was used to investigate dorsal horn inflammation following CFA and drug treatment. ANOVAs were used to assess differences between drug treatment groups. RESULTS: As expected, morphine increased and prolonged pain in all experiments compared to vehicle treatment. However, ZH853 treatment reduced the overall time spent in pain and the severity of pain scores compared to morphine. ZH853 not only reduced inflammation versus morphine treatment but also, in some instances, acted as an anti-inflammatory drug compared to vehicle treatment. Finally, ZH853 prevented the development of LS while vehicle- and morphine-treated animals showed robust relapse to pain. CONCLUSIONS: ZH853 has a favorable side effect profile versus morphine and provides superior analgesia in a number of pain states. We now know that chronic use of this compound reduces time spent in a chronic pain state, the opposite of common opioids like morphine, and reduces the risk of LS, making ZH853 an excellent candidate for clinical development in humans for inflammatory and postoperative pain.


Assuntos
Analgésicos Opioides/uso terapêutico , Analgésicos/uso terapêutico , Imunomodulação/efeitos dos fármacos , Morfina/uso terapêutico , Dor Pós-Operatória/tratamento farmacológico , Peptídeos Cíclicos/uso terapêutico , Analgésicos/farmacologia , Analgésicos Opioides/farmacologia , Animais , Imunomodulação/fisiologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Masculino , Morfina/farmacologia , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Dor Pós-Operatória/imunologia , Peptídeos Cíclicos/farmacologia , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia
12.
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
13.
Pharmacol Biochem Behav ; 181: 28-36, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30991059

RESUMO

A fixed dose combination of bupropion (BPP) and naltrexone (NTX), Contrave®, is an FDA approved pharmacotherapy for the treatment of obesity. A recent study found that combining BPP with low-dose NTX reduced alcohol drinking in alcohol-preferring male rats. To explore potential pharmacological effects of the BPP + NTX combination on alcohol drinking, both male and female C57Bl/6J mice were tested on one-week drinking-in-the dark (DID) and three-week intermittent access (IA) models. Neuronal proopiomelanocortin (POMC) enhancer knockout (nPE-/-) mice with hypothalamic-specific deficiency of POMC, and its bioactive peptides melanocyte stimulating hormone and beta-endorphin, were used as a genetic control for the effects of the BPP + NTX. A single administration of BPP + NTX (10 mg/kg + 1 mg/kg) decreased alcohol intake after DID in C57Bl/6J males, but not females. Also in C57Bl/6J males, BPP + NTX reduced intake of the caloric reinforcer sucrose, but not the non-caloric reinforcer saccharin. In contrast, BPP + NTX had no effect on alcohol DID in nPE-/- males. Pretreatment with the selective melanocortin 4 receptor (MC4R) antagonist HS014 reversed the anti-dipsogenic effect of BPP + NTX on alcohol DID in C57Bl/6J males. In the 3-week chronic IA model, single or repeated administrations for four days of BPP + NTX reduced alcohol intake and preference in C57Bl/6J males only. The behavioral measures observed in C57Bl/6J mice provide clear evidence that BPP + NTX profoundly reduced alcohol drinking in males, but the doses tested were not effective in females. Furthermore, our results suggest a hypothalamic POMC/MC4R-dependent mechanism for the observed BPP + NTX effects on alcohol drinking in male mice.


Assuntos
Consumo de Bebidas Alcoólicas/tratamento farmacológico , Alcoolismo/tratamento farmacológico , Bupropiona/farmacologia , Bupropiona/uso terapêutico , Avaliação Pré-Clínica de Medicamentos/métodos , Naltrexona/farmacologia , Naltrexona/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Bupropiona/administração & dosagem , Combinação de Medicamentos , Sinergismo Farmacológico , Etanol/administração & dosagem , Feminino , Técnicas de Inativação de Genes , Hipotálamo/metabolismo , Injeções Intraperitoneais , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Naltrexona/administração & dosagem , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/uso terapêutico , Fotoperíodo , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Receptor Tipo 4 de Melanocortina/metabolismo , Sacarina/farmacologia , Fatores Sexuais , Sacarose/farmacologia
14.
Appl Microbiol Biotechnol ; 103(11): 4377-4392, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30997554

RESUMO

Candida albicans is a fungal pathogen that is difficult to cure clinically. The current clinic C. albicans-inhibiting drugs are very harmful to humans. This study revealed the potential of iturin fractions from Bacillus subtilis to inhibit C. albicans in free status (MIC = 32 µg/mL) and natural biofilm in vitro. The inhibition mechanism was identified as an apoptosis pathway via the decrease of mitochondrial membrane potential, the increase of the reactive oxygen species (ROS) accumulation, and the induction of nuclear condensation. For in vivo experiments, the C. albicans infection model was constructed via intraperitoneal injection of 1 × 108C. albicans cells into mice. One day after the infection, iturin was used to treat infected mice at different concentrations alone and in combination with amphotericin B (AmB) by intraperitoneal injection. The treatment with AmB alone could cause the death of infected mice, whereas treatment with 15 mg/kg iturin per day alone led to the survival of all infected mice throughout the study. After continuously treated for 6 days, all mice were sacrificed and analyzed. As results, the combination of 15 mg/kg iturin and AmB at a ratio of 2:1 had the most efficient effect to remove the fungal burden in the kidney and cure the infected mice by reversing the symptoms caused by C. albicans infection, such as the loss of body weight, change of immunology cells in blood and cytokines in serum, and damage of organ structure and functions. Overall, iturin had potential in the development of efficient and safe drugs to cure C. albicans infection.


Assuntos
Antifúngicos/farmacologia , Bacillus subtilis/metabolismo , Candida albicans/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Animais , Antifúngicos/isolamento & purificação , Antifúngicos/uso terapêutico , Biofilmes/efeitos dos fármacos , Candidíase/tratamento farmacológico , Modelos Animais de Doenças , Camundongos , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Peptídeos Cíclicos/isolamento & purificação , Peptídeos Cíclicos/uso terapêutico , Resultado do Tratamento
15.
Neuropharmacology ; 151: 112-126, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30981749

RESUMO

Glycine-proline-glutamate (GPE) is a cleaved tripeptide of IGF-I that can be processed to cycloprolylglycine (cPG) in the brain. IGF-I protects the hippocampal somatostatinergic system from ß-amyloid (Aß) insult and although neither IGF-I-derived peptides bind to IGF-I receptors, they exert protective actions in several neurological disorders. As their effects on the hippocampal somatostatinergic system remain unknown, the objective of this study was to evaluate if cPG and/or GPE prevent the deleterious effects of Aß25-35 infusion on this system and whether changes in intracellular-related signaling and interleukin (IL) content are involved in their protective effect. We also determined the effect of cPG or GPE co-administration with Aß25-35 on IL secretion in glial cultures and the influence of these ILs on signaling activation and somatostatin synthesis in neuronal cultures. cPG or GPE co-administration reduced Aß-induced cell death and pro-inflammatory ILs, increased IL-4 and partially avoided the reduction of components of the somatostatinergic system affected by Aß25-35. GPE increased activation of Akt and CREB and reduced GSK3ß activation and astrogliosis, whereas cPG increased phosphorylation of extracellular signal-regulated kinases. Both peptides converged in the activation of mTOR and S6 kinase. Co-administration of these peptides with Aß25-35 to glial cultures increased IL-4 and reduced IL-1ß; this release of IL-4 could be responsible for activation of Akt and increased somatostatin in neuronal cultures. Our findings suggest that cPG and GPE exert protective effects against Aß on the somatostatinergic system by a reduction of the inflammatory environment that may activate different pro-survival pathways in these neurons.


Assuntos
Peptídeos beta-Amiloides/farmacologia , Hipocampo/efeitos dos fármacos , Inflamação/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Oligopeptídeos/uso terapêutico , Fragmentos de Peptídeos/farmacologia , Peptídeos Cíclicos/uso terapêutico , Somatostatina/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Inflamação/metabolismo , Inflamação/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Oligopeptídeos/farmacologia , Peptídeos Cíclicos/farmacologia , Fosforilação/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de Somatostatina/metabolismo , Transdução de Sinais/efeitos dos fármacos
16.
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
17.
J Oncol Pharm Pract ; 25(6): 1425-1433, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30924737

RESUMO

BACKGROUND: Lanreotide and octreotide acetate suspension for injectable (LAR) are both recommended for clinical use in patients with locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors. However, each agent possesses unique attributes in terms of their drug-delivery characteristics. The study objective was to compare overall drug-delivery efficiency between lanreotide and octreotide LAR in gastroenteropancreatic neuroendocrine tumor patients. METHODS: This study employed an observational time and motion design among patients treated with lanreotide or octreotide LAR across five US cancer centers. Baseline patient data collection included age, disease grade and duration, prior therapies and performance status. Drug-delivery time (drug preparation and administration), total patient time and resource use data were collected for gastroenteropancreatic neuroendocrine tumors receiving lanreotide (n = 22) or octreotide LAR (n = 22). Following each administration, qualitative data on the drug-delivery experience was collected from patients and nurses. RESULTS: Lanreotide was associated with a significant reduction in mean delivery time (2.5 min; 95% CI:2.0 to 3.1) compared to octreotide LAR (6.2 min; 95%CI: 4.4 to 7.9; p = 0.004). The mean total patient time for lanreotide and octreotide LAR was comparable between groups (32.1 vs. 36.6 minutes; p = 0.97). Nurses reported increased concerns with octreotide LAR related to needle clogging (p = 0.034) and device failures (p = 0.057). Overall, lanreotide had a median satisfaction score of 5.0 compared to a score of 4.0 with octreotide LAR (p = 0.03). CONCLUSIONS: Lanreotide was associated with significant reductions in drug-delivery time compared to octreotide LAR, which contributed to an improvement in overall healthcare efficiency. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT03017690.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Intestinais/tratamento farmacológico , Sistemas de Medicação/organização & administração , Tumores Neuroendócrinos/tratamento farmacológico , Octreotida/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Peptídeos Cíclicos/uso terapêutico , Somatostatina/análogos & derivados , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Atitude do Pessoal de Saúde , Composição de Medicamentos , Falha de Equipamento , Feminino , Recursos em Saúde/estatística & dados numéricos , Humanos , Injeções , Masculino , Pessoa de Meia-Idade , Agulhas/efeitos adversos , Satisfação do Paciente , Estudos Prospectivos , Somatostatina/uso terapêutico , Estudos de Tempo e Movimento
18.
Drug Discov Today ; 24(3): 685-702, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30776482

RESUMO

Breast cancer (BC) remains the most frequently diagnosed cancer in women. A balance in the opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs) is necessary for epigenetic regulation of gene expression. Impairment in the balance between the actions of HATs and HDACs has been reported in the development of BC. By targeting histone and several non-histone proteins, histone deacetylase inhibitors (HDACi) can maintain the cellular acetylation profile and reverse the function of several proteins responsible for BC development. Preclinical and clinical data show that HDACi can evoke different anticancer mechanisms in distinct BC types.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Inibidores de Histona Desacetilases/uso terapêutico , Animais , Benzamidas/uso terapêutico , Ácidos Graxos Voláteis/uso terapêutico , Humanos , Ácidos Hidroxâmicos/uso terapêutico , MicroRNAs , Peptídeos Cíclicos/uso terapêutico , Sirtuínas/antagonistas & inibidores
19.
Biochem J ; 476(1): 67-83, 2019 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-30635453

RESUMO

The use of disulfide-rich backbone-cyclized polypeptides, as molecular scaffolds to design a new generation of bioimaging tools and drugs that are potent and specific, and thus might have fewer side effects than traditional small-molecule drugs, is gaining increasing interest among the scientific and in the pharmaceutical industries. Highly constrained macrocyclic polypeptides are exceptionally more stable to chemical, thermal and biological degradation and show better biological activity when compared with their linear counterparts. Many of these relatively new scaffolds have been also found to be highly tolerant to sequence variability, aside from the conserved residues forming the disulfide bonds, able to cross cellular membranes and modulate intracellular protein-protein interactions both in vitro and in vivo These properties make them ideal tools for many biotechnological applications. The present study provides an overview of the new developments on the use of several disulfide-rich backbone-cyclized polypeptides, including cyclotides, θ-defensins and sunflower trypsin inhibitor peptides, in the development of novel bioimaging reagents and therapeutic leads.


Assuntos
Ciclotídeos , Defensinas , Modelos Moleculares , Imagem Molecular , Peptídeos Cíclicos , Animais , Ciclização , Ciclotídeos/síntese química , Ciclotídeos/química , Ciclotídeos/uso terapêutico , Defensinas/síntese química , Defensinas/química , Defensinas/uso terapêutico , Dissulfetos/química , Humanos , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Peptídeos Cíclicos/uso terapêutico
20.
Pharmacol Res ; 141: 264-275, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30634050

RESUMO

Augmented vasoconstriction is a hallmark of hypertension and is mediated partly by hyper-stimulation of G protein couple receptors (GPCRs) and downstream signaling components. Although GPCR blockade is a key component of current anti-hypertensive strategies, whether hypertension is better managed by directly targeting G proteins has not been thoroughly investigated. Here, we tested whether inhibiting Gq/11 proteins in vivo and ex vivo using natural cyclic depsipeptide, FR900359 (FR) from the ornamental plant, Ardisia crenata, and YM-254890 (YM) from Chromobacterium sp. QS3666, or it's synthetic analog, WU-07047 (WU), was sufficient to reverse hypertension in mice. All three inhibitors blocked G protein-dependent vasoconstriction, but to our surprise YM and WU and not FR inhibited K+-induced Ca2+ transients and vasoconstriction of intact vessels. However, each inhibitor blocked whole-cell L-type Ca2+ channel current in vascular smooth muscle cells. Subcutaneous injection of FR or YM (0.3 mg/kg, s.c.) in normotensive and hypertensive mice elicited bradycardia and marked blood pressure decrease, which was more severe and long lasting after the injection of FR relative to YM (FRt1/2 ≅ 12 h vs. YMt1/2 ≅ 4 h). In deoxycorticosterone acetate (DOCA)-salt hypertension mice, chronic injection of FR (0.3 mg/kg, s.c., daily for seven days) reversed hypertension (vehicle SBP: 149 ± 5 vs. FR SBP: 117 ± 7 mmHg), without any effect on heart rate. Our results together support the hypothesis that increased LTCC and Gq/11 activity is involved in the pathogenesis of hypertension, and that dual targeting of both proteins can reverse hypertension and associated cardiovascular disorders.


Assuntos
Anti-Hipertensivos/uso terapêutico , Depsipeptídeos/uso terapêutico , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Hipertensão/tratamento farmacológico , Peptídeos Cíclicos/uso terapêutico , Animais , Anti-Hipertensivos/química , Ardisia/química , Chromobacterium/química , Depsipeptídeos/química , Feminino , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/antagonistas & inibidores , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peptídeos Cíclicos/química , Vasoconstrição/efeitos dos fármacos
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