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1.
Bioorg Chem ; 144: 107112, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38237390

RESUMO

We report here the virtual screening design, synthesis and activity of eight new inhibitors of SphK1. For this study we used a pre-trained Graph Convolutional Network (GCN) combined with docking calculations. This exploratory analysis proposed nine compounds from which eight displayed significant inhibitory effect against sphingosine kinase 1 (SphK1) demonstrating a high level of efficacy for this approach. Four of these compounds also displayed anticancer activity against different tumor cell lines, and three of them (5), (6) and (7) have shown a wide inhibitory action against many of the cancer cell line tested, with GI50 below 5 µM, being (5) the most promising with TGI below 10 µM for the half of cell lines. Our results suggest that the three most promising compounds reported here are the pyrimidine-quinolone hybrids (1) and (6) linked by p-aminophenylsulfanyl and o-aminophenol fragments respectively, and (8) without such aryl linker. We also performed an exhaustive study about the molecular interactions that stabilize the different ligands at the binding site of SphK1. This molecular modeling analysis was carried out by using combined techniques: docking calculations, MD simulations and QTAIM analysis. In this study we also included PF543, as reference compound, in order to better understand the molecular behavior of these ligands at the binding site of SphK1.These results provide useful information for the design of new inhibitors of SphK1 possessing these structural scaffolds.


Assuntos
Antineoplásicos , Fosfotransferases (Aceptor do Grupo Álcool) , Quinolonas , Quinolonas/farmacologia , Inibidores de Proteínas Quinases , Antineoplásicos/química , Modelos Moleculares , Linhagem Celular Tumoral , Simulação de Acoplamento Molecular , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células , Relação Estrutura-Atividade , Estrutura Molecular
2.
ACS Omega ; 8(29): 26479-26496, 2023 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-37521653

RESUMO

A library of structurally related coumarins was generated through synthesis reactions and chemical modification reactions to obtain derivatives with antiproliferative activity both in vivo and in vitro. Out of a total of 35 structurally related coumarin derivatives, seven of them showed inhibitory activity in in vitro tests against Taq DNA polymerase with IC50 values lower than 250 µM. The derivatives 4-(chloromethyl)-5,7-dihydroxy-2H-chromen-2-one (2d) and 4-((acetylthio)methyl)-2-oxo-2H-chromen-7-yl acetate (3c) showed the most promising anti-polymerase activity with IC50 values of 20.7 ± 2.10 and 48.25 ± 1.20 µM, respectively. Assays with tumor cell lines (HEK 293 and HCT-116) were carried out, and the derivative 4-(chloromethyl)-7,8-dihydroxy-2H-chromen-2-one (2c) was the most promising, with an IC50 value of 8.47 µM and a selectivity index of 1.87. In addition, the derivatives were evaluated against Saccharomyces cerevisiae strains that report about common modes of actions, including DNA damage, that are expected for agents that cause replicative stress. The coumarin derivatives 7-(2-(oxiran-2-yl)ethoxy)-2H-chromen-2-one (5b) and 7-(3-(oxiran-2-yl)propoxy)-2H-chromen-2-one (5c) caused DNA damage in S. cerevisiae. The O-alkenylepoxy group stands out as that with the most important functionality within this family of 35 derivatives, presenting a very good profile as an antiproliferative scaffold. Finally, the in vitro antiretroviral capacity was tested through RT-PCR assays. Derivative 5c showed inhibitory activity below 150 µM with an IC50 value of 134.22 ± 2.37 µM, highlighting the O-butylepoxy group as the functionalization responsible for the activity.

3.
Indian J Orthop ; 55(Suppl 1): 27-37, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34122752

RESUMO

BACKGROUND: With the advances of modern medicine and technology there has been an increase of indications of shoulder reconstruction techniques and shoulder arthroplasty. Consequently, the number of complications and failures have increased in parallel. Not negligible number of cases are driven to an end-stage situation where salvage procedures, such as glenohumeral arthrodesis (GHA) and shoulder resection arthroplasty (SRA), are the only remaining solution. METHODS: The current literature on glenohumeral arthrodesis and shoulder resection arthroplasty was reviewed to determine the indications, surgical technique, complications and outcomes. The electronic search was conducted using the MEDLINE and EMBASE databases and the strategies used were "glenohumeral arthrodesis", "glenohumeral fusion", "shoulder arthrodesis" and "shoulder resection arthroplasty". RESULTS: Indications for glenohumeral arthrodesis (GHA) include brachial plexus injury, tumor resections, chronic infection, failed prosthetic arthroplasty, persistent refractory instability or pseudoparalysis of the shoulder with combined irreparable rotator cuff and deltoid injuries. GHA provides good stability, pain resolution, although function is markedly compromised and relying mostly on scapulothoracic joint. The gold standard surgical technique continues to be open shoulder arthrodesis and still has a high complication rate. Shoulder resection arthroplasty (SRA) indications have evolved through the years, being nowadays a salvage procedure for recalcitrant infection of shoulder arthroplasty the main indication. Shoulder function after SRA is often severely compromised, but has a high infection rate resolution. SRA is not technically demanding and complications are rare, being the persistence of infection the most common one. DISCUSSION: Despite GHA and SRA having negative connotations, in selected patients, these procedures can diminish pain, resolve persistent infections and provide an acceptable shoulder function. Hence, they should be retained as part of the treatment algorithm for complex shoulder pathology.

5.
Eur J Public Health ; 31(4): 688-694, 2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-33993239

RESUMO

BACKGROUND: The cardiovascular risk increases in a multiplicative way when patients present more risk factors simultaneously. Moreover, the General Practitioners (GPs) play a crucial role in risk factors prevention and reduction. This work aimed to evaluate a multicomponent intervention in the Primary Care Department in an Italian Local Health Unit. METHODS: A pre-post study was conducted in Northern Italy (2018). Patients were eligible if: aged between 30 and 60 years, not chronic patients, not affected by hypertension or hypercholesterolaemia. The GPs assessed body mass index, hypertension, abdominal obesity, low-density lipoprotein (LDL) values, glycaemic values, smoking and exercise habit (T0). A counselling by GPs to at-risk patients and a multicomponent health education intervention were performed. Reassessment occurred after at least 3 months (T1). Main analyses were chi-squared tests for gender differences, McNemar or marginal homogeneity tests for changes in paired data (P < 0.05 as significant). RESULTS: Participants were 5828 at T0 (54.0% females) and 4953 at T1 (53.4% females). At T0, 99.1% presented at least one risk factor. Significant changes in paired data were reported for each risk factor. The greatest improvement frequencies occurred in glycaemia values (51.0%) and hypertension (45.6%), the lowest in abdominal obesity (3.7%). Some differences were recorded between genders, e.g. females reported higher improvement frequencies in hypertension (P = 0.001) and abdominal obesity (P < 0.001), whereas males in physical activity (P = 0.011) and LDL values (P = 0.032). CONCLUSION: The results showed significant changes for each risk factor, both for men and women. GPs and multicomponent educational interventions could play a key role in reducing cardiovascular risk factors.


Assuntos
Doenças Cardiovasculares , Clínicos Gerais , Hipertensão , Adulto , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Exercício Físico , Feminino , Humanos , Hipertensão/epidemiologia , Hipertensão/prevenção & controle , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco
6.
JBJS Case Connect ; 11(2)2021 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-33979811

RESUMO

CASE: Fifty-year-old woman who presented an atraumatic anterior hip dislocation during a local traditional dance exhibition. The dislocation occurred during a dance step in which extreme hip position in extension and external rotation was held. After urgent closed reduction under general anesthesia, the patient underwent conservative management with a follow-up of 24 months. There were no further dislocation events or sequelae, with the Hip Disability and Osteoarthritis Outcome Score-12 scale score was 100 points at the end of follow-up. CONCLUSIONS: Atraumatic hip dislocation is the highest grade and exceptional presentation of hip instability and requires immediate treatment. Conservative treatment is satisfactory, although in case of recurrence or persistent residual symptoms, other treatments are warrant.


Assuntos
Luxação do Quadril , Luxações Articulares , Tratamento Conservador , Feminino , Luxação do Quadril/complicações , Luxação do Quadril/diagnóstico por imagem , Luxação do Quadril/cirurgia , Humanos , Luxações Articulares/etiologia , Pessoa de Meia-Idade
7.
Pharmacol Ther ; 225: 107844, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33811956

RESUMO

Acute myeloid leukemia (AML) is a hematological malignancy characterized by clonal expansion and differentiation arrest of the myeloid progenitor cells, which leads to the accumulation of immature cells called blasts in the bone marrow and peripheral blood. Mutations in the receptor tyrosine kinase FLT3 occur in 30% of normal karyotype patients with AML and are associated with a higher incidence of relapse and worse survival. Targeted therapies against FLT3 mutations using small-molecule FLT3 tyrosine kinase inhibitors (TKIs) have long been investigated, with some showing favorable clinical outcomes. However, major setbacks such as limited clinical efficacy and the high risk of acquired resistance remain unresolved. FLT3 signaling, mutations, and FLT3 inhibitors are topics that have been extensively reviewed in recent years. Strategies to target FLT3 beyond the small molecule kinase inhibitors are expanding, nevertheless they are not receiving enough attention. These modalities include antibody-based FLT3 targeted therapies, immune cells mediated targeting strategies, and approaches targeting downstream signaling pathways and FLT3 translation. Here, we review the most recent advances and the challenges associated with the development of therapeutic modalities targeting FLT3 beyond the kinase inhibitors.


Assuntos
Tirosina Quinase 3 Semelhante a fms , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Mutação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/genética , Tirosina Quinase 3 Semelhante a fms/efeitos dos fármacos , Tirosina Quinase 3 Semelhante a fms/genética
8.
J Pediatr Orthop ; 41(4): e328-e336, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33560708

RESUMO

PURPOSE: The purpose of this study was to analyze the long-term results of humeral lengthening in achondroplastic patients and make suggestions on the most appropriate surgical technique to improve patient outcomes. METHODS: Fifty-four humeral lengthening procedures performed in 27 achondroplastic patients were reviewed. Elongations were performed by means of callotasis with unilateral external fixation. Inclusion criteria were: achondroplastic patients under 17 years without prior arm operations and minimum follow-up of 36 months. RESULTS: Fifty humeri in 25 patients (13 men and 12 women), aged between 9 and 17 years, met the inclusion criteria. Mean humeral lengthening was 8.82 cm (range: 5 to 10.5 cm), which represented an elongation of 54.80% (range: 46% to 63%) of the original length. The healing index was 0.91 months (range: 0.72 to 1.4 mo) per centimeter gained. Shoulder and elbow range of motion and stability were preserved in 47 limbs. Noncomplicated cases consistently experienced a significant functional improvement in the performance of activities of daily living such as putting on footwear and personal hygiene. Short-term complications included 11 pin-tract infections, 1 radial nerve neuropraxia, and 1 failure of the regenerated bone formation. None of these complications prevented from completion of treatment. Long-term complications included 2 cases of nonunion, 3 elbow flexion contractures, and 2 cases of psychological dissatisfaction, all of them in 4 patients. Factors associated with long-term complications were intraoperative fragment displacement and distal humeral osteotomy. No fractures of the regenerated bone were identified in the long term. CONCLUSIONS: Callotasis with unilateral external fixation is a reliable and well-tolerated procedure for humeral lengthening in achondroplastic patients, with an acceptable complication rate. Guided fixator placement and a proximal humeral osteotomy are strongly recommended technical tips as they may help prevent complications and improve outcomes. LEVEL OF EVIDENCE: Level IV-case series.


Assuntos
Acondroplasia/cirurgia , Úmero/crescimento & desenvolvimento , Úmero/cirurgia , Atividades Cotidianas , Adolescente , Criança , Articulação do Cotovelo/fisiopatologia , Fixadores Externos/efeitos adversos , Feminino , Humanos , Masculino , Osteogênese por Distração/efeitos adversos , Osteogênese por Distração/métodos , Osteotomia/efeitos adversos , Amplitude de Movimento Articular , Articulação do Ombro/fisiopatologia , Resultado do Tratamento , Cicatrização
9.
J Pediatr Orthop B ; 30(2): 180-189, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32694434

RESUMO

The objective of the study is to evaluate the natural history of the medial epicondyle avulsion in children with nonoperative treatment (NOPT) on different magnitude of displacement and long-term follow-up. A prospective study of 34 patients with medial epicondyle avulsion with (NOPT) was performed. Clinical test (stability, strength, atrophy, tenderness, Tinel test, and range of motion), subjective scores [Visual Analog Scale (VAS), Likert scale, side-to-side valgus test], and objective four scores were performed. Age at the time of injury was 8.9 ± 2.81 years. Follow-up was 7 ± 2.81 years. Four of the patients had anterior displacement. Displacement varied between 3 and 26 mm (10.49 ± 6.16 mm). Subjective: VAS and ordinal three-point Likert scale were excellent. Objective results were also excellent Mayo Elbow Score: 98.67 ± 4.31 (85-100), Oxford Elbow Score: 59.35 ± 1.68 (51-100), Elbow Assessment Score System: 96.27 ± 9.77 (57-100), Disabilities of the Arm, Shoulder, and Hand (DASH) score 0.64 ± 1.001 (0-4.16). We did not find any differences in strength or forearm diameter. There was an extension deficit in seven cases with a significant association with the magnitude of displacement (P = 0.02) and with the presence of concomitant lesions or anterior displacement of the medial epicondyle >5 mm. All except one were stable clinically on valgus stress. There is a significant association between the objective outcomes (scores) and concomitant lesions but not with regards to the DASH score P = 0.102). There is no association between the magnitude of medial epicondyle displacement or the follow-up and the objective outcomes. Instability was associated with valgus stress activities. There is no association between the magnitude of displacement of the medial epicondyle or the follow-up and the objective outcomes. NOPT produces excellent subjective and objective outcomes that worsened when there were associated lesions, anterior medial epicondyle displacement, or in patients who performed activities with repeated valgus stress. Based on our study, NOPT is suitable except for Open Reduction Internal Fixation indications: absolute indications, high energy injury with associated lesions, medial humeral epicondyle fracture in the dominant elbow in patients subject to activities with chronic valgus stress, and anterior displacement.


Assuntos
Articulação do Cotovelo , Fraturas do Úmero , Criança , Articulação do Cotovelo/diagnóstico por imagem , Fixação Interna de Fraturas , Humanos , Fraturas do Úmero/diagnóstico por imagem , Fraturas do Úmero/terapia , Úmero , Estudos Prospectivos , Amplitude de Movimento Articular , Resultado do Tratamento
10.
Curr Opin Pediatr ; 33(1): 79-89, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33337607

RESUMO

PURPOSE OF REVIEW: Premature Physeal Closure (PPC) is the most common consequence of a mostly posttraumatic, physeal injury. They are of utmost importance because they can significantly alter physeal function and lead to disorders such as limb length discrepancies and angular deformities. RECENT FINDINGS: The type of physeal fracture has not demonstrated a solid predictive value in the formation of PPC, especially in the knee where almost any type of fracture can produce it. The detection of physeal damage with imaging tests (simple radiology and MRI) is very accurate; however, their predictive capacity to foretell which injury will generate a physeal bridge is still poor. For this reason, it is not advisable to make surgical decisions at the first medical assessment. Direct surgical management of PPC's (resection-interposition technique) has generally shown high unpredictability. Nevertheless, the latest interposition materials (chondrocytes and mesenchymal stem cells) showed promising results. SUMMARY: PPC is an often devastating consequence of physeal injury and as such deserves further research. To date little is known about etiopathogenesis, risk factors and natural history among other aspects. Until direct surgery offers more consistent results, acute osteotomies and bone distraction for progressive correction continue to be the most widespread treatments for PPCs.


Assuntos
Lâmina de Crescimento , Imageamento por Ressonância Magnética , Humanos , Radiografia
11.
Rev. cuba. ortop. traumatol ; 34(2): e273, jul.-dic. 2020. ilus
Artigo em Espanhol | LILACS, CUMED | ID: biblio-1156599

RESUMO

RESUMEN Cronobacter sakazakii es una bacteria Gram negativa que pertenece a un grupo emergente de patógenos oportunistas de la familia de los Enterococos, que causa infecciones nosocomiales. Afecta típicamente a los recién nacidos de bajo peso; puede causar graves infecciones como meningitis, sepsis o enterocolitis necrotizante, potencialmente mortales, aunque la gran mayoría de las infecciones se producen en pacientes ancianos, en los que son mucho más leves. Se reporta el primer caso confirmado de infección de herida quirúrgica en España causada por C. sakazakii en un adulto inmunocompetente(AU)


ABSTRACT Cronobacter sakazakii is a Gram negative bacterium that belongs to an emerging group of opportunistic pathogens of the Enterococci family, which causes nosocomial infections. It typically affects low birth weight newborns. It can cause serious infections such as meningitis, sepsis, or life-threatening necrotizing enterocolitis, although the vast majority of infections occur in elderly patients, where they are much milder. We report the first confirmed case of surgical wound infection in Spain, caused by C. sakazakii in an immunocompetent adult(AU)


Assuntos
Humanos , Masculino , Idoso , Infecção da Ferida Cirúrgica/etiologia , Infecções por Enterobacteriaceae/etiologia , Fraturas Ósseas/cirurgia , Fíbula/lesões , Redução Aberta/efeitos adversos
12.
J Pharm Sci ; 109(12): 3524-3534, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32971125

RESUMO

The field of human therapeutics has expanded tremendously from small molecules to complex biological modalities, and this trend has accelerated in the last two decades with a greater diversity in the types and applications of novel modalities, accompanied by increasing sophistication in drug delivery technology. These innovations have led to a corresponding increase in the number of therapies seeking regulatory approval, and as the industry continues to evolve regulations will need to adapt to the ever-changing landscape. The growth in this field thus represents a challenge for regulatory authorities as well as for sponsors. This review provides a brief description of novel biologics, including innovative antibody therapeutics, genetic modification technologies, new developments in vaccines, and multifunctional modalities. It also describes a few pertinent drug delivery mechanisms such as nanoparticles, liposomes, coformulation, recombinant human hyaluronidase for subcutaneous delivery, pulmonary delivery, and 3D printing. In addition, it provides an overview of the current CMC regulatory challenges and discusses potential methods of accelerating regulatory mechanisms for more efficient approvals. Finally, we look at the future of biotherapeutics and emphasize the need to bring these modalities to the forefront of patient care from a global perspective as effectively as possible.


Assuntos
Sistemas de Liberação de Medicamentos , Nanopartículas , Impressão Tridimensional , Vacinas , Humanos , Lipossomos
13.
Eur J Med Chem ; 208: 112792, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32949964

RESUMO

In medicinal chemistry, it is extremely important to evaluate, as accurately as possible, the molecular interactions involved in the formation of different ligand-receptor (L-R) complexes. Evaluating the different molecular interactions by quantum mechanics calculations is not a simple task, since formation of an L-R complex is a dynamic process. In this case, the use of combined techniques of molecular dynamics (MD) and quantum calculations is one the best possible approaches. In this work we report a comparative study using combined MD and QTAIM (Quantum Theory of Atoms In Molecules) calculations for five biological systems with different levels of structural complexity. We have studied Acetylcholinesterase (AChE), D2 Dopamine Receptor (D2DR), beta Secretase (BACE1), Dihydrofolate Reductase (DHFR) and Sphingosine Kinase 1 (SphK1). In these molecular targets, we have analyzed different ligands with diverse structural characteristics. The inhibitory activities of most of them have been previously measured in our laboratory. Our results indicate that QTAIM calculations can be extremely useful for in silico studies. It is possible to obtain very accurate information about the strength of the molecular interactions that stabilize the formation of the different L-R complexes. Better correlations can be obtained between theoretical and experimental data by using QTAIM calculations, allowing us to discriminate among ligands with similar affinities. QTAIM analysis gives fairly accurate information for weak interactions which are not well described by MD simulations. QTAIM study also allowed us to evaluate and determine which parts of the ligand need to be modified in order to increase its interactions with the molecular target. In this study we have discussed the importance of combined MD/QTAIM calculations for this type of simulations, showing their scopes and limitations.


Assuntos
Acetilcolinesterase/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Receptores de Dopamina D2/metabolismo , Tetra-Hidrofolato Desidrogenase/metabolismo , Acetilcolinesterase/química , Secretases da Proteína Precursora do Amiloide/química , Ligantes , Modelos Químicos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Fosfotransferases (Aceptor do Grupo Álcool)/química , Teoria Quântica , Receptores de Dopamina D2/química , Tetra-Hidrofolato Desidrogenase/química , Termodinâmica
14.
Trends Pharmacol Sci ; 41(8): 518-530, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32576386

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected several millions and killed more than quarter of a million worldwide to date. Important questions have remained unanswered: why some patients develop severe disease, while others do not; and what roles do genetic variabilities play in the individual immune response to this viral infection. Here, we discuss the critical role T cells play in the orchestration of the antiviral response underlying the pathogenesis of the disease, COVID-19. We highlight the scientific rationale for comprehensive and longitudinal TCR analyses in COVID-19 and reason that analyzing TCR repertoire in COVID-19 patients would reveal important findings that may explain the outcome disparity observed in these patients. Finally, we provide a framework describing the different strategies, the advantages, and the challenges involved in obtaining useful TCR repertoire data to advance our fight against COVID-19.


Assuntos
Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , Receptores de Antígenos de Linfócitos T/imunologia , Animais , COVID-19 , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Humanos , Pandemias , Pneumonia Viral/genética , Pneumonia Viral/imunologia , SARS-CoV-2 , Linfócitos T/imunologia
15.
Molecules ; 25(7)2020 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-32290227

RESUMO

Neurodegenerative diseases in which the decrease of the acetylcholine is observed are growing worldwide. In the present study, a series of new arylaminopropanone derivatives with N-phenylcarbamate moiety (1-16) were prepared as potential acetylcholinesterase and butyrylcholinesterase inhibitors. In vitro enzyme assays were performed; the results are expressed as a percentage of inhibition and the IC50 values. The inhibitory activities were compared with reference drugs galantamine and rivastigmine showing piperidine derivatives (1-3) as the most potent. A possible mechanism of action for these compounds was determined from a molecular modelling study by using combined techniques of docking, molecular dynamics simulations and quantum mechanics calculations.


Assuntos
Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Propanolaminas/química , Propanolaminas/farmacologia , Inibidores da Colinesterase/síntese química , Ativação Enzimática/efeitos dos fármacos , Humanos , Modelos Moleculares , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Propanolaminas/síntese química , Ligação Proteica , Relação Estrutura-Atividade
16.
Mol Inform ; 39(11): e1900125, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32048433

RESUMO

Alzheimer's dementia is a neurodegenerative disease that affects the elderly population and causes memory impairment and cognitive deficit. Manifestation of this disease is associated to acetylcholine decrease; thus, Cholinesterase inhibition is the main therapeutic strategy for the treatment of Alzheimer's disease. In the present study, a series of aporphinoid alkaloids were tested as potential acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors in vitro. Alkaloids liriodenine (3) and cassythicine (10) were the best inhibitors of both cholinesterases with IC50 values lower than 10 µM. In addition, these alkaloids demonstrated better inhibition of BChE than reference drug galantamine. In addition, some alkaloids showed selective inhibition. Laurotetatine clorhydrate (13) selectively inhibit AChE over BChE. On the contrary, pachyconfine (7) interacted more efficiently with BChE active site. Molecular modelling studies were performed in order to illustrate key interactions between most active compounds and the enzymes and to explain their selectivity. These studies reveal that the benzodioxole moiety exhibits strong interactions due to hydrogen bonds that form with the Glu201 (AChE) and Tyr440 (BChE) residues, which is reflected in the IC50 values.


Assuntos
Alcaloides/farmacologia , Aporfinas/farmacologia , Inibidores da Colinesterase/farmacologia , Simulação de Acoplamento Molecular , Acetilcolinesterase/metabolismo , Alcaloides/química , Animais , Aporfinas/química , Butirilcolinesterase/metabolismo , Electrophorus , Galantamina/química , Cavalos , Concentração Inibidora 50 , Teoria Quântica , Eletricidade Estática
17.
Future Med Chem ; 12(4): 277-297, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32043377

RESUMO

Aim: DNA gyrase and topoisomerase IV are essential bacterial enzymes, and in the fight against bacterial resistance, they are important targets for the development of novel antibacterial drugs. Results: Building from our first generation of 4,5,6,7-tetrahydrobenzo[d]thiazole-based DNA gyrase inhibitors, we designed and prepared an optimized series of analogs that show improved inhibition of DNA gyrase and topoisomerase IV from Staphylococcus aureus and Escherichia coli, with IC50 values in the nanomolar range. Importantly, these inhibitors also show improved antibacterial activity against Gram-positive strains. Conclusion: The most promising inhibitor, 29, is active against Enterococcus faecalis, Enterococcus faecium and S. aureus wild-type and resistant strains, with minimum inhibitory concentrations between 4 and 8 µg/ml, which represents good starting point for development of novel antibacterials.


Assuntos
Antibacterianos/farmacologia , Benzotiazóis/farmacologia , DNA Girase/metabolismo , Bactérias Gram-Positivas/efeitos dos fármacos , Inibidores da Topoisomerase II/farmacologia , Antibacterianos/química , Benzotiazóis/química , Relação Dose-Resposta a Droga , Bactérias Gram-Positivas/enzimologia , Bactérias Gram-Positivas/crescimento & desenvolvimento , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/química
18.
Bioorg Chem ; 94: 103414, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31757412

RESUMO

Sphingosine-1-phosphate is now emerging as an important player in cancer, inflammation, autoimmune, neurological and cardiovascular disorders. Abundance evidence in animal and humans cancer models has shown that SphK1 is linked to cancer. Thus, there is a great interest in the development new SphK1 inhibitors as a potential new treatment for cancer. In a search for new SphK1 inhibitors we selected the well-known SKI-II inhibitor as the starting structure and we synthesized a new inhibitor structurally related to SKI-II with a significant but moderate inhibitory effect. In a second approach, based on our molecular modeling results, we designed new structures based on the structure of PF-543, the most potent known SphK1 inhibitor. Using this approach, we report the design, synthesis and biological evaluation of a new series of compounds with inhibitory activity against both SphK1 and SphK2. These new inhibitors were obtained incorporating new connecting chains between their polar heads and hydrophobic tails. On the other hand, the combined techniques of molecular dynamics simulations and QTAIM calculations provided complete and detailed information about the molecular interactions that stabilize the different complexes of these new inhibitors with the active sites of the SphK1. This information will be useful in the design of new SphK inhibitors.


Assuntos
Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Pirimidinas/uso terapêutico , Desenho de Fármacos , Humanos , Modelos Moleculares , Pirimidinas/farmacologia
19.
Rev. chil. ortop. traumatol ; 61(3): 101-107, 2020. ilus, tab
Artigo em Espanhol | LILACS | ID: biblio-1177772

RESUMO

INTRODUCCIÓN Y OBJETIVOS La artroplastia de resección de hombro (ARH) se presenta como una técnica obsoleta y una opción no válida en la actualidad, debido a la evolución de las técnicas quirúrgicas y de los implantes. Pero, como consecuencia del aumento exponencial del uso de artroplastias de hombro, están aumentando en paralelo el número de fracasos e infecciones, con necesidad de revisión y rescate. Es por ello que, en determinadas situaciones y pacientes, esa técnica vuelve a ser una opción necesaria como salvataje, aunque tiene un alto coste funcional. El objetivo de nuestro trabajo, es presentar dos casos de artroplastia de resección de hombro como una opción válida de tratamiento en la actualidad y la revisión de la literatura. CASOS Se presentan dos casos de ARH como tratamiento de rescate, en un caso de osteomielitis crónica de cabeza humeral y un caso de infección de hemiartroplastia de hombro. Ambos pacientes se encontraban sin dolor y libres de infección con un seguimiento de más de 30 meses. En un caso la funcionalidad fue limitada con un Constant de 45 pero el otro caso la funcionalidad fue aceptable con un Constant de 67. CONCLUSIONES La ARH sigue siendo una técnica útil tras el fracaso de procedimientos de revisión, para resolver infecciones protésicas recalcitrantes u osteomielitis. Los resultados funcionales son pobres, por lo que debe reservarse para pacientes con baja demanda funcional y como salvataje, tras agotar otras opciones.


INTRODUCTION AND OBJECTIVES shoulder resection arthroplasty (SRA) is currently considered as an outdated technique, due to the advances in surgical techniques and new prosthesis designs. However, with the exponential increase in the use of shoulder arthroplasties, the number of failures and infections is equally increasing, as well as the revisions and salvage procedures. In certain situations, SRA is therefore a necessary solution, although it grossly compromise shoulder function. The aim of our study is to present two cases who underwent SRA as a valid treatment option nowadays and a literature review. CASES We present two cases of SRA as salvatage treatment. First case in a chronic humeral head osteomyelitis and second in a partial shoulder prosthesis recalcitrant infection. Both patients had complete pain relief and infection was solved with a follow-up over 30 months. In the first case, postoperative shoulder function was limited with a Constant­Murley score of 45. In the second case, function was fairly good with a Constant of 67. CONCLUSIONS SRA remains a valuable technique after the failure of revision procedures, as a salvage for recalcitrant prosthetic infections or osteomyelitis. The functional results are poor, so it should be reserved for patients with low functional demand and as salvatage procedure, after assess other options.


Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Artroplastia/métodos , Ombro/cirurgia , Infecções Relacionadas à Prótese/cirurgia , Artroplastia do Ombro/efeitos adversos , Osteomielite , Reoperação , Terapia de Salvação , Infecções Relacionadas à Prótese/etiologia , Prótese de Ombro
20.
J Surg Case Rep ; 2019(6): rjz184, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31249660

RESUMO

We present a patient who suffered an unstable intertrochanteric hip fracture and underwent osteosynthesis with a trochanteric nail. During the postoperative period, he presented a pseudoaneurysm of the lateral circumflex branch of the deep femoral artery secondary to a displaced fracture of the lesser trochanter. With the suspected diagnosis due to indirect clinical and radiological signs and confirmation by Doppler ultrasound and computed tomography angiography, a transverse arterial embolization with resolution of the symptoms was carried out. The pseudoaneurysm of the deep femoral artery or its branches is a very rare complication after intertrochanteric hip fractures, which must be taken into account in the late appearance of edema and hematoma in the thigh and evidence of medial and superior displacement of the lesser trochanter. The diagnosis is confirmed by CT angiography and the treatment by percutaneous arterial embolization has good results without the need of excising the lesser trochanter.

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