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1.
Obesity (Silver Spring) ; 28(7): 1171-1172, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32374528

RESUMO

Obesity treatment is highly stigmatized, mainly because of the stigma of obesity itself. The frequent withdrawal of medications, lorcaserin being the last example, contributes to this stigma, but it is also probably a reflection of it, as data suggest that the threshold for a withdrawal is lower than with other classes of drugs. Safety should always be an absolute priority for every new medication, especially when used on a chronic basis; however, the safety scrutiny given to antiobesity medications is not given for other medications, such as postmenopausal hormone therapy and central nervous system drugs for psychiatric use. The withdrawal of medications for obesity can also impact future research in the area, so we need transparency and equality. Transparency in knowing exactly what reason led to a drug being discontinued and equality in long-term safety should be a concern with any medication prescribed for chronic diseases.


Assuntos
Fármacos Antiobesidade/efeitos adversos , Benzazepinas/efeitos adversos , Doença Crônica/tratamento farmacológico , Medicamentos sob Prescrição/uso terapêutico , Estigma Social , Fármacos Antiobesidade/uso terapêutico , Benzazepinas/uso terapêutico , Doença Crônica/epidemiologia , Humanos , Assistência de Longa Duração , Obesidade/tratamento farmacológico , Obesidade/epidemiologia , Obesidade/psicologia , Medicamentos sob Prescrição/classificação , Vigilância de Produtos Comercializados/normas , Retirada de Medicamento Baseada em Segurança , Estereotipagem , Estados Unidos/epidemiologia , United States Food and Drug Administration/normas
3.
Clin Drug Investig ; 40(5): 503-509, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32253717

RESUMO

BACKGROUND: Perihematomal edema (PHE) growth in intracranial hemorrhage (ICH) is a biomarker for worse outcomes. Although the management of PHE is potentially beneficial for ICH patients, there is currently no proven clinical therapy that both reduces PHE and improves outcomes in this population. OBJECTIVE: To examine the safety and tolerability of conivaptan, a non-peptide vasopressin (AVP) receptor antagonist, for the management of PHE in ICH patients. METHODS: We performed a single-center, open-label, phase I study in seven patients with ICH at risk for developing PHE. Conivaptan (20 mg) was administered every 12 h for 2 days, along with the standard ICH management. Electrolyte levels, renal and cardiac function, and vital signs were monitored throughout treatment. Neurological status, ICH, and PHE volumes were assessed at study baseline, 24 h, 72 h, and 7 days from the first conivaptan administration, as well as at the 3-month follow-up. RESULTS: Conivaptan was well tolerated in our patients. We observed the expected increase in sodium levels following conivaptan administration (p = 0.01), with no change in cardiac or renal function. All patients survived to follow-up, and adverse event rates were comparable with those of the neurocritical care unit overall. CONCLUSIONS: These data indicate that conivaptan can be safely administered to ICH patients and support further clinical investigation into the efficacy of this drug for ICH treatment. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov; NCT03000283, 22 December 2016.


Assuntos
Benzazepinas/uso terapêutico , Edema Encefálico/prevenção & controle , Hemorragia Cerebral/complicações , Idoso , Benzazepinas/efeitos adversos , Edema Encefálico/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
4.
Proc Natl Acad Sci U S A ; 117(11): 6056-6066, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32123118

RESUMO

T helper (Th) cells are CD4+ effector T cells that play a critical role in immunity by shaping the inflammatory cytokine environment in a variety of physiological and pathological situations. Using a combined chemico-genetic approach, we identify histone H3K27 demethylases KDM6A and KDM6B as central regulators of human Th subsets. The prototypic KDM6 inhibitor GSK-J4 increases genome-wide levels of the repressive H3K27me3 chromatin mark and leads to suppression of the key transcription factor RORγt during Th17 differentiation. In mature Th17 cells, GSK-J4 induces an altered transcriptional program with a profound metabolic reprogramming and concomitant suppression of IL-17 cytokine levels and reduced proliferation. Single-cell analysis reveals a specific shift from highly inflammatory cell subsets toward a resting state upon demethylase inhibition. The root cause of the observed antiinflammatory phenotype in stimulated Th17 cells is reduced expression of key metabolic transcription factors, such as PPRC1. Overall, this leads to reduced mitochondrial biogenesis, resulting in a metabolic switch with concomitant antiinflammatory effects. These data are consistent with an effect of GSK-J4 on Th17 T cell differentiation pathways directly related to proliferation and include regulation of effector cytokine profiles. This suggests that inhibiting KDM6 demethylases may be an effective, even in the short term, therapeutic target for autoimmune diseases, including ankylosing spondylitis.


Assuntos
Benzazepinas/farmacologia , Histona Desmetilases/metabolismo , Histonas/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Pirimidinas/farmacologia , Células Th17/metabolismo , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Benzazepinas/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/imunologia , Código das Histonas/efeitos dos fármacos , Histona Desmetilases/antagonistas & inibidores , Humanos , Interleucina-17/metabolismo , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Cultura Primária de Células , Pirimidinas/uso terapêutico , RNA-Seq , Espondilite Anquilosante/tratamento farmacológico , Espondilite Anquilosante/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Fatores de Transcrição/metabolismo
5.
J Pharmacol Exp Ther ; 373(2): 248-260, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32165443

RESUMO

It has been identified that arginine vasopressin (AVP), vasopressin receptor 2(V2R), and the aquaporin 2 (AQP2) signaling pathway in the inner ear play important roles in hearing and balance functions through regulating the endolymph equilibrium; however, the contributions of this signaling pathway to the development of motion sickness are unclear. The present study was designed to investigate whether the activation of the AVP-V2R-AQP2 signaling pathway in the inner ear is involved in the induction of motion sickness and whether mozavaptan, a V2R antagonist, could reduce motion sickness. We found that both rotatory stimulus and intraperitoneal AVP injection induced conditioned taste aversion (a confirmed behavioral index for motion sickness) in rats and activated the AVP-V2R-AQP2 signaling pathway with a responsive V2R downregulation in the inner ears, and AVP perfusion in cultured epithelial cells from rat endolymphatic sacs induced similar changes in this pathway signaling. Vestibular training, V2R antagonist mozavaptan, or PKA inhibitor H89 blunted these changes in the V2R-AQP2 pathway signaling while reducing rotatory stimulus- or DDAVP (a V2R agonist)-induced motion sickness in rats and dogs. Therefore, our results suggest that activation of the inner ear AVP-V2R-AQP2 signaling pathway is potentially involved in the development of motion sickness; thus, mozavaptan targeting AVP V2Rs in the inner ear may provide us with a new application option to reduce motion sickness. SIGNIFICANCE STATEMENT: Motion sickness affects many people traveling or working. In the present study our results showed that activation of the inner ear arginine vasopressin-vaspopressin receptor 2 (V2R)-aquaporin 2 signaling pathway was potentially involved in the development of motion sickness and that blocking V2R with mozavaptan, a V2R antagonist, was much more effective in reducing motion sickness in both rat and dog; therefore, we demonstrated a new mechanism to underlie motion sickness and a new candidate drug to reduce motion sickness.


Assuntos
Aquaporina 2/fisiologia , Arginina Vasopressina/fisiologia , Orelha Interna/fisiologia , Enjoo devido ao Movimento/etiologia , Receptores de Vasopressinas/fisiologia , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Arginina Vasopressina/sangue , Benzazepinas/uso terapêutico , Células Cultivadas , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Cães , Feminino , Masculino , Enjoo devido ao Movimento/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia
6.
Orthop Nurs ; 39(2): 121-127, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32218009

RESUMO

Obesity, a chronic multifactorial disease, has been on the rise in the United States in recent years. It paves a way to other chronic conditions and related morbidity and mortality. The treatment of obesity should have a chronic approach involving lifestyle modifications from the very beginning. Along with reduced calorie diet, increased physical activity, and behavior modifications, various short- and long-term pharmacological agents are available to help with the weight loss. For qualifying patients, selection of an appropriate agent based on its mechanism, efficacy, and safety profile as well as patient preference can provide desired outcomes. This medical weight management should be a multidisciplinary approach involving nurses to provide continuous patient education and motivation.


Assuntos
Tratamento Farmacológico/métodos , Obesidade/tratamento farmacológico , Programas de Redução de Peso/métodos , Benzazepinas/farmacologia , Benzazepinas/uso terapêutico , Bupropiona/farmacologia , Bupropiona/uso terapêutico , Combinação de Medicamentos , Tratamento Farmacológico/estatística & dados numéricos , Exercício Físico/fisiologia , Exercício Físico/psicologia , Frutose/análogos & derivados , Frutose/farmacologia , Frutose/uso terapêutico , Humanos , Liraglutida/farmacologia , Liraglutida/uso terapêutico , Naltrexona/farmacologia , Naltrexona/uso terapêutico , Obesidade/psicologia , Orlistate/farmacologia , Orlistate/uso terapêutico , Fentermina/farmacologia , Fentermina/uso terapêutico , Programas de Redução de Peso/normas
7.
Expert Opin Pharmacother ; 21(5): 581-590, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32011186

RESUMO

Introduction: Rates of tobacco smoking are high in people with schizophrenia with greater difficulty of quitting smoking compared to the general population, which also relate to the increased cardiovascular and cancer risks in this co-occurring disorder. Therefore, effective smoking cessation pharmacotherapies addressing tobacco co-morbidity are imperative.Areas covered: In this review, the authors performed an extensive systematic electronic literature review examining the efficacy and safety of first-line pharmacotherapies for smoking cessation, including varenicline, sustained-release bupropion, and nicotine replacement therapies (NRT) using continuous abstinence rates over 10-12-week periods in smokers with schizophrenia. Twelve trials reporting smoking cessation outcomes using interventions in schizophrenia were included and risk ratio (RR) was used.Expert opinion: Our findings support the efficacy and safety of first-line pharmacotherapies for the treatment of tobacco use disorder in smokers with schizophrenia. Further research on the long-term effectiveness and safety of these agents in community samples is warranted. Smoking cessation pharmacotherapies may warrant the consideration of the emerging use of electronic nicotine delivery systems while neuromodulation techniques also offer promise.


Assuntos
Esquizofrenia/tratamento farmacológico , Abandono do Hábito de Fumar/métodos , Fumar/tratamento farmacológico , Benzazepinas/uso terapêutico , Bupropiona/uso terapêutico , Humanos , Agonistas Nicotínicos/uso terapêutico , Quinoxalinas/uso terapêutico , Fumar/psicologia , Dispositivos para o Abandono do Uso de Tabaco , Vareniclina/uso terapêutico
8.
J Vet Cardiol ; 27: 34-53, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32032923

RESUMO

INTRODUCTION: Efficacy of renin-angiotensin-aldosterone system (RAAS) blockade using angiotensin-converting enzyme inhibitors (ACEi) in dogs with preclinical myxomatous mitral valve disease (MMVD) is controversial. HYPOTHESIS: Administration of spironolactone (2-4 mg q 24 h) and benazepril (0.25-0.5 mg q 24 h) in dogs with preclinical MMVD, not receiving any other cardiac medications, delays the onset of heart failure (HF) and cardiac-related death. Moreover, it reduces the progression of the disease as indicated by echocardiographic parameters and level of cardiac biomarkers N-terminal pro brain natriuretic peptide (NT-proBNP) and cardiac troponin I (cTnI). ANIMALS: 184 dogs with pre-clinical MMVD and left atrium-to-aortic root ratio (LA:Ao) ≥1.6 and normalized left ventricular end-diastolic diameter (LVEDDn) ≥1.7. METHODS: This is a prospective, randomized, multicenter, single-blinded, placebo-controlled study. Primary outcome variable was time-to-onset of first occurrence of HF or cardiac death. Secondary end points included effect of treatment on progression of the disease based on echocardiographic and radiographic parameters, as well as variations of NT-proBNP and cTnI concentrations. RESULTS: The median time to primary end point was 902 days (95% confidence interval (CI) 682-not available) for the treatment group and 1139 days (95% CI 732-NA) for the control group (p = 0.45). Vertebral heart score (p = 0.05), LA:Ao (p < 0.001), LVEDDn (p < 0.001), trans-mitral E peak velocity (p = 0.011), and NT-proBNP (p = 0.037) were lower at the end of study in the treatment group. CONCLUSIONS: This study failed in demonstrating that combined administration of spironolactone and benazepril delays onset of HF in dogs with preclinical MMVD. However, such treatment induces beneficial effects on cardiac remodeling and these results could be of clinical relevance.


Assuntos
Benzazepinas/uso terapêutico , Doenças do Cão/tratamento farmacológico , Doenças das Valvas Cardíacas/veterinária , Espironolactona/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina , Animais , Cães , Ecocardiografia/veterinária , Feminino , Doenças das Valvas Cardíacas/tratamento farmacológico , Masculino , Valva Mitral , Peptídeo Natriurético Encefálico , Fragmentos de Peptídeos , Estudos Prospectivos , Troponina I
9.
Sci Rep ; 10(1): 492, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31949193

RESUMO

Recent research has identified a population of PD-1hiCXCR5- 'peripheral helper' T (Tph) cells that simulate plasma cell differentiation by interactions between IL-21 and SLAMF5. However, the alteration of circulating Tph and CD138+ B in IgA nephropathy (IgAN) remains poorly understood. Flow cytometry analysis was used to measure the frequency of circulating PD-1hiCXCR5- T cells and CD138+ B cells in 37 patients with IgAN and 23 healthy controls (HCs). Estimated glomerular filtration rate (eGFR), 24 h urinary protein and serum cytokine concentrations were measured. The percentage of different subsets of circulating PD-1hiCXCR5- T cells and CD138+ B cells were significantly higher in patients with IgAN compared to HCs. Pretreatment, the percentage of different subsets of circulating PD-1hiCXCR5- T cells and CD138+ B cells were negatively correlated with eGFR, the percentage of circulating CD138+ B cells was positively correlated with 24-h urinary protein concentration, and the percentage of circulating PD-1hiCXCR5-, CD28+ and ICOS+ T cells. Posttreatment, the percentage of different subsets of circulating PD-1hiCXCR5- T cells and CD138+ B cells and serum IL-21 concentration were significantly reduced. Different subsets of circulating PD-1hiCXCR5- T cells contribute to the progression and pathogenesis of IgAN by regulating the differentiation of CD138+ B cells through a combination of surface molecules.


Assuntos
Linfócitos B/imunologia , Glomerulonefrite por IGA/tratamento farmacológico , Receptor de Morte Celular Programada 1/metabolismo , Receptores CXCR5/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo , Adolescente , Adulto , Idoso , Benzazepinas/administração & dosagem , Benzazepinas/uso terapêutico , Estudos de Casos e Controles , Feminino , Glomerulonefrite por IGA/metabolismo , Humanos , Interleucinas/sangue , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/uso terapêutico , Sindecana-1/metabolismo , Valsartana/administração & dosagem , Valsartana/uso terapêutico , Adulto Jovem
10.
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
11.
J Vet Intern Med ; 33(6): 2559-2571, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31560137

RESUMO

BACKGROUND: Heart disease is an important cause of morbidity and mortality in cats, but there is limited evidence of the benefit of any medication. HYPOTHESIS: The angiotensin-converting enzyme inhibitor benazepril would delay the time to treatment failure in cats with heart disease of various etiologies. ANIMALS: One hundred fifty-one client-owned cats. METHODS: Cats with heart disease, confirmed by echocardiography, with or without clinical signs of congestive heart failure, were recruited between 2002 and 2005 and randomized to benazepril or placebo in a prospective, multicenter, parallel-group, blinded clinical trial. Benazepril (0.5-1.0 mg/kg) or placebo was administered PO once daily for up to 2 years. The primary endpoint was treatment failure. Analyses were conducted separately for all-cause treatment failure (main analysis) and heart disease-related treatment failure (supportive analysis). RESULTS: No benefit of benazepril versus placebo was detected for time to all-cause treatment failure (P = .42) or time to treatment failure related to heart disease (P = .21). Hazard ratios (95% confidence interval [CI]) from multivariate analysis for benazepril compared with placebo were 1.00 (0.57-1.74) for all-cause failure, and 0.99 (0.50-1.94) for forward selection and 0.93 (0.48-1.81) for bidirectional selection models for heart disease-related failure. There were no significant differences between groups over time after administration of the test articles in left atrium diameter, left ventricle wall thickness, quality of life scores, adverse events, or plasma biochemistry or hematology variables. CONCLUSIONS AND CLINICAL RELEVANCE: Benazepril was tolerated well in cats with heart disease, but no evidence of benefit was detected.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Benzazepinas/uso terapêutico , Doenças do Gato/tratamento farmacológico , Cardiopatias/veterinária , Animais , Gatos , Feminino , Cardiopatias/tratamento farmacológico , Masculino
12.
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
13.
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
14.
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
15.
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
16.
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
17.
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
18.
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
19.
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
20.
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
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