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1.
Acta Pharm Sin B ; 13(4): 1648-1659, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37139407

RESUMO

Peptides are increasingly important resources for biological and therapeutic development, however, their intrinsic susceptibility to proteolytic degradation represents a big hurdle. As a natural agonist for GLP-1R, glucagon-like peptide 1 (GLP-1) is of significant clinical interest for the treatment of type-2 diabetes mellitus, but its in vivo instability and short half-life have largely prevented its therapeutic application. Here, we describe the rational design of a series of α/sulfono-γ-AA peptide hybrid analogues of GLP-1 as the GLP-1R agonists. Certain GLP-1 hybrid analogues exhibited enhanced stability (t 1/2 > 14 days) compared to t 1/2 (<1 day) of GLP-1 in the blood plasma and in vivo. These newly developed peptide hybrids may be viable alternative of semaglutide for type-2 diabetes treatment. Additionally, our findings suggest that sulfono-γ-AA residues could be adopted to substitute canonical amino acids residues to improve the pharmacological activity of peptide-based drugs.

2.
Can J Aging ; 42(2): 217-229, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36373328

RESUMO

Community support services are an integral enabler of aging in place. In social housing, older adult tenants struggle to access these services because of the siloed nature of housing and health services. This study examined the provision of government-funded community support services to 83 seniors' social housing buildings in Toronto, Ontario. Although there were 56 different agencies operating within the buildings, only about one third of older tenants were actually receiving services. There was a subset of services that were available in more than 80 per cent of the buildings, and the most widely accessed services were food supports, crisis intervention, transportation, caregiver support, and hearing/vision care. There were also many cases in which multiple agencies offered duplicative services within the same building, suggesting that there are opportunities for improving service coordination. Practice recommendations for increasing access to community support services among low-income older adults in social housing are provided.


Assuntos
Apoio Comunitário , Habitação , Humanos , Idoso , Ontário , Vida Independente , Pobreza
3.
ACS Chem Biol ; 17(5): 1249-1258, 2022 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-35417146

RESUMO

Recent clinical trials have revealed that the chimeric peptide hormones simultaneously activating glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) demonstrate superior efficacy in glycemic control and body weight reduction, better than those activating the GLP-1R alone. However, the linear peptide-based GLP-1R/GIPR dual agonists are susceptible to proteolytic cleavage by common digestive enzymes present in the gastrointestinal tract and thus not suitable for oral administration. Here, we report the design and synthesis of biaryl-stapled peptides, with and without fatty diacid attachment, that showed potent GLP-1R/GIPR dual agonist activities. Compared to a linear peptide dual agonist and semaglutide, the biaryl-stapled peptides displayed drastically improved proteolytic stability against the common digestive enzymes. Furthermore, two stapled peptides showed excellent efficacy in an oral glucose tolerance test in mice, owing to their potent receptor activity in vitro and good pharmacokinetics exposure upon subcutaneous injection. By exploring a more comprehensive set of biaryl staplers, we expect that this stapling method could facilitate the design of the stapled peptide-based dual agonists suitable for oral administration.


Assuntos
Receptores dos Hormônios Gastrointestinais , Animais , Polipeptídeo Inibidor Gástrico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Camundongos , Peptídeos/farmacologia , Receptores Acoplados a Proteínas G , Receptores dos Hormônios Gastrointestinais/agonistas
4.
J Med Chem ; 64(18): 13893-13901, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34506138

RESUMO

Peptide drugs have the advantages of target specificity and good drugability and have become one of the most increasingly important hotspots in new drug research in biomedical sciences. However, peptide drugs generally have low bioavailability and metabolic stability, and therefore, the modification of existing peptide drugs for the purpose of improving stability and retaining activity is of viable importance. It is known that glucagon is an effective therapy for treating severe hypoglycemia, but its short half-life prevents its wide therapeutic use. Herein, we report that combined unnatural residues and long fatty acid conjugation afford potent α/sulfono-γ-AApeptide hybrid analogues of Glucagon with enhanced stability and prolonged in vivo activity. This strategy could be adopted to develop stabilized analogues of other short-acting bioactive peptides.


Assuntos
Glucagon/análogos & derivados , Glucagon/uso terapêutico , Hipoglicemia/tratamento farmacológico , Sequência de Aminoácidos , Animais , Feminino , Glucagon/metabolismo , Glucagon/farmacocinética , Humanos , Masculino , Camundongos Endogâmicos C57BL , Engenharia de Proteínas , Estabilidade Proteica
5.
Psychol Health ; 36(1): 78-95, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32400190

RESUMO

OBJECTIVE: Matching between affect orientations and message frames have been shown to enhance the persuasiveness of health messages. Based on a two-dimensional regulatory model (direction: approach/avoidance, valence: appetitive/aversive), this study examined whether a precise matching between affect and message frame would enhance physical activity (PA) attitudes, intentions, and behaviours. DESIGN: Using a 2 (gain/loss frames) x 2 (positive/negative end-states) design, 147 college students were randomly assigned to one message-frame condition (gain-positive, gain-negative, loss-positive, or loss-negative). Four identified affect types (approach-positive, approach-negative, avoidance-positive, and avoidance-negative) were considered as matched, respectively, with the four message-frame conditions. The participants were subsequently grouped into fully-matched, direction-matched only, valence-matched only, or unmatched. MAIN OUTCOME MEASURES: The immediate PA attitude and intention after the experiment and the PA attitudes, intentions, and behaviours at a two-week follow-up were reported. RESULTS: Post-manipulation and follow-up intentions were greater in the fully-matched as compared with the unmatched group. Follow-up physical activity was more in the valence-matched than the unmatched group. No other differences were found across the matching types. CONCLUSION: Findings partially supported the importance of a precise matching between affect orientations and message frames. The affect types may characterize an individual's sensitivity towards the corresponding regulatory information.


Assuntos
Afeto , Exercício Físico/psicologia , Promoção da Saúde/métodos , Comunicação Persuasiva , Adolescente , Adulto , Feminino , Seguimentos , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Intenção , Masculino , Adulto Jovem
6.
Front Microbiol ; 11: 534404, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33123098

RESUMO

Global warming is considered a major threat to marine ecosystems, which affects bacterioplankton activity, diversity, and community composition. However, few studies focus on the potential effects of warming on bacterioplankton in subtropical coastal waters in different seasons. Here we investigated the influences of warming on growth, grazing and community composition of bacterioplankton in Hong Kong coastal waters during winter and summer via 1-day incubation experiments. Our results revealed that without grazers, bacterioplankton displayed higher growth rate during summer compared to winter, while warming only significantly increased the growth rate of bacterioplankton in winter. Grazers with size <5 µm were major predators of bacterioplankton. Warming had little effect on grazing in summer but significantly enhanced grazing rates of >5 µm grazers in winter. In both seasons, warming had little influence on bacterial diversity and community composition. Nevertheless, in family and OTU levels, bacterioplankton had different responses to grazing and warming which may result from the selective grazing preference of predators and different temperature optima for bacterioplankton. Furthermore, the presence of >5 µm and <5 µm grazers would result in significant increase of some bacterial families under warming condition. Together, our results suggest that warming have direct impacts on bacterioplankton in subtropical coastal waters during winter and may thus affect global biogeochemical cycles.

7.
Can J Hosp Pharm ; 73(4): 257-265, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33100357

RESUMO

BACKGROUND: With the increasing use of electronic point-of-care resources, it is imperative to clearly understand what health professionals consider valuable when selecting a drug information database. A current analysis of the preferences of staff in selected British Columbia health authorities was deemed helpful for determining which electronic drug information database should be purchased. OBJECTIVES: To determine the factors that BC hospital pharmacists, nurses, and other health professionals value in an electronic drug information database and to better understand the general preferences of staff in choosing between the Lexicomp and Micromedex databases. METHODS: An electronic survey was created for data collection. The survey was open from August 10 to September 15, 2018, and again from November 11 to December 7, 2018. The survey link was sent by e-mail to staff in the following health authorities: Fraser Health, Providence Health Care, Provincial Health Services Authority, and Vancouver Coastal Health. Qualitative and quantitative methods were used to analyze the survey data. RESULTS: A total of 247 responses were received, of which 145 (58.7%) were complete. Completed surveys were received from 77 pharmacists, 52 nurses, and 16 other health professionals. Participants ranked dosing information and ease of use as the most important factors that they considered when choosing a drug information database. There were no significant differences between the Lexicomp and Micromedex resources in terms of usability, quality, and preference. CONCLUSIONS: This survey provided insights into what BC health authority staff perceive as important when utilizing a drug information database. Those considering either renewing or initiating a subscription to an online drug information database can use these results to better understand the preferences of health care professionals. Survey respondents ranked dosing information and ease of use as the 2 most important factors in selecting a drug information database. Pharmacists were more particular about using their preferred database than were other health professionals.


CONTEXTE: Avec l'utilisation croissante de ressources électroniques aux points de services, il est impératif de bien comprendre ce que les professionnels de la santé estiment important lorsqu'ils choisissent une base de données sur les médicaments. Une analyse actuelle des préférences des membres du personnel des autorités sanitaires sélectionnées de la Colombie-Britannique a été jugée utile pour déterminer le type de base de données sur les médicaments à acheter. OBJECTIFS: Déterminer quels facteurs sont importants pour les pharmaciens d'hôpitaux, les infirmiers et les autres professionnels de la santé de la C.-B. lors du choix d'une base de données électronique sur les médicaments et mieux cerner les préférences générales des membres du personnel lorsqu'ils choisissent entre les bases de données Lexicomp et Micromedex. MÉTHODES: Un sondage électronique a servi à la collecte des données. Il s'est déroulé du 10 août au 15 septembre 2018, et à nouveau du 11 novembre au 7 décembre 2018. Les membres du personnel des autorités sanitaires suivantes ont reçu le lien menant au sondage: Fraser Health, Providence Health Care, Provincial Health Services Authority et Vancouver Coastal Health. L'analyse des données a été effectuée à l'aide de méthodes qualitatives et quantitatives. RÉSULTATS: Les investigateurs ont reçu 247 réponses, dont 145 étaient complètes (58,7 %). Soixante-dix-sept (77) pharmaciens, 52 infirmiers et 16 autres professionnels de la santé ont dument rempli le sondage. Les participants ont indiqué que les renseignements sur le dosage et la facilité d'utilisation étaient les deux facteurs les plus importants à prendre en compte lors du choix d'une base de données sur les médicaments. Aucune différence significative n'est ressortie entre les bases de données Lexicomp et Micromedex quant à l'opérabilité, la qualité et la préférence. CONCLUSIONS: Ce sondage a permis de fournir un aperçu sur ce que les membres du personnel des autorités sanitaires de la C.-B. percevaient comme important pour l'utilisation d'une base de données sur les médicaments. Les personnes qui ont l'intention de renouveler ou de souscrire un abonnement à une base de données sur les médicaments en ligne peuvent utiliser ces résultats pour mieux cerner les préférences des professionnels de la santé. Les répondants ont indiqué que les renseignements sur le dosage et la facilité d'utilisation étaient les deux facteurs les plus importants à prendre en compte lors du choix d'une base de données sur les médicaments. Les pharmaciens étaient moins disposés que les autres professionnels de la santé à changer leur base de données préférée pour une autre.

8.
Can J Hosp Pharm ; 73(3): 186-192, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616944

RESUMO

BACKGROUND: Sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor indicated in the management of heart failure with reduced ejection fraction, based on the results of the PARADIGM-HF trial. Practice-based studies are needed to validate its effect in real-world settings. Clinical pharmacists are ideally situated to assess and titrate sacubitril/valsartan. OBJECTIVE: To evaluate the utilization, safety, and tolerability of sacubitril/valsartan in a multidisciplinary heart failure clinic, with assessment and titration by a clinical pharmacist or a nurse practitioner. METHODS: A retrospective cohort study was conducted at a heart failure clinic in Abbotsford, Canada. Included were adult patients with heart failure who were currently or formerly taking sacubitril/valsartan. Data collected for the period October 2015 to February 2019 included patient characteristics, New York Heart Association (NYHA) classification, concurrent medications, sacubitril/valsartan dose, adverse effects, and discontinuation rate. RESULTS: In total, 128 patients were included. Mean age was 70.1 years, 98 (77%) of the patients were men, and 79 (62%) had NYHA class 2 heart failure. The clinical pharmacist managed care for 78 (61%) of the patients, and the nurse practitioner managed care for 50 (39%). Forty-one (32%) of the patients met modified PARADIGM-HF inclusion criteria. Eighty-five (66%) of the patients achieved the target dose of sacubitril/valsartan, with similar proportions for the clinical pharmacist and nurse practitioner groups, over a mean of 2.2 clinic visits. Patients who achieved the sacubitril/valsartan target dose, relative to those who did not, were significantly younger and had higher mean systolic blood pressure at baseline. Twenty-nine percent of patients (35/119) had an improvement in NYHA classification from before initiation of sacubitril/valsartan to achievement of target or maximally tolerated dose. Eighty-five (66%) of the patients experienced an adverse effect, primarily hypotension, and 12 (9%) required a dose reduction. Only 9 (7%) patients discontinued therapy. CONCLUSIONS: This study demonstrates the real-world safety and tolerability of sacubitril/valsartan in the treatment of heart failure, and reinforces that clinical pharmacists can effectively assess and titrate medications in a multidisciplinary heart failure clinic.


CONTEXTE: Le sacubitril-valsartan est un inhibiteur novateur des récepteurs de l'angiotensine-néprilysine, indiqué dans la gestion de l'insuffisance cardiaque accompagnée d'une baisse de la fraction d'éjection, selon les résultats de l'essai PARADIGM-HF. Des études fondées sur la pratique sont nécessaires pour valider ses effets en contexte réel. Les pharmaciens cliniciens sont bien placés pour évaluer et titrer le sacubitril-valsartan. OBJECTIF: Évaluer l'utilisation, l'innocuité et le seuil de tolérance du sacubitril-valsartan en clinique multidisciplinaire d'insuffisance cardiaque, l'évaluation et le titrage étant effectués par un pharmacien clinicien ou une infirmière praticienne. MÉTHODES: Une étude de cohorte rétrospective a été menée au sein d'une clinique d'insuffisance cardiaque à Abbotsford, au Canada. Les patients adultes inclus dans l'étude souffraient d'insuffisance cardiaque, ils prenaient ou avaient pris du sacubitril-valsartan. Les données recueillies entre octobre 2015 et février 2019 comprenaient les caractéristiques des patients, la classification de la New York Heart Association (NYHA), les médicaments pris de façon concomitante, la dose de sacubitril-valsartan, les effets secondaires et le taux d'abandon. RÉSULTATS: Au total, 128 patients ont participé à l'étude. L'âge moyen des patients était de 70,1 ans, 98 d'entre eux (77 %) étaient des hommes et 79 (62 %) souffraient d'une insuffisance cardiaque de classe 2 selon la classification de la NYHA. Le pharmacien clinicien gérait les soins de 78 patients (61 %) et la pharmacienne praticienne gérait ceux de 50 patients (39 %). Quarante-et-un patients (32 %) répondaient aux critères d'inclusion modifiés de PARADIGM-HF. Quatre-vingt-cinq (66 %) patients atteignaient le dosage ciblé de sacubitril-valsartan dans des proportions similaires entre le groupe du pharmacien clinicien et celui de l'infirmière praticienne, à raison d'une moyenne de 2,2 visites en clinique. Les patients ayant atteint le dosage ciblé de sacubitril-valsartan, par rapport à ceux ne l'ayant pas atteint, étaient considérablement plus jeunes et leur tension artérielle systolique moyenne de base était plus élevée. Une amélioration de la classification NYHA a été observée chez 29 % des patients (35/119) entre le début de la prise de sacubitril-valsartan et l'atteinte du dosage ciblé ou de la dose maximale tolérée. Des effets secondaires ont été observés chez 85 patients (66 %), principalement une hypotension, et 12 d'entre eux (9 %) ont dû réduire la dose. Seuls 9 patients (7 %) ont dû abandonner la thérapie. CONCLUSIONS: Cette étude démontre l'innocuité et le seuil de tolérance en contexte réel du sacubitril-valsartan pour le traitement de l'insuffisance cardiaque. Elle renforce le fait que les pharmaciens cliniciens peuvent efficacement évaluer et titrer des médicaments au sein d'une clinique d'insuffisance cardiaque multidisciplinaire.

9.
Molecules ; 25(11)2020 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-32481528

RESUMO

Owing to their pleiotropic metabolic benefits, glucagon-like peptide-1 receptor (GLP-1R) agonists have been successfully utilized for treating metabolic diseases, such as type 2 diabetes and obesity. As part of our efforts in developing long-acting peptide therapeutics, we have previously reported a peptide engineering strategy that combines peptide side chain stapling with covalent integration of a serum protein-binding motif in a single step. Herein, we have used this strategy to develop a second generation extendin-4 analog rigidified with a symmetrical staple, which exhibits an excellent in vivo efficacy in an animal model of diabetes and obesity. To simplify the scale-up manufacturing of the lead GLP-1R agonist, a semisynthesis protocol was successfully developed, which involves recombinant expression of the linear peptide followed by attachment of a polyethylene glycol (PEG)-fatty acid staple in a subsequent chemical reaction step.


Assuntos
Exenatida/análogos & derivados , Exenatida/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Animais , Diabetes Mellitus Tipo 2 , Exenatida/química , Ácidos Graxos/química , Masculino , Camundongos , Estrutura Molecular , Obesidade , Peptídeos/química , Peptídeos/metabolismo , Polietilenoglicóis/química
10.
Sci Adv ; 6(20): eaaz4988, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32440547

RESUMO

Existing long α-helix mimicking necessitates the retention of most natural amino acid residues to maintain their biological activity. Here, we report the exploration of helical sulfono-γ-AApeptides with entire unnatural backbones for their ability to structurally and functionally mimic glucagon-like peptide 1 (GLP-1). Our findings suggest that efficient construction of novel GLP-1 receptor (GLP-1R) agonists could be achieved with nanomolar potencies. In addition, the resulting sulfono-γ-AApeptides were also proved to display remarkable stability against enzymatic degradation compared to GLP-1, augmenting their biological potential. This alternative strategy of α-helix mimicking, as a proof of concept, could provide a new paradigm to prepare GLP-1R agonists.


Assuntos
Peptídeo 1 Semelhante ao Glucagon , Peptidomiméticos , Peptídeos/química , Peptidomiméticos/química , Conformação Proteica em alfa-Hélice
11.
Bioconjug Chem ; 31(4): 1167-1176, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32243137

RESUMO

Oxyntomodulin (OXM) is an intestinal peptide hormone that activates both glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptors. The natural peptide reduces body weight in obese subjects and exhibits direct acute glucoregulatory effects in patients with type II diabetes. However, the clinical utility of OXM is limited due to its lower in vitro potency and short in vivo half-life. To overcome these issues, we developed stapled, long-acting, and highly potent OXM analogs with balanced activities at both GLP-1 and GCG receptors. The lead molecule O14 exhibits potent and long-lasting effects on glucose control, body weight loss, and reduction of hepatic fat reduction in DIO mice. Importantly, O14 significantly reversed hepatic steatosis; reduced liver weight, total cholesterol, and hepatic triglycerides; and improved markers of liver function in a nonalcoholic steatohepatitis (NASH) mouse model. A symmetrical version of the peptide was also shown to be more efficacious and long-lasting in controlling glucose than semaglutide and the clinical candidate cotadutide in wild-type mice, highlighting the utility of our designs of the dual agonist as a potential new therapy for diabetes and liver diseases.


Assuntos
Peso Corporal/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Oxintomodulina/farmacologia , Oxintomodulina/farmacocinética , Animais , Glicemia/metabolismo , Colesterol/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Hepatopatia Gordurosa não Alcoólica/sangue , Oxintomodulina/uso terapêutico , Triglicerídeos/metabolismo
12.
J Med Chem ; 63(1): 382-390, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31850759

RESUMO

The effects of oxytocin on food intake and body weight reduction have been demonstrated in both animal models and human clinical studies. Despite being efficacious, oxytocin is enzymatically unstable and thus considered to be unsuitable for long-term use in patients with obesity. Herein, a series of oxytocin derivatives were engineered through conjugation with fatty acid moieties that are known to exhibit high binding affinities to serum albumin. One analog (OT-12) in particular was shown to be a potent full agonist at the oxytocin receptor (OTR) in vitro with good selectivity and long half-life (24 h) in mice. Furthermore, OT-12 is peripherally restricted, with very limited brain exposure (1/190 of the plasma level). In a diet-induced obesity mouse model, daily subcutaneous administration of OT-12 exhibited more potent anorexigenic and body weight reducing effects than carbetocin. Thus, our results suggest that the long-acting, peripherally restricted OTR agonist may offer potential therapeutic benefits for obesity.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Depressores do Apetite/uso terapêutico , Lipopeptídeos/uso terapêutico , Ocitocina/análogos & derivados , Ocitocina/uso terapêutico , Receptores de Ocitocina/agonistas , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacocinética , Depressores do Apetite/síntese química , Depressores do Apetite/farmacocinética , Peso Corporal/efeitos dos fármacos , Humanos , Lipopeptídeos/síntese química , Lipopeptídeos/farmacocinética , Masculino , Camundongos Endogâmicos BALB C , Obesidade/tratamento farmacológico , Ocitocina/farmacocinética , Engenharia de Proteínas , Redução de Peso/efeitos dos fármacos
13.
ACS Med Chem Lett ; 10(8): 1166-1172, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31413801

RESUMO

Anorexigenic peptides offer promise as potential therapies targeting the escalating global obesity epidemic. Prolactin-releasing peptide (PrRP), a novel member of the RFamide family secreted by the hypothalamus, shows therapeutic potential by decreasing food intake and body weight in rodent models via GPR10 activation. Here we describe the design of a long-acting PrRP using our recently developed novel multiple ethylene glycol-fatty acid (MEG-FA) stapling platform. By incorporating serum albumin binding fatty acids onto a covalent side chain staple, we have generated a series of MEG-FA stapled PrRP analogs with enhanced serum stability and in vivo half-life. Our lead compound 18-S4 exhibits good in vitro potency and selectivity against GPR10, improved serum stability, and extended in vivo half-life (7.8 h) in mouse. Furthermore, 18-S4 demonstrates a potent body weight reduction effect in a diet-induced obesity (DIO) mouse model, representing a promising long-acting PrRP analog for further evaluation in the chronic obesity setting.

14.
Bioconjug Chem ; 30(1): 83-89, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30543420

RESUMO

Peptide hormone relaxin-2, a member of the insulin family of peptides, plays a key role in hemodynamics and renal function and has shown preclinical efficacy in multiple disease models, including acute heart failure, fibrosis, preeclampsia, and corneal wound healing. Recently, serelaxin, a recombinant version of relaxin-2, has been studied in a large phase 3 clinical trial (RELAX-AHF-2) for acute decompensated heart failure patients with disappointing outcome. The poor in vivo half-life of relaxin-2 may have limited its therapeutic efficacy and long-term cardiovascular benefit. Herein, we have developed a semisynthetic methodology and generated potent, fatty acid-conjugated relaxin analogs with long-acting pharmacokinetic (PK) profile in rodents. The enhanced PK properties translated into improved and long-lasting pharmacodynamic effect in pubic ligament elongation (PLE) studies. The resultant novel relaxin analog, R9-13, represents the first long-acting relaxin-2 analog and could potentially improve the clinical efficacy and outcome for this important peptide hormone. This semisynthetic methodology could also be applied to other cysteine-rich peptides and proteins for half-life extension.


Assuntos
Desenho de Fármacos , Lipídeos/química , Relaxina/química , Relaxina/uso terapêutico , Sequência de Aminoácidos , Animais , Meia-Vida , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapêutico , Relaxina/farmacocinética
15.
Am J Occup Ther ; 72(5): 7205195020p1-7205195020p7, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30157010

RESUMO

The main purpose of this study was to estimate the minimal detectable change (MDC) on the Lawton Instrumental Activities of Daily Living (LIADL) scale in community-dwelling patients with schizophrenia. Fifty-seven patients completed the LIADL assessment twice, about 14 days apart. Two scoring methods (dichotomous and polytomous) were used to record the patients' performance on the LIADL scale. The MDCs of the LIADL scale were 1.5 (dichotomous) and 4.4 (polytomous) points. The MDC percentages were 22.0% (dichotomous) and 22.5% (polytomous), both of which are within acceptable measurement errors. The test-retest reliabilities of the LIADL scale were both acceptable with two different scoring methods (dichotomous = .75; polytomous = .76). Users can choose the scoring method according to their individual needs.


Assuntos
Atividades Cotidianas/classificação , Vida Independente/psicologia , Psicometria/estatística & dados numéricos , Esquizofrenia/reabilitação , Psicologia do Esquizofrênico , Inquéritos e Questionários , Adulto , Feminino , Seguimentos , Humanos , Masculino , Reprodutibilidade dos Testes
16.
J Med Chem ; 61(7): 3218-3223, 2018 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-29528634

RESUMO

Glucagon-like peptide 2 (GLP-2) is a hormone that has been shown to stimulate intestinal growth and attenuate intestinal inflammation. Despite being efficacious in a variety of animal models of disease, its therapeutic potential is hampered by the short half-life in vivo. We now describe a highly potent, stapled long-acting GLP-2 analog, peptide 10, that has a more than 10-fold longer half-life than teduglutide and improved intestinotrophic and anti-inflammatory effects in mouse models of DSS-induced colitis.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Colite/tratamento farmacológico , Fármacos Gastrointestinais/farmacologia , Peptídeo 2 Semelhante ao Glucagon/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacocinética , Colite/induzido quimicamente , Reagentes de Ligações Cruzadas , AMP Cíclico/biossíntese , Sulfato de Dextrana , Desenho de Fármacos , Feminino , Fármacos Gastrointestinais/síntese química , Fármacos Gastrointestinais/farmacocinética , Peptídeo 2 Semelhante ao Glucagon/síntese química , Peptídeo 2 Semelhante ao Glucagon/farmacocinética , Meia-Vida , Intestinos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Conformação Molecular , Peptídeos/farmacocinética , Peptídeos/farmacologia
17.
Res Dev Disabil ; 69: 30-38, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28802160

RESUMO

Visual perceptual motor skills have been proposed as underlying courses of handwriting difficulties. However, there is no evaluation tool currently available to assess these skills comprehensively and to serve as a sensitive measure. The purpose of this study was to validate the Computerized Perceptual Motor Skills Assessment (CPMSA), a newly developed evaluation tool for children in early elementary grades. Its test-retest reliability, concurrent validity, discriminant validity, and responsiveness were examined in 43 typically developing children and 26 children with handwriting difficulty. The CPMSA demonstrated excellent reliability across all subtests with intra-class correlation coefficients (ICCs)≥0.80. Significant moderate correlations between the domains of the CPMSA and corresponding gold standards including Beery VMI, the TVPS-3, and the eye-hand coordination subtest of the DTVP-2 demonstrated good concurrent validity. In addition, the CPMSA showed evidence of discriminant validity in samples of children with and without handwriting difficulty. This article provides evidence in support of the CPMSA. The CPMSA is a reliable, valid, and promising measure of visual perceptual motor skills for children in early elementary grades. Directions for future study and improvements to the assessment are discussed.


Assuntos
Avaliação da Deficiência , Escrita Manual , Psicometria/métodos , Desempenho Psicomotor , Criança , Desenho Assistido por Computador , Feminino , Humanos , Masculino , Destreza Motora , Reprodutibilidade dos Testes , Taiwan , Percepção Visual
18.
Can J Hosp Pharm ; 70(3): 215-223, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28680175

RESUMO

BACKGROUND: Increased prescribing of proton pump inhibitors (PPIs) in the past few decades can be attributed mainly to long-term use of this type of therapy. Recent evidence indicates signals of harm associated with long-term use of PPIs, such as increased risk of Clostridium difficile infection, recurrence of C. difficile infection, and fracture. A few studies have assessed the effectiveness of step-down management of patients receiving long-term PPI therapy in ambulatory care settings. However, it is unknown whether PPIs can be discontinued in older people without return of gastrointestinal symptoms. OBJECTIVES: To determine the proportion of residents receiving long-term PPI therapy who were able to discontinue the drug without experiencing gastrointestinal symptoms warranting recommencement of the PPI or initiation of a histamine-2 receptor antagonist. METHODS: The records of residents who had been taking a PPI for longer than 6 months at a single residential care site were audited by one pharmacist to determine the PPI indication. For residents who fit the criteria for discontinuation (no indication for long-term PPI therapy, not currently experiencing gastrointestinal symptoms, no previous trial of PPI discontinuation without success, and no anxiety when medications are discontinued), the pharmacist faxed a recommendation to discontinue PPI therapy without tapering to the physicians' offices. For cases in which the recommendation was accepted, 3 pharmacists followed the residents weekly for 8 weeks to assess whether gastrointestinal symptoms returned. RESULTS: The pharmacist identified 28 residents who fit the criteria, and the recommendation to discontinue therapy was accepted for 27. At 8 weeks after the intervention, 19 (70%) of these residents were still asymptomatic and did not require re-initiation of medications to manage their gastrointestinal symptoms. CONCLUSIONS: These results support discontinuation of long-term PPI therapy for older people who fit the criteria for discontinuation. The study provided limited evidence to support the use of tapering. However, tapering can be used to identify the lowest effective dose and may increase patient comfort with deprescribing. Further research is needed to determine the effects of and best approaches to PPI discontinuation in older populations.


CONTEXTE: L'augmentation des prescriptions d'inhibiteurs de la pompe à protons (IPP) au cours des dernières décennies peut être attribuée principalement à l'utilisation à long terme de ce type de traitement. Des données récentes indiquent que l'utilisation à long terme des IPP comporte des dangers potentiels, notamment une augmentation du risque d'infection par Clostridium difficile, de récurrence de cette infection et de fracture. Quelques études ont évalué l'efficacité de la déprescription des IPP chez des patients recevant un traitement prolongé en milieu ambulatoire. Cependant, on ne sait pas s'il est possible de cesser l'utilisation d'IPP chez le patient âgé tout en évitant la réapparition de symptômes gastro-intestinaux. OBJECTIF: Déterminer la proportion de résidents pour qui l'on a été en mesure de cesser le traitement à long terme par IPP sans qu'apparaissent des symptômes gastro-intestinaux nécessitant la reprise du traitement par IPP ou l'amorce d'un traitement par antagoniste des récepteurs H2 de l'histamine. MÉTHODES: L'étude a eu lieu dans un seul centre d'hébergement et de soins de longue durée. Un pharmacien y a analysé les dossiers médicaux des résidents qui prenaient des IPP depuis plus de six mois afin de déterminer l'indication du médicament. Pour les résidents répondant aux critères de déprescription (aucune indication pour un traitement d'entretien, aucun symptôme gastro-intestinal à l'heure actuelle, aucune tentative antérieure de déprescrire un IPP en vain et aucune réaction anxieuse à l'arrêt de traitements), le pharmacien a envoyé par télécopieur aux bureaux des médecins un document recommandant l'interruption du traitement par IPP sans posologie dégressive. Dans les cas où la recommandation a été acceptée, trois pharmaciens ont suivi hebdomadairement les résidents pendant huit semaines afin de vérifier si des symptômes gastro-intestinaux réapparaissaient. RÉSULTATS: Le pharmacien a repéré 28 résidents répondant aux critères et la recommandation d'interruption de traitement a été acceptée pour 27 d'entre eux. Huit semaines après l'intervention, 19 (70 %) de ces résidents étaient toujours asymptomatiques et n'ont pas eu besoin qu'on leur prescrive de nouveau des médicaments pour traiter des symptômes gastro-intestinaux. CONCLUSIONS: Ces résultats viennent appuyer l'interruption du traitement à long terme d'IPP chez le patient âgé qui répond aux critères d'interruption. Cette étude n'a founi que peu de preuves qui appuient le recours à la posologie dégressive. Cependant, celle-ci peut servir à déterminer quelle est la plus faible dose efficace et elle peut aider les patients à être plus à l'aise avec l'interruption du traitement. Des recherches plus approfondies sont nécessaires pour préciser les conséquences de l'arrêt des IPP chez les personnes âgées et la meilleure approche à cette fin.

19.
Free Radic Biol Med ; 110: 196-205, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28625484

RESUMO

The Nrf1 (Nuclear factor E2-related factor 1) transcription factor performs a critical role in regulating cellular homeostasis. Using a proteomic approach, we identified Host Cell Factor-1 (HCF1), a co-regulator of transcription, and O-GlcNAc transferase (OGT), the enzyme that mediates protein O-GlcNAcylation, as cellular partners of Nrf1a, an isoform of Nrf1. Nrf1a directly interacts with HCF1 through the HCF1 binding motif (HBM), while interaction with OGT is mediated through HCF1. Overexpression of HCF1 and OGT leads to increased Nrf1a protein stability. Addition of O-GlcNAc decreases ubiquitination and degradation of Nrf1a. Transcriptional activation by Nrf1a is increased by OGT overexpression and treatment with PUGNAc. Together, these data suggest that OGT can act as a regulator of Nrf1a.


Assuntos
Fator C1 de Célula Hospedeira/metabolismo , N-Acetilglucosaminiltransferases/metabolismo , Fator 1 Nuclear Respiratório/metabolismo , Processamento de Proteína Pós-Traducional , Acetilglucosamina/análogos & derivados , Acetilglucosamina/farmacologia , Sequência de Aminoácidos , Sítios de Ligação , Clonagem Molecular , Expressão Gênica , Glicosilação , Células HEK293 , Fator C1 de Célula Hospedeira/química , Fator C1 de Célula Hospedeira/genética , Humanos , N-Acetilglucosaminiltransferases/química , N-Acetilglucosaminiltransferases/genética , Fator 1 Nuclear Respiratório/química , Fator 1 Nuclear Respiratório/genética , Oximas/farmacologia , Fenilcarbamatos/farmacologia , Plasmídeos/química , Plasmídeos/metabolismo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estabilidade Proteica , Proteólise , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Ativação Transcricional/efeitos dos fármacos , Transfecção , Ubiquitinação
20.
FEBS J ; 280(15): 3609-20, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23702335

RESUMO

The ubiquitin-proteasome system is important in maintaining protein homeostasis. NFE2-related factor 1 (Nrf1), a transcription factor in the cap 'n' collar basic-leucine zipper family, regulates expression of cytoprotective genes. It was previously shown that liver-specific knockout of Nrf1 (Nrf1LKO) leads to hepatic cell death, steatohepatitis and cancer. However, the mechanisms underlying these pathologies are not clear. Here, we report that Nrf1 is critical for proteasome gene expression in the liver. Liver-specific knockout of Nrf1 results in impaired basal and induced expression of proteasome genes, and diminished proteasome activity in hepatocytes. In addition, our findings demonstrated that endoplasmic reticulum stress signaling pathway was also activated in Nrf1LKO livers. Inhibition of proteasome activity leads to endoplasmic reticulum stress in Nrf1-deficient hepatocytes, prompting the development of steatosis in the liver. Our results indicate that Nrf1 plays an integral role in the maintenance of proteasome function in hepatocytes and in the prevention of liver steatosis development. Moreover, these results highlight an association between proteasome dysfunction, endoplasmic reticulum stress and steatosis.


Assuntos
Estresse do Retículo Endoplasmático , Fígado Gorduroso/metabolismo , Hepatócitos/enzimologia , Fator 1 Relacionado a NF-E2/fisiologia , Complexo de Endopeptidases do Proteassoma/genética , Animais , Ácidos Borônicos , Bortezomib , Fígado Gorduroso/induzido quimicamente , Expressão Gênica , Regulação Enzimológica da Expressão Gênica , Fígado/metabolismo , Camundongos , Camundongos Knockout , Complexo de Endopeptidases do Proteassoma/metabolismo , Pirazinas
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