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1.
Ren Fail ; 41(1): 899-906, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31552773

RESUMO

Objective: To investigate effects of combination use of leflunomide and benazepril on diabetic nephropathy (DN) both in vivo and in vitro. Methods: The streptozotocin (STZ) induced Sprague-Dawley rats were treated with leflunomide (15 mg/kg/d), benazepril (15 mg/kg/d) or both the two drugs. Fasting blood glucose (FBG) and renal function indexes including blood urea nitrogen (BUN), serum creatinine (Scr), and proteinuria and kidney/body weight ratio (KW/BW) were measured. HE staining was used for histological analysis. The rat glomerular mesangial cells (RMCs) were treated with high-glucose (150 mg/ml) and the leflunomide and benazepril with both concentrations of 50 µmol/l were used to treat the high-glucose induced cells. TUNEL assay was used for measurement of cell apoptosis. Western blotting was conducted to determine expression of nuclear factor Kappa B (NF-κB), transforming growth factor-ß (TGF-ß) and transient receptor potential canonical 6 (TRPC6). Results: The body weight was significantly lower and all indexes of FBG, BUN, Scr, proteinuria and KW/BW ratio, GFR, as well as inflammatory factors TNF-α and IL-6 were significantly increased in the DN group after STZ treatment for 4 weeks. The treatment with leflunomide, benazepril or the both dramatically reduced the above effects induced by STZ, and the alteration was the most significant in the combination group. Treatment of leflunomide and benazepril significantly reduced expression levels of NF-κB, TGF-ß and TRPC6 in renal tissues of DN rats as well as in high-glucose induced RMCs. It was also observed leflunomide and benazepril reduced high-glucose induced cell apoptosis of RMCs. Conclusion: The combination use of leflunomide and benazepril could improve the renal function and reduce the renal injury of DN rats and could reduce the levels of NF-κb, TGF-ß and TRPC6 in both DN rats and high-glucose induced RMCs.


Assuntos
Apoptose/efeitos dos fármacos , Benzazepinas/farmacologia , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/tratamento farmacológico , Hiperglicemia/complicações , Leflunomida/farmacologia , Animais , Benzazepinas/uso terapêutico , Glicemia/análise , Linhagem Celular , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Sinergismo Farmacológico , Quimioterapia Combinada , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Hiperglicemia/sangue , Hiperglicemia/induzido quimicamente , Leflunomida/uso terapêutico , Masculino , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/patologia , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/toxicidade , Canais de Cátion TRPC/metabolismo , Fator de Crescimento Transformador beta/metabolismo
2.
Cochrane Database Syst Rev ; 8: CD009164, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31425618

RESUMO

BACKGROUND: Pharmacological treatments for tobacco dependence, such as nicotine replacement therapy (NRT), have been shown to be safe and effective interventions for smoking cessation. Higher levels of adherence to these medications increase the likelihood of sustained smoking cessation, but many smokers use them at a lower dose and for less time than is optimal. It is important to determine the effectiveness of interventions designed specifically to increase medication adherence. Such interventions may address motivation to use medication, such as influencing beliefs about the value of taking medications, or provide support to overcome problems with maintaining adherence. OBJECTIVES: To assess the effectiveness of interventions aiming to increase adherence to medications for smoking cessation on medication adherence and smoking abstinence compared with a control group typically receiving standard care. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group Specialized Register, and clinical trial registries (ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform) to the 3 September 2018. We also conducted forward and backward citation searches. SELECTION CRITERIA: Randomised, cluster-randomised or quasi-randomised studies in which adults using active pharmacological treatment for smoking cessation were allocated to an intervention arm where there was a principal focus on increasing adherence to medications for tobacco dependence, or a control arm providing standard care. Dependent on setting, standard care may have comprised minimal support or varying degrees of behavioural support. Included studies used a measure that allowed assessment of the degree of medication adherence. DATA COLLECTION AND ANALYSIS: Two authors independently screened studies for eligibility, extracted data for included studies and assessed risk of bias. For continuous outcome measures, we calculated effect sizes as standardised mean differences (SMDs). For dichotomous outcome measures, we calculated effect sizes as risk ratios (RRs). In meta-analyses for adherence outcomes, we combined dichotomous and continuous data using the generic inverse variance method and reported pooled effect sizes as SMDs; for abstinence outcomes, we reported and pooled dichotomous outcomes. We obtained pooled effect sizes with 95% confidence intervals (CIs) using random-effects models. We conducted subgroup analyses to assess whether the primary focus of the adherence treatment ('practicalities' versus 'perceptions' versus both), the delivery approach (participant versus clinician-centred) or the medication type were associated with effectiveness. MAIN RESULTS: We identified two new studies, giving a total of 10 studies, involving 3655 participants. The medication adherence interventions studied were all provided in addition to standard behavioural support.They typically provided further information on the rationale for, and emphasised the importance of, adherence to medication or supported the development of strategies to overcome problems with maintaining adherence (or both). Seven studies targeted adherence to NRT, two to bupropion and one to varenicline. Most studies were judged to be at high or unclear risk of bias, with four of these studies judged at high risk of attrition or detection bias. Only one study was judged to be at low risk of bias.Meta-analysis of all 10 included studies (12 comparisons) provided moderate-certainty evidence that adherence interventions led to small improvements in adherence (i.e. the mean amount of medication consumed; SMD 0.10, 95% CI 0.03 to 0.18; I² = 6%; n = 3655), limited by risk of bias. Subgroup analyses for the primary outcome identified no significant subgroup effects, with effect sizes for subgroups imprecisely estimated. However, there was a very weak indication that interventions focused on the 'practicalities' of adhering to treatment (i.e. capabilities, resources, levels of support or skills) may be effective (SMD 0.21, 95% CI 0.03 to 0.38; I² = 39%; n = 1752), whereas interventions focused on treatment 'perceptions' (i.e. beliefs, cognitions, concerns and preferences; SMD 0.10, 95% CI -0.03 to 0.24; I² = 0%; n = 839) or on both (SMD 0.04, 95% CI -0.08 to 0.16; I² = 0%; n = 1064), may not be effective. Participant-centred interventions may be effective (SMD 0.12, 95% CI 0.02 to 0.23; I² = 20%; n = 2791), whereas those that are clinician-centred may not (SMD 0.09, 95% CI -0.05 to 0.23; I² = 0%; n = 864).Five studies assessed short-term smoking abstinence (five comparisons), while an overlapping set of five studies (seven comparisons) assessed long-term smoking abstinence of six months or more. Meta-analyses resulted in low-certainty evidence that adherence interventions may slightly increase short-term smoking cessation rates (RR 1.08, 95% CI 0.96 to 1.21; I² = 0%; n = 1795) and long-term smoking cessation rates (RR 1.16, 95% CI 0.96 to 1.40; I² = 48%; n = 3593). In both cases, the evidence was limited by risk of bias and imprecision, with CIs encompassing minimal harm as well as moderate benefit, and a high likelihood that further evidence will change the estimate of the effect. There was no evidence that interventions to increase adherence to medication led to any adverse events. Studies did not report on factors plausibly associated with increases in adherence, such as self-efficacy, understanding of and attitudes toward treatment, and motivation and intentions to quit. AUTHORS' CONCLUSIONS: In people who are stopping smoking and receiving behavioural support, there is moderate-certainty evidence that enhanced behavioural support focusing on adherence to smoking cessation medications can modestly improve adherence. There is only low-certainty evidence that this may slightly improve the likelihood of cessation in the shorter or longer-term. Interventions to increase adherence can aim to address the practicalities of taking medication, change perceptions about medication, such as reasons to take it or concerns about doing so, or both. However, there is currently insufficient evidence to confirm which approach is more effective. There is no evidence on whether such interventions are effective for people who are stopping smoking without standard behavioural support.


Assuntos
Adesão à Medicação/estatística & dados numéricos , Agonistas Nicotínicos/uso terapêutico , Abandono do Hábito de Fumar/métodos , Dispositivos para o Abandono do Uso de Tabaco , Tabagismo/tratamento farmacológico , Benzazepinas/uso terapêutico , Bupropiona/uso terapêutico , Quimioterapia Combinada/métodos , Humanos , Nortriptilina/uso terapêutico , Quinoxalinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Prevenção do Hábito de Fumar
3.
Eur J Med Chem ; 177: 47-62, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31129453

RESUMO

The class of tetrahydro-1H-3-benzazepines was systematically modified in 1-, 3- and 7-position. In particular, a F-atom was introduced in ß- or γ-position of the 4-phenylbutyl side chain in 3-position. Ligands with the F-atom in γ-position possess higher GluN2B affinity than analogs bearing the F-atom in ß-position. This effect was attributed to the reduced basicity of ß-fluoro amines. 3-Benzazepines with a benzylic OH moiety show moderate GluN2B affinity, but considerable selectivity over the σ2 receptor. However, removal of the benzylic OH moiety led to increased GluN2B affinity, but reduced GluN2B/σ2 selectivity. With respect to GluN2B affinity the phenol 17b with a γ-fluorophenylbutyl moiety in 3-position represents the most interesting fluorinated ligand (Ki(GluN2B) = 16 nM). Most of the synthesized ligands reveal either similar GluN2B and σ1 affinity or higher σ1 affinity than GluN2B affinity. The methyl ether 16b shows high σ1 affinity (Ki(σ1) = 6.6 nM) and high selectivity over a broad panel of receptors and transporters. The high antiallodynic activity in the mouse capsaicin assay proved the σ1 antagonistic activity of 16b.


Assuntos
Analgésicos/uso terapêutico , Benzazepinas/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Hiperalgesia/tratamento farmacológico , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores sigma/antagonistas & inibidores , Analgésicos/síntese química , Analgésicos/química , Analgésicos/toxicidade , Animais , Benzazepinas/síntese química , Benzazepinas/química , Benzazepinas/toxicidade , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/síntese química , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/toxicidade , Feminino , Humanos , Ligantes , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Piperidinas/uso terapêutico , Ratos , Estereoisomerismo , Relação Estrutura-Atividade
4.
Wien Klin Wochenschr ; 131(Suppl 1): 67-70, 2019 May.
Artigo em Alemão | MEDLINE | ID: mdl-30980165

RESUMO

Smoking and second-hand smoke strongly increase incidence of diabetes and probability for its complications. Smoking cessation can lead to weight gain and increased diabetes risk; however, it decreases cardiovascular and total mortality. A basal diagnostics (Fagerström Test, exhaled CO) is the basis for successful smoking cessation. Supporting medication include Varenicline, Nicotine Replacement Therapy and Bupropion. Socio-economic as well as psychological factors play an important role for smoking and smoking cessation.Moderate consumption of alcohol possibly decreases risk for diabetes and cardiovascular diseases. Selection bias and underreporting in studies maybe contribute to a too optimistic view. On the other hand, alcohol increases in a dose dependant fashion excess morbidity and disability adjusted life years, especially by cancer, liver diseases and infections.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Diabetes Mellitus , Abandono do Hábito de Fumar , Fumar/efeitos adversos , Benzazepinas/uso terapêutico , Bupropiona/uso terapêutico , Humanos , Nicotina , Guias de Prática Clínica como Assunto , Quinoxalinas , Abandono do Hábito de Fumar/métodos , Dispositivos para o Abandono do Uso de Tabaco , Vareniclina/uso terapêutico
5.
Chem Biol Interact ; 305: 134-147, 2019 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-30922767

RESUMO

Methiopropamine (MPA) is structurally categorized as a thiophene ring-based methamphetamine (MA) derivative. Although abusive potential of MPA was recognized, little is known about the neurotoxic potential of MPA up to now. We investigated whether MPA induces dopaminergic neurotoxicity, and whether MPA activates a specific dopamine receptor. Here, we observed that treatment with MPA resulted in dopaminergic neurotoxicity in a dose-dependent manner. MPA treatment potentiated oxidative parameters (i.e., increases in the level of reactive oxygen species, 4-hydroxynonenal, and protein carbonyl), M1 phenotype-related microglial activity, and pro-apoptotic property (i.e., increases in Bax- and cleaved caspase-3-expressions, while a decrease in Bcl-2-expression). Moreover, treatment with MPA resulted in significant impairments in dopaminergic parameters [i.e., changes in dopamine level, dopamine turnover rate, tyrosine hydroxylase (TH) levels, dopamine transporter (DAT) expression, and vesicular monoamine transporter-2 (VMAT-2) expression], and in behavioral deficits. Both dopamine D1 receptor antagonist SCH23390 and D2 receptor antagonist sulpiride protected from these neurotoxic consequences. Therefore, our results suggest that dopamine D1 and D2 receptors simultaneously mediate MPA-induced dopaminergic neurodegeneration in mice via oxidative burdens, microgliosis, and pro-apoptosis.


Assuntos
Metanfetamina/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Benzazepinas/farmacologia , Benzazepinas/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Dopamina/metabolismo , Antagonistas dos Receptores de Dopamina D2/farmacologia , Antagonistas dos Receptores de Dopamina D2/uso terapêutico , Febre/prevenção & controle , Locomoção/efeitos dos fármacos , Masculino , Metanfetamina/síntese química , Metanfetamina/química , Camundongos , Camundongos Endogâmicos ICR , Microglia/citologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D2/química , Sulpirida/farmacologia , Sulpirida/uso terapêutico , Tirosina 3-Mono-Oxigenase/metabolismo
6.
Oncol Rep ; 41(5): 2667-2678, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896884

RESUMO

Uterine serous carcinoma (USC) is a subtype of endometrial cancer. Compared with endometrial endometroid carcinoma, the majority of USC cases are more aggressive. Cyclin-dependent kinase inhibitor 2A (P16INK4A) is a canonical tumor suppressor that blocks cell cycle progression; however, P16INK4A is overexpressed in USC. The aim of the present study was to determine the role of P16INK4A in P16INK4A­positive endometrial cancer, with the hope of elucidating a novel therapeutic approach for this type of malignancy. A total of 2 endometrial cancer cell lines, ETN­1 and EFE­184, were selected for further investigation, due to them being known to express high levels of P16INK4A. Using short hairpin RNA targeting P16INK4A, P16INK4A was downregulated in these cancer cell lines. Cell viability and migration were examined via 2D/3D clonogenic and wound healing assays. Subsequently, GSK­J4, a histone demethylase inhibitor, was employed to deplete P16INK4A in these cancer cell lines and an ex vivo culture system of a patient­derived xenograft (PDX) endometrial tumor sample. Following P16INK4A knockdown, the proliferation and migration of ETN­1 and EFE­184 cells markedly declined. When exposed to GSK­J4, the levels of KDM6B and P16INK4A were almost completely abrogated, and the cell viability was significantly reduced in these cell lines and the ex vivo­cultured PDX tumor explants. The association between the levels of P16INK4A, lysine demethylase 6B (KDM6B) and the methylation status of histone 3 lysine 27 (H3K27) in these cell lines and the human USC tumor sample was also demonstrated. P16INK4A appears to be oncogenic in a number of endometrial cancer cell lines. The level of P16INK4A is associated with the methylation status of H3K27. Increased methylation of H3K27 coexists with downregulation of KDM6B and, subsequently, P16INK4A, which reduces cell proliferation and invasiveness in endometrial cancer. The observations of the present study may enable the development of a novel therapeutic strategy for P16INK4A­positive endometrial cancer, particularly USC.


Assuntos
Antineoplásicos/farmacologia , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Cistadenocarcinoma Seroso/patologia , Metilação de DNA/efeitos dos fármacos , Neoplasias do Endométrio/patologia , Adulto , Idoso , Animais , Antineoplásicos/uso terapêutico , Benzazepinas/farmacologia , Benzazepinas/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/genética , Regulação para Baixo , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genética , Endométrio/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Células HEK293 , Histonas/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Histona Desmetilases com o Domínio Jumonji/metabolismo , Camundongos , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/prevenção & controle , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , RNA Interferente Pequeno/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Intern Med ; 58(11): 1587-1591, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30713322

RESUMO

A 73-year-old man with liver cirrhosis and advanced chronic kidney disease was admitted to our hospital due to bilateral lower leg edema and appetite loss. Furosemide to treat fluid retention markedly decreased extracellular water compared with intracellular water, but the addition of tolvaptan equally decreased both with a greater diuretic response than furosemide alone. Furthermore, tolvaptan administration increased the plasma colloid osmotic pressure, which might facilitate the shift of fluid from the extravascular space to the intravascular space. This is the first case showing different effects on the fluid distribution between furosemide and additional tolvaptan in the same patient.


Assuntos
Deslocamentos de Líquidos Corporais/efeitos dos fármacos , Furosemida/farmacologia , Cirrose Hepática/complicações , Insuficiência Renal Crônica/complicações , Tolvaptan/farmacologia , Idoso , Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacologia , Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Benzazepinas/farmacologia , Benzazepinas/uso terapêutico , Diuréticos/farmacologia , Quimioterapia Combinada , Edema/tratamento farmacológico , Edema/etiologia , Edema/fisiopatologia , Furosemida/uso terapêutico , Humanos , Perna (Membro) , Masculino , Tolvaptan/uso terapêutico
8.
Psychooncology ; 28(3): 561-569, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30680852

RESUMO

OBJECTIVE: Continuing to smoke after a cancer diagnosis undermines prognosis. Yet few trials have tested Food and Drug Administration (FDA)-approved tobacco use medications in this population. Extended use varenicline may represent an effective treatment for cancer patients who smoke given barriers to cessation including a prolonged time line for relapse. METHODS: A placebo-controlled randomized trial tested 12 weeks of varenicline plus 12 weeks of placebo (standard [ST]) vs 24 weeks of varenicline (extended [ET]) with seven counseling sessions for treatment-seeking cancer patients who smoke (N = 207). Primary outcomes were 7-day biochemically confirmed abstinence at weeks 24 and 52. Treatment adherence and side effects, adverse and serious adverse events, and blood pressure were assessed. RESULTS: Point prevalence and continuous abstinence quit rates at weeks 24 and 52 were not significantly different across treatment arms (P's > 0.05). Adherence (43% of sample) significantly interacted with treatment arm for week 24 point prevalence (odds ratio [OR] = 2.31; 95% confidence interval [CI], 1.15-4.63; P = 0.02) and continuous (OR = 5.82; 95% CI, 2.66-12.71; P < 0.001) abstinence. For both outcomes, adherent participants who received ET reported higher abstinence (60.5% and 44.2%) vs ST (44.7% and 27.7%), but differences in quit rates between arms were not significant for nonadherent participants (ET: 9.7% and 4.8%; ST: 12.7% and 10.9%). There were no significant differences between treatment arms on side effects, adverse and serious adverse events, and rates of high blood pressure (P's > 0.05). CONCLUSIONS: Compared with ST, ET varenicline does not increase patient risk and increases smoking cessation rates among patients who adhere to treatment. Studies are needed to identify effective methods to increase medication adherence to treat patient tobacco use effectively.


Assuntos
Adesão à Medicação/estatística & dados numéricos , Neoplasias/terapia , Agentes de Cessação do Hábito de Fumar/uso terapêutico , Abandono do Hábito de Fumar/métodos , Vareniclina/uso terapêutico , Adulto , Benzazepinas/uso terapêutico , Aconselhamento/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Nicotina/efeitos adversos , Fumar/tratamento farmacológico , Síndrome de Abstinência a Substâncias/prevenção & controle , Resultado do Tratamento
9.
Expert Opin Pharmacother ; 20(5): 585-593, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30614740

RESUMO

INTRODUCTION: Obesity is a growing health problem that has numerous comorbidities, including cardiovascular disease (CVD). The multi-disciplinary treatment of obesity now includes the use of pharmacotherapy. When treating patients with obesity and CVD, certain medications may be more appropriate than others. AREAS COVERED: Herein, the authors review the most commonly used FDA approved medications for the treatment of obesity, describing their mechanism of action, and the efficacy and safety of the medications as seen in recent studies, particularly in patients with CVD. EXPERT OPINION: In the population of patients with obesity and CVD, the medications orlistat, lorcaserin and liraglutide are considered the most appropriate options for their treatment, in terms of safety. Sympathomimetic medications, such as phentermine, should be avoided in this group. The recent CAMELLIA-TIMI 61 trial supports the safety of lorcaserin in patients with CVD. Until there are more studies, it is reasonable to extrapolate the findings of the LEADER trial, which found improved CV outcomes in subjects with type 2 diabetes taking liraglutide, to the population of nondiabetic patients being treated for obesity. Further cardiovascular outcomes trials (CVOT) are needed to assess the safety of other pharmacotherapeutic options for weight loss.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Doenças Cardiovasculares/fisiopatologia , Obesidade/tratamento farmacológico , Fármacos Antiobesidade/efeitos adversos , Benzazepinas/uso terapêutico , Diabetes Mellitus Tipo 2/fisiopatologia , Humanos , Liraglutida/uso terapêutico , Orlistate/uso terapêutico , Fentermina/uso terapêutico , Perda de Peso/efeitos dos fármacos
10.
Vet Ophthalmol ; 22(2): 161-167, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29667738

RESUMO

PURPOSE: To investigate factors associated with long-term visual outcome in cats with hypertensive chorioretinopathy. ANIMALS STUDIED: Eighty-eight client-owned cats diagnosed with hypertensive chorioretinopathy. PROCEDURE: Medical records from cats with systemic hypertension and associated retinal lesions were reviewed. RESULTS: Most cats (61%) were blind in both eyes at presentation. Presence of menace response at last follow-up evaluation was positively correlated with presence of menace response at presentation (P = .0025), time to complete retinal reattachment (P < .0001), and gender (P = .0137). Seventy-six of 132 eyes (57.6%) that were blind at presentation regained some vision following treatment. At the time of last evaluation, 101/176 eyes (60%) had a positive menace response, while 34/46 (74%) eyes with a follow-up of >6 months had a positive menace response. Eyes that had a menace response at presentation were 17 and 37 times more likely to have a menace response at last examination compared to eyes blind for less than 2 weeks and eyes blind greater than 2 weeks, respectively. Female cats were overrepresented (62.5% of cases), and male cats were 4.2 times more likely to be visual at time of last examination compared to female cats. CONCLUSIONS: With treatment, the prognosis for long-term vision in cats with hypertensive chorioretinopathy, even following complete retinal detachment, is good.


Assuntos
Anti-Hipertensivos/uso terapêutico , Doenças do Gato/tratamento farmacológico , Doenças da Coroide/veterinária , Hipertensão/veterinária , Retinopatia Hipertensiva/tratamento farmacológico , Retinopatia Hipertensiva/veterinária , Anlodipino/uso terapêutico , Animais , Benzazepinas/uso terapêutico , Cegueira/veterinária , Gatos , Doenças da Coroide/tratamento farmacológico , Doenças da Coroide/etiologia , Feminino , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Retinopatia Hipertensiva/etiologia , Masculino , Prognóstico , Resultado do Tratamento , Visão Ocular
11.
Intern Med ; 58(4): 471-475, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30210135

RESUMO

Tolvaptan (TLV) is a diuretic agent administrated for heart failure (HF) only in Japan. Many clinical findings have been obtained from the accumulation of clinical experience, and the administration of TLV reportedly avoids causing a reduction in the renal function. In addition, TLV has been reported to exert effects other than diuresis. The early start of TLV after hospitalization shortens the length of the hospital stay, and continuous TLV after discharge extends the period until re-hospitalization of HF patients. TLV is thought to function via vasopressin V2 receptor antagonism. However, no significant differences in the long-term prognosis were noted between the group using TLV and not using TLV in the Endovascular Valve Edge-to-Edge Repair Study (EVEREST) trial, and effects other than diuresis are not useful for all HF patients. Therefore, it is necessary to identify patients who may experience effects other than diuresis with TLV administration. The accumulation of more patients and findings from further large-scale clinical trials will be necessary in order to clarify these points.


Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Benzazepinas/uso terapêutico , Diurese/efeitos dos fármacos , Diuréticos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Tolvaptan/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Hemodinâmica , Hospitalização/estatística & dados numéricos , Humanos , Japão , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Alta do Paciente/estatística & dados numéricos , Prognóstico
12.
Pain ; 160(2): 334-344, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30325872

RESUMO

Neuropathic pain represents a challenge to clinicians because it is resistant to commonly prescribed analgesics due to its largely unknown mechanisms. Here, we investigated a descending dopaminergic pathway-mediated modulation of trigeminal neuropathic pain. We performed chronic constriction injury of the infraorbital nerve from the maxillary branch of trigeminal nerve to induce trigeminal neuropathic pain in mice. Our retrograde tracing showed that the descending dopaminergic projection from hypothalamic A11 nucleus to spinal trigeminal nucleus caudalis is bilateral. Optogenetic/chemogenetic manipulation of dopamine receptors D1 and D2 in the spinal trigeminal nucleus caudalis produced opposite effects on the nerve injury-induced trigeminal neuropathic pain. Specific excitation of dopaminergic neurons in the A11 nucleus attenuated the trigeminal neuropathic pain through the activation of D2 receptors in the spinal trigeminal nucleus caudalis. Conversely, specific ablation of the A11 dopaminergic neurons exacerbated such pain. Our results suggest that the descending A11-spinal trigeminal nucleus caudalis dopaminergic projection is critical for the modulation of trigeminal neuropathic pain and could be manipulated to treat such pain.


Assuntos
Encéfalo/patologia , Antagonistas de Dopamina/uso terapêutico , Neurônios Dopaminérgicos/patologia , Receptores de Dopamina D2/metabolismo , Espiperona/uso terapêutico , Doenças do Nervo Trigêmeo/terapia , Animais , Benzazepinas/uso terapêutico , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Condicionamento Operante/fisiologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neurônios Dopaminérgicos/fisiologia , Lateralidade Funcional , Hiperalgesia/fisiopatologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Limiar da Dor/fisiologia , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Doenças do Nervo Trigêmeo/fisiopatologia
13.
Obes Rev ; 20(3): 375-384, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30589980

RESUMO

Four new medicines-liraglutide, lorcaserin, bupropion/naltrexone, and phentermine/topiramate-have been recently added to the pharmacological arsenal for obesity treatment and could represent important tools to manage this epidemic disease. To achieve satisfactory anti-obesity goals, the use of these new medicines should be optimized and tailored to specific patient subpopulations also by applying dose adjustments if needed. In the present review, we posit that gender could be among the factors influencing the activity of the new obesity drugs both because of pharmacokinetic and pharmacodynamic factors. Although evidence from premarketing clinical studies suggested that no dose adjustment by gender is necessary for any of these new medicines, these studies were not specifically designed to identify gender-related differences. This observation, together with the strong theoretical background supporting the hypothesis of a gender-dimorphic response, strongly call upon an urgent need of new real-life data on gender-related difference in the pharmacology of these new obesity drugs.


Assuntos
Fármacos Antiobesidade/farmacologia , Obesidade/tratamento farmacológico , Perda de Peso/efeitos dos fármacos , Fármacos Antiobesidade/uso terapêutico , Benzazepinas/farmacologia , Benzazepinas/uso terapêutico , Bupropiona/farmacologia , Bupropiona/uso terapêutico , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Feminino , Humanos , Liraglutida/farmacologia , Liraglutida/uso terapêutico , Masculino , Naltrexona/farmacologia , Naltrexona/uso terapêutico , Seleção de Pacientes , Fatores Sexuais , Topiramato/farmacologia , Topiramato/uso terapêutico , Resultado do Tratamento
14.
Circulation ; 139(3): 366-375, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30586726

RESUMO

BACKGROUND: Obesity is thought to increase renal hyperfiltration, thereby increasing albuminuria and the progression of renal disease. The effect of pharmacologically mediated weight loss on renal outcomes is not well-described. Lorcaserin, a selective serotonin 2C receptor agonist that promotes appetite suppression, led to sustained weight loss without any increased risk for major adverse cardiovascular (CV) events in the CAMELLIA-TIMI 61 trial (Cardiovascular and Metabolic Effects of Lorcaserin in Overweight and Obese Patients-Thrombolysis in Myocardial Infarction 61). METHODS: CAMELLIA-TIMI 61 randomly assigned 12 000 overweight or obese patients with or at high risk for atherosclerotic CV disease to lorcaserin or placebo on a background of lifestyle modification. The primary renal outcome was a composite of new or worsening persistent micro- or macroalbuminuria, new or worsening chronic kidney disease, doubling of serum creatinine, end-stage renal disease, renal transplant, or renal death. RESULTS: At baseline, 23.8% of patients had an estimated glomerular filtration rate (eGFR) <60 mL·min-1·1.73 m-2 and 19.0% had albuminuria (urinary albumin:creatinine ratio ≥30 mg/g). Lorcaserin reduced the risk of the primary renal composite outcome (4.2% per year versus 4.9% per year; hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.79-0.96; P=0.0064). The benefit was consistent across subpopulations at increased baseline CV and renal risk. Lorcaserin improved both eGFR and urinary albumin:creatinune ratio within the first year after randomization. The effect of lorcaserin on weight, hemoglobin A1c, and systolic blood pressure was consistent regardless of baseline renal function. Likewise, there was no excess in cardiovascular events in patients assigned to lorcaserin in comparison with placebo, regardless of renal function. After adjustment for baseline characteristics, those with evidence of kidney disease were at increased risk of major CV events. Compared with patients with an eGFR ≥90 mL·min-1·1.73 m-2, those with an eGFR 60-90 and those <60 mL·min-1·1.73 m-2 had HRs of 1.25 (95% CI, 1.01, 1.56) and 1.51 (95% CI, 1.17, 1.95), respectively ( P for trend 0.0015). Likewise, compared with patients with no albuminuria (<30 mg/g), those microalbuminuria and those with macroalbuminuria had HRs of 1.46 (95% CI, 1.22, 1.74) and 2.10 (95% CI, 1.58, 2.80), respectively ( P for trend <0.0001). CONCLUSIONS: Renal dysfunction was associated with increased CV risk in overweight and obese patients. When added to diet and lifestyle, lorcaserin reduced the rate of new-onset or progressive renal impairment in comparison with placebo. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02019264.


Assuntos
Depressores do Apetite/uso terapêutico , Regulação do Apetite/efeitos dos fármacos , Benzazepinas/uso terapêutico , Taxa de Filtração Glomerular/efeitos dos fármacos , Nefropatias/epidemiologia , Rim/efeitos dos fármacos , Obesidade/tratamento farmacológico , Agonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Depressores do Apetite/efeitos adversos , Benzazepinas/efeitos adversos , Biomarcadores/sangue , Pressão Sanguínea/efeitos dos fármacos , Dieta Redutora , Progressão da Doença , Método Duplo-Cego , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Rim/metabolismo , Rim/fisiopatologia , Nefropatias/mortalidade , Nefropatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Obesidade/mortalidade , Obesidade/fisiopatologia , Obesidade/psicologia , Medição de Risco , Fatores de Risco , Comportamento de Redução do Risco , Agonistas do Receptor 5-HT2 de Serotonina/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Perda de Peso/efeitos dos fármacos
15.
Int J Cardiol ; 274: 245-247, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30193794

RESUMO

BACKGROUND: Targeted treatment for decompensated right heart failure (RHF) with or without left heart failure is lacking. Vasopressin antagonists (vaptans) may offer an option by increasing urine output and fluid mobilization when used in acute decompensated RHF without impacting blood pressure or renal function, both common complications of loop diuretics. METHODS AND RESULTS: We searched electronic medical records from 2 institutions over 4 years for patients with RHF treated with vaptans. Urine output, creatinine, BUN and sodium, 1 day pre- versus 1 day post-vaptan initiation were compared. Baseline (admission) pre-vaptan values for patients with RHF who met inclusion criteria (n = 112) were RAP, median (interquartile range) = 19 (13-24) mmHg; cardiac index, mean ±â€¯standard deviation = 1.8 ±â€¯0.4 L/min/m2; BNP, 1078 (523-1690) pg/ml; creatinine clearance of 51 (39-69) ml/min, BUN, 37 (26-54) mg/dl, and serum [Na+] 132 (126-135) mEq/L. Most patients (n = 103/112) received intravenous inotrope (prior to vaptan, n = 91). Overall length of stay was 27 (16-43) days. Vaptan treatment (90% tolvaptan, 10% conivaptan) was associated with increased 24 h urine output, 1517 (906-2394) vs 2337 (1425-3744) mL, p = 0.005, and [Na+], 127 (124-130) vs 130 (126-135) mEq/L, p = 0.001, without significant change in Cr or BUN. Furosemide IV dose equivalent decreased or remained unchanged in 75% of patients at 24 h and 64% at 72 h compared to the 24 h prior to vaptan use. CONCLUSION: Vaptans were associated with a significant increase in urine output and serum sodium with an apparent reduction or stabilization of furosemide equivalent dosing in the early treatment period in patients with decompensated RHF. Vaptans may offer a management option for patients failing conventional diuretic-based treatment.


Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Volume Sistólico/fisiologia , Função Ventricular Direita/fisiologia , Benzazepinas/uso terapêutico , Creatinina/sangue , Diurese/efeitos dos fármacos , Feminino , Seguimentos , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Volume Sistólico/efeitos dos fármacos , Tolvaptan/uso terapêutico , Resultado do Tratamento , Função Ventricular Direita/efeitos dos fármacos
16.
Pharmacol Biochem Behav ; 176: 16-22, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30419272

RESUMO

Tobacco addiction each year causes millions of deaths worldwide. Brain nicotinic acetylcholine receptors have been shown to be central to tobacco addiction. Nicotine replacement therapy aids tobacco cessation, but the success rate is still far too low. This may in part be due to the fact that neurons with nicotinic receptors are not the only neural systems involved in tobacco addiction. Interacting neural systems also play important roles in tobacco addiction. Nicotine increases the release of a variety of neurotransmitters, including dopamine and serotonin. Dopamine, in particular dopamine D1 receptors, has been shown to be involved in the reinforcing action of nicotine. Serotonin through its actions on 5-HT2C receptors has been shown to play a key role in modulating the reinforcement of addictive drugs, including nicotine and alcohol. Combination of treatments could provide greater treatment efficacy. These studies were conducted to evaluate combination therapies utilizing nicotine replacement therapy in conjunction with either a dopamine D1 receptor antagonist SCH-23390 or a serotonin 5-HT2C receptor agonist, lorcaserin. Female Sprague-Dawley rats were given access to self-administer nicotine via IV infusions. Osmotic pumps were implanted to reproduce the kinetic of chronic nicotine patch therapy. SCH-23390 (0.02 mg/kg) or lorcaserin (0.6 mg/kg) were administered prior to nicotine self-administration sessions. Reproducing earlier findings SCH-23390, lorcaserin and nicotine replacement therapy were effective at reducing IV nicotine self-administration. 5HT2C agonist treatment had additive effects with chronic nicotine infusion for significantly lowering nicotine self-administration. This study demonstrates the feasibility of combination of chronic nicotine with therapies targeting non-nicotinic receptors as treatment options for tobacco addiction.


Assuntos
Benzazepinas/farmacologia , Benzazepinas/uso terapêutico , Nicotina/administração & dosagem , Receptores de Dopamina D1/antagonistas & inibidores , Agonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Tabagismo/tratamento farmacológico , Animais , Comportamento Animal/efeitos dos fármacos , Benzazepinas/administração & dosagem , Quimioterapia Combinada , Feminino , Bombas de Infusão Implantáveis , Nicotina/farmacologia , Ratos , Ratos Sprague-Dawley , Autoadministração , Agonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Abandono do Hábito de Fumar/métodos , Dispositivos para o Abandono do Uso de Tabaco
17.
Lancet ; 392(10161): 2269-2279, 2018 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-30293771

RESUMO

BACKGROUND: There is a direct relationship between bodyweight and risk of diabetes. Lorcaserin, a selective serotonin 2C receptor agonist that suppresses appetite, has been shown to facilitate sustained weight loss in obese or overweight patients. We aimed to evaluate the long-term effects of lorcaserin on diabetes prevention and remission. METHODS: In this randomised, double-blind, placebo-controlled trial done in eight countries, we recruited overweight or obese patients (body-mass index ≥27 kg/m2) with or at high risk for atherosclerotic vascular disease. Eligible patients were aged 40 years or older; patients at high risk for atherosclerotic vascular disease had to be aged 50 years or older with diabetes and at least one other risk factor. Patients were randomly assigned to receive either lorcaserin (10 mg twice daily) or matching placebo. Additionally, all patients had access to a standardised weight management programme based on lifestyle modification. The prespecified primary metabolic efficacy endpoint of time to incident diabetes was assessed in patients with prediabetes at baseline. The prespecified secondary outcomes for efficacy were incident diabetes in all patients without diabetes, achievement of normoglycaemia in patients with prediabetes, and change in glycated haemoglobin (HbA1c) in patients with diabetes. Hypoglycaemia was a prespecified safety outcome. Analysis was by intention to treat, using Cox proportional hazard models for time-to-event analyses. This trial is registered with ClinicalTrials.gov, number NCT02019264. FINDINGS: Between Feb 7, 2014, and Nov 20, 2015, 12 000 patients were randomly assigned to lorcaserin or placebo (6000 patients in each group) and followed up for a median of 3·3 years (IQR 3·0-3·5). At baseline, 6816 patients (56·8%) had diabetes, 3991 (33·3%) prediabetes, and 1193 (9·9%) normoglycaemia. At 1 year, patients treated with lorcaserin had a net weight loss beyond placebo of 2·6 kg (95% CI 2·3-2·9) for those with diabetes, 2·8 kg (2·5-3·2) for those with prediabetes, and 3·3 kg (2·6-4·0) for those with normoglycaemia (p<0·0001 for all analyses). Lorcaserin reduced the risk of incident diabetes by 19% in patients with prediabetes (172 [8·5%] of 2015 vs 204 [10·3%] of 1976; hazard ratio 0·81, 95% CI 0·66-0·99; p=0·038) and by 23% in patients without diabetes (174 [6·7%] of 2615 vs 215 [8·4%] of 2569; 0·77, 0·63-0·94; p=0·012). Lorcaserin resulted in a non-significant increase in the rate of achievement of normoglycaemia in patients with prediabetes (185 [9·2%] vs 151 [7·6%]; 1·20, 0·97-1·49; p=0·093). In patients with diabetes, lorcaserin resulted in a reduction of 0·33% (95% CI 0·29-0·38; p<0·0001) in HbA1c compared with placebo at 1 year from a mean baseline of 53 mmol/mol (7·0%). In patients with diabetes at baseline, severe hypoglycaemia with serious complications was rare, but more common with lorcaserin (12 [0·4%] vs four [0·1%] events; p=0·054). INTERPRETATION: Lorcaserin decreases risk for incident diabetes, induces remission of hyperglycaemia, and reduces the risk of microvascular complications in obese and overweight patients, supporting the role of lorcaserin as an adjunct to lifestyle modification for chronic management of weight and metabolic health. FUNDING: Eisai.


Assuntos
Depressores do Apetite/uso terapêutico , Benzazepinas/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Obesidade/complicações , Idoso , Aterosclerose/complicações , Aterosclerose/tratamento farmacológico , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/prevenção & controle , Método Duplo-Cego , Feminino , Hemoglobina A Glicada/análise , Humanos , Masculino , Pessoa de Meia-Idade , Sobrepeso/complicações , Estado Pré-Diabético/complicações , Estado Pré-Diabético/tratamento farmacológico , Estado Pré-Diabético/prevenção & controle , Indução de Remissão , Perda de Peso/efeitos dos fármacos
19.
Neurol Res ; 40(12): 1080-1087, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30222083

RESUMO

OBJECTIVE: The objective of this article is to study the role of the dopamine (DA) D1 receptor in the midbrain periaqueductal grey (PAG) on learning and memory in morphine-addicted rats. METHODS: DA D1 receptor agonist SKF81297 and D1 receptor antagonist SCH SCH23390 were administrated into the PAG, respectively, and the learning and memory behavioral changes of morphine addicted rats were detected by water maze. Western blot and immunohistochemistry were used to detect glutamate decarboxylase 67 (GAD67) and tyrosine receptor kinase B (TrkB) in PAG. RESULTS: D1 receptor agonist shortened the latency to platform and increased the number of platform crossings, indicating improved learning and memory ability of morphine addict rat. D1 receptor agonist increased GAD67 expression and decreased TrkB in PAG. CONCLUSION: (1) The PAG is involved in the learning and memory changes of the addicted rats; (2) the activation of DA D1 receptor will increase the GAD67, reduce the damage to peripheral neurons, and improve the learning and memory of the addicted rats; and (3) D1 receptor agonists further reduced TrkB expression in morphine-addicted rats, whereas TrkB levels deviated from changes in rat behavior.


Assuntos
Benzazepinas/uso terapêutico , Agonistas de Dopamina/uso terapêutico , /tratamento farmacológico , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Morfina/toxicidade , Animais , Modelos Animais de Doenças , Antagonistas de Dopamina/uso terapêutico , Relação Dose-Resposta a Droga , Glutamato Descarboxilase/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Entorpecentes/toxicidade , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Substância Cinzenta Periaquedutal/metabolismo , Ratos , Ratos Wistar , Receptor trkB/metabolismo , Receptores de Dopamina D1
20.
Heart Fail Clin ; 14(4): 493-500, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30266358

RESUMO

Heart failure affects more than 6 million people in the United States each year and the prognosis is poor. The elevated heart rate in heart failure patents is problematic, because it increases myocardial oxygen demand, decreases myocardial perfusion, and has been associated with increased rates of hospitalization and mortality. For these reasons, heart rate reduction has long been a therapeutic target in heart failure. Ivabradine is a selective inhibitor of the sinoatrial pacemaker modulating "f-current" (If) and provides heart rate reduction that can be beneficial in patients with heart failure with reduced ejection fraction.


Assuntos
Benzazepinas/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Frequência Cardíaca/efeitos dos fármacos , Fármacos Cardiovasculares/uso terapêutico , Insuficiência Cardíaca/fisiopatologia , Humanos , Ivabradina
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