The influence of benazepril and amlodipine on the expression of secretin and somatostatin in spontaneously hypertensive rats / 中国应用生理学杂志

OBJECTIVES@#Investigate the influence of benazepril and amlodipine on the expression of secretin (PZ) and somatostatin (SS) in spontaneously hypertensive rats (SHR).@*METHODS@#Forty-five SHRs (14 weeks old, male) were randomly assigned into 3 groups (=15):SHR group, Benazepril group (which was given benazepril 0.90 mg·kg·d) and Amlodipine group (SHRs were given amlodipine 0.45 mg· kg·d), taking WistarKyoto(WKY) as normal control (=15), meanwhile, rats in SHR group and WKY group were given the same volume of distilled water. After 8 weeks of intervention, the expression of protein and mRNA of PZ in duodenum and SS in sinuses ventriculi was detected by enzyme-linked immunoassay and RT-PCR.@*RESULTS@#After 8 weeks of intervention, compared with the WKY group, the expression of protein and mRNA of PZ in duodenum and SS in sinuses ventriculi was increased significantly in SHR group (<0. 05). Compared with SHR group, the expression of PZ in duodenum and SS in sinuses ventriculi was decreased significantly in Benazepril group and Amlodipine group (<0.05). Compared with Benazepril group, in Amlodipine group the expression of PZ mRNA in duodenum and SS mRNA in sinuses ventriculi was decreased more significantly (<0.05).@*CONCLUSIONS@#The regulation disorder of PZ in duodenum and SS in sinuses ventriculi exists in SHR. The antihypertensive effect of benazepril and amlodipine may be realized by regulating the expression of PZ and SS, while the regulation of amlodipine is more obvious than benazepril.

Utility and Safety of Tolvaptan in Cirrhotic Patients with Hyponatremia: a Prospective Cohort Study

Abstract: Introduction and aim. Hyponatremia is common in patients with decompensated cirrhosis and is associated with increased mortality. Tolvaptan, a vasopressor V2 receptor antagonist, can increase free wáter excretion, but its efficacy and safety in cirrhotic patients remain unclear. Material and methods. We studied the usage and safety of tolvaptan in cirrhotic patients in a real-life, non-randomized, multicenter prospective cohort study. Forty-nine cirrhotic patients with hyponatremia were treated with tolvaptan 15 mg daily, and 48 patients not treated with tolvaptan in the same period served as controls. Improvement in serum sodium level was defined as an increase in serum sodium from < 125 to ≥ 125 mmol/L or from 125-134 to ≥ 135 mmol/L on day 7. Results. Twenty-three (47%) patients in the tolvaptan group and 17 (35%) in the control group had normal serum sodium on day 7 (p = 0.25). Serum sodium improved in 30 (61%) patients in the tolvaptan group and 17 (35%) patients in the control group (p = 0.011). Adverse events occurred in 46-47% of patients in both groups, and tolvaptan was not associated with worsened liver function. No patient with normal serum sodium on day 7 died within 30 days of treatment, whereas 16% of those with persistent hyponatremia died (p = 0.0019). Conclusion. In conclusion, short-term tolvaptan treatment is safe and can improve serum sodium level in cirrhotic patients with hyponatremia. Normalization of serum sodium level is associated with better survival.

A study on toxic effects of sodium salicylate on rat cochlear spiral ganglion neurons: dopamine receptors mediate expressions of NMDA and GABAreceptors / 生理学报

The aim of the present study was to observe whether dopamine receptor (DR) was involved in the effects of sodium salicylate (SS) on the expressions of N-methyl-D-aspartic acid (NMDA) and γ-aminobutyric acid (GABA) receptors in rat cochlear spiral ganglion neurons (SGNs). Forty-eight hours after primary culture of rat SGNs, immunofluorescence technique was applied to detect expressions of DR1 and DR2, the two subtypes of dopamine receptors. Western blot was performed to assess NMDA receptor NR1 subunit and GABAreceptor subunit α2 (GABRα2) protein expressions in the SGNs after the treatments of SS alone or in combination with DR antagonists. The results demonstrated that: (1) The DR1 and DR2 were expressed in the bodies and axons of the SGN; (2) After the treatment with SS, the surface protein expressions of GABRα2 and NR1 were decreased by 44.69% and 21.57%, respectively, while the total protein expressions showed no significant changes; (3) Neither SS + SCH23390 (DR1 antagonist) group nor SS + Eticlopride (DR2 antagonist) group showed significant differences in GABRα2 and NR1 surface protein expressions compared with the control group. These results suggest that SS regulates the surface GABAand NMDA receptors trafficking on SGN, and the mechanism may involve DR mediation.

SIADH secundario a adenocarcinoma seroso de ovario tratado con tolvaptán / SIADH secondary to serous ovarian adenocarcinoma treated with tolvaptan

La hiponatremia es la alteración electrolítica más frecuente en el medio hospitalario, y en un 30% de los casos se debe a un síndrome de secreción inapropiada de vasopresina (SIADH). El SIADH está descrito como cuadro paraneoplásico endocrinológico en múltiples tumores, entre los que excepcionalmente se encuentra el de ovario y las neoplasias ginecológicas en general. Presentamos un caso de SIADH paraneoplásico por un citoadenocarcinoma seroso de ovario de alto grado, estadio IV. Se trata del primer caso de SIADH crónico por cáncer de ovario tratado con Tolvaptán. En el presente caso el objetivo de eunatremia se alcanzó con una dosis baja de acuarético, lo que apoya la elevada sensibilidad, ya previamente documentada, de los SIADH tumorales al tratamiento con Tolvaptán.

Hyponatremia is the most common electrolyte disturbance in hospitals, and 30% of cases are due to syndrome of inappropriate secretion of antidiuretic hormone (SIADH). SIADH is described as an endocrine paraneoplastic syndrome in multiple tumors including, ovary and gynecological malignancies in general, although these are exceptional. We report a case of paraneoplastic SIADH for high-grade serous ovarian cystoadenocarcinoma stage IV. This is the first case of chronic SIADH for ovarian cancer treated with Tolvaptan. In this case the target of eunatremia was reached with a low dose of aquaretic, which supports the high sensitivity, as previously documented, of paraneoplasic SIADH to Tolvaptan.

Ivabradina para o tratamento de insuficiência cardíaca crônica moderada a grave em indivíduos com frequência cardíaca ≥70 bpm e que toleram menos de 50% da dose alvo recomendada de agentes betabloqueadores / Ivabradine for the treatment of moderate to severe chronic heart failure in subjects with heart rate ≥70 bpm and tolerating less than 50% of the recommended target dose of beta-blocking agents

Contexto: A insuficiência cardíaca crônica é uma síndrome sistêmica complexa e progressiva que se caracteriza por comprometimento da perfusão tecidual, com sintomas característicos de dispneia, fadiga, além de piora da qualidade de vida. A síndrome está relacionada a altas taxas de mortalidade e hospitalização. Ivabradina é um protótipo de medicamentos que agem na frequência cardíaca e que recentemente foi aprovada para tratamento de insuficiência cardíaca crônica associada a betabloqueadores em indivíduos em estágios mais avançados da doença e que mantêm a frequência cardíaca alta mesmo em tratamento com as doses mais altas toleradas desses medicamentos. Pergunta: A associação de ivabradina ao tratamento convencional com betabloqueadores é eficaz e segura no tratamento de pacientes com insuficiência cardíaca crônica, quando comparada ao tratamento com betabloqueadores? Evidências científicas: Foram avaliados 15 estudos, dentre os quais um ensaio clínico duplo-cego, randomizado e controlado por placebo no qual se incluíram 6.500 indivíduos com insuficiência cardíaca crônica em estágio funcional NYHA II a IV e frequência cardíaca ≥70 bpm. O tratamento com ivabradina em dose média de 6 mg duas vezes ao dia em associação a betabloqueadores por 23 meses diminuiu o risco de internação por piora no quadro de insuficiência cardíaca em 26%, ao que se associa um NNT de 20 (IC 95% 15 a 31). O medicamento não demonstrou efeito no desfecho primário mortalidade por causas cardiovasculares como também não se observou diminuição de risco de mortalidade por todas as causas. Observou-se uma diminuição no risco de mortalidade por insuficiência cardíaca, desfecho secundário, embora associada à imprecisão importante, em função das baixas taxas de eventos e do amplo intervalo de confiança (NNT 83, IC 95% 52 a 333). Por meio de outros estudos sugere-se que o medicamento tenha efeitos na reversão do remodelamento cardíaco associada à progressividade da doença, diminuição de biomarcadores relacionados à insuficiência cardíaca e na diminuição da pós-carga cardíaca, melhorando o funcionamento ventricular e acoplamento ventrículo arterial, sem, entretanto, interferir na função renal. Identificaram-se efeitos na diminuição da frequência cardíaca e da variação da frequência cardíaca. O uso do medicamento está associado a um NNH de 58 (no período de dois anos) em relação ao desfecho fibrilação atrial em indivíduos com frequência cardíaca maior que 70 bpm. Discussão: O principal benefício do medicamento, cujo efeito foi avaliado por meio de evidência de alta qualidade, é evitar internações por piora no quadro de insuficiência cardíaca. O efeito relativo é de uma diminuição de 26% quando se compara ao uso isolado de betabloqueadores. Entretanto, mesmo para o desfecho de maior benefício, o efeito absoluto ainda é muito baixo, atingindo uma diminuição de 4,9% apenas. Para outros desfechos de hospitalização, o efeito absoluto é ainda mais baixo e mais impreciso. Não houve efeito na mortalidade de forma que o uso do medicamento não obteve efeito nos desfechos mortalidade por todas as causas e por causas cardiovasculares. O efeito estatisticamente significativo observado para diminuição em mortalidade por insuficiência cardíaca partiu de uma medida de baixa qualidade e, portanto, um efeito de baixa confiabilidade e bastante passível de modificação por trabalhos futuros. O medicamento aumenta o risco de fibrilação atrial, como um NNH de 83. Os resultados da análise econômica são frágeis e partem de informações imprecisas, principalmente sobre a estimativa, em termos quantitativos, da população elegível ao tratamento com ivabradina. Decisão: Não incorporar a ivabradina para o tratamento de insuficiência cardíaca crônica moderada a grave em indivíduos com frequência cardíaca ≥ 70 bpm e que toleram menos de 50% da dose alvo recomendada de agentes betabloqueadores, no âmbito do Sistema Único de Saúde - SUS. Foi publicada a Portaria Nº 19, de 24 de maio de 2016.

Status of β-blocker use and heart rate control in Chinese patients with stable coronary artery disease / 中华心血管病杂志

<p><b>OBJECTIVE</b>To observe the current status of β-blocker (BB) use and heart rate control in Chinese patients with stable coronary artery disease (SCAD) based on subgroup data of the prospective observational longitudinal registry of patients with stable coronary artery disease (CLARIFY).</p><p><b>METHODS</b>The CLARIFY study is an international prospective observational registry of outpatients with SCAD. From November 2009 to July 2010, patients with SCAD were enrolled, and demographic information, clinical indicators, medication and blood flow reconstruction were collected. Patients were divided in three mutually exclusive categories by baseline pulse palpation heart rate(HR)≤60 beats per minute (bpm)(n=397), 61-69 bpm(n=782), and ≥70 bpm(n=1 443). The patients were also divided into taking BB or not taking BB groups. The aim of present study is to describe and analyze the current status and factors related to the HR control and BB use in the Chinese subgroup of CLARIFY.</p><p><b>RESULTS</b>A total of 2 622 patients were enrolled from 56 centers across China. The mean age was (63.6±10.3) years old with 75.6% (1 983) male patients, 55.0% (1 443) patients had HR≥70 bpm. Mean HR measure by electrocardiogram(ECG) was (69.4±10.2)bpm, 50.9% (1 334 cases) patients had myocardial infarction(MI) history. A total of 21.9%(575 cases) patients had anginal symptoms; coronary angiography was performed in 88.8%(2 327 cases) of the patients. 76.2%(1 997 cases) patients were treated with BB (any molecule and any dose), 2.7% (70 cases) with digoxin or derivatives, 3.9% (103 cases) with verapamil or diltiazem, and 1.8% (47 cases) with amiodarone or dronedarone and 0.1%(2 cases) received ivabradine. BB use was similar among 3 HR groups(P>0.05). The independent risk factors associated with HR≥70 bpm were diabetes(OR=1.31), current smoker(OR=1.57), chronic heart failure(CHF) with NYHA Ⅲ (OR=2.13) and increased diastolic blood pressure (OR=1.30). Conversely, high physical activity (OR=0.61), former smoker (OR=0.76) and history of percutaneous coronary intervention(PCI, OR=0.80) were associated with lower risk of HR≥70 bpm (all P<0.05). The independent risk factors associated with non-BB use were older age (OR=1.11, 95%CI 1.01-1.47, P=0.005), lower diastolic blood pressure (OR=1.47, 95%CI 1.32-1.68, P=0.012), no history of MI (OR=1.86, 95%CI 1.43-2.44, P<0.001) or PCI (OR=1.94, 95%CI 1.55-3.73, P<0.001), asthma/chronic obstructive pulmonary disease (OR=1.32, 95%CI 1.15-1.99, P<0.001).</p><p><b>CONCLUSIONS</b>A total of 76.2% Chinese SCAD patients received BB medication but more than half of them did not reach the optimal HR. Clinical characteristics including diabetes, current smoker, CHF, increased diastolic blood pressure and no PCI were associated with poorly controlled HR(≥70 bpm). More efforts including adjusting the type and dose of heart rate lowering drugs are needed to achieve optimal HR control in Chinese SCAD patients. Clinical Trail Registry International Standard Randomized Controlled Trial, ISRCTN43070564.</p>

Renin-Angiotensin System Blockade Associated with Statin Improves Endothelial Function in Diabetics / Bloqueio do Sistema Renina-Angiotensina Associado a Estatina Melhora a Função Endotelial em Diabéticos

Abstract Background: Studies suggest that statins have pleiotropic effects, such as reduction in blood pressure, and improvement in endothelial function and vascular stiffness. Objective: To analyze if prior statin use influences the effect of renin-angiotensin-aldosterone system inhibitors on blood pressure, endothelial function, and vascular stiffness. Methods: Patients with diabetes and hypertension with office systolic blood pressure ≥ 130 mmHg and/or diastolic blood pressure ≥ 80 mmHg had their antihypertensive medications replaced by amlodipine during 6 weeks. They were then randomized to either benazepril or losartan for 12 additional weeks while continuing on amlodipine. Blood pressure (assessed with ambulatory blood pressure monitoring), endothelial function (brachial artery flow-mediated dilation), and vascular stiffness (pulse wave velocity) were evaluated before and after the combined treatment. In this study, a post hoc analysis was performed to compare patients who were or were not on statins (SU and NSU groups, respectively). Results: The SU group presented a greater reduction in the 24-hour systolic blood pressure (from 134 to 122 mmHg, p = 0.007), and in the brachial artery flow-mediated dilation (from 6.5 to 10.9%, p = 0.003) when compared with the NSU group (from 137 to 128 mmHg, p = 0.362, and from 7.5 to 8.3%, p = 0.820). There was no statistically significant difference in pulse wave velocity (SU group: from 9.95 to 9.90 m/s, p = 0.650; NSU group: from 10.65 to 11.05 m/s, p = 0.586). Conclusion: Combined use of statins, amlodipine, and renin-angiotensin-aldosterone system inhibitors improves the antihypertensive response and endothelial function in patients with hypertension and diabetes.

Resumo Fundamentos: Estudos sugerem que as estatinas possuem efeitos pleotrópicos, como melhora da função endotelial, da rigidez vascular e redução da pressão arterial. Objetivo: Analisar se o uso prévio de estatina influenciou o efeito sobre a pressão arterial, a função endotelial e a rigidez vascular de drogas inibidoras do sistema renina-angiotensina-aldosterona. Métodos: Pacientes hipertensos e diabéticos com pressão arterial de consultório sistólica ≥ 130 mmHg e/ou diastólica ≥ 80 mmHg tiveram suas medicações anti-hipertensivas substituídas por anlodipino durante 6 semanas. Em seguida, foram randomizados para associação de benazepril ou losartana por mais 12 semanas. Pressão arterial (através da monitorização ambulatorial da pressão arterial), função endotelial (dilatação mediada por fluxo da artéria braquial) e rigidez vascular (velocidade da onda de pulso) foram avaliados antes e após o tratamento combinado. Neste trabalho, uma análise post-hoc foi realizada para comparar pacientes que vinham (grupo CE) ou não (grupo SE) em uso de estatina. Resultados: O grupo CE apresentou maior redução na pressão arterial sistólica nas 24 horas (134 para 122 mmHg, p = 0,007) e na dilatação mediada por fluxo da artéria braquial (6,5 para 10,9%, p = 0,003) quando comparado com o grupo SE (137 para 128 mmHg, p = 0,362, e 7,5 para 8,3%, p = 0,820). Não houve diferença estatisticamente significante na velocidade de onda de pulso (grupo CE 9,95 para 9,90 m/s, p = 0,650 e grupo SE 10,65 para 11,05 m/s, p = 0,586). Conclusão: O uso combinado de estatinas, anlodipino e inibidores do sistema renina-angiotensina-aldosterona melhora a resposta anti-hipertensiva e a função endotelial em pacientes hipertensos e diabéticos.

Effects and mechanisms of low concentration dopamine on hydrogen peroxide-induced apoptosis in cultured neonatal rat cardiomyocytes / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To study the effects of low concentration dopamine(DA) on hydrogen peroxide-induced apoptosis in cultured rat cardiomyocytes as well as the possible molecular mechanisms.</p><p><b>METHODS</b>Cultured neonatal rat cardiomyocytes were randomly divided into the following groups: control group (control), hydrogen peroxide group (H2O2), pretreated with low concentration dopamine ( DA + H2O2), dopamine receptor l(DR1) antagonist group (DR1 + DA + H2O2), dopamine receptor 2(DR2) antagonist group (DR2 + DA + H2O2). The cell apoptosis was then assessed by MTT and flow cytometry. The cellular ultrastructure changes were observed by transmission electron micro- scope. The activity of lactate dehydrogenase(LDH )and superoxide dismutase (SOD) in cell medium was analyzed by colorimetry. The protein expressions of Cytochrone c, Caspase 3 and Caspase 9 were obtained by Western blot.</p><p><b>RESULTS</b>Compared with hydrogen peroxide group, low concentration dopamine(10 µmol/L) decreased the apoptosis rate and the expression of protein of apoptosis related protein, enhanced SOD activity, decreased LDH activity. DR1 antagonist SCH-23390 treatment inhibited dopamine induced cardiac protective effect. DR2 antagonist haloperido treatment had no changes compared with dopamine group.</p><p><b>CONCLUSION</b>Above findings indicate that low concentration dopanine inhibits apoptosis induced by hydrogen peroxide in neonatal rat cardiomyocytes, which is partly associated with the activation of DR1.</p>

Effects of stable isotope labeled internal standard on determination of ivabradine and N-demethylivabradine in human plasma / 药学学报

This study aims to develop a liquid chromatography with tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of ivabradine and N-demethylivabradine in human plasma, and investigate effects of stable isotope labeled (SIL) internal standard (IS) on ivabradine. The analytes and IS were extracted from plasma by protein precipitation with acetonitrile, and chromatographied on a Capcell PAK C18 (100 mm x 4.6 mm, 5 μm) column using a mobile phase of methanol and 5 mmol x L(-1) ammonium acetate. Multiple reaction monitoring with electrospray ionization (ESI) was used in the positive mode for mass spectrometric detection. The effect of ivabradine isotope peak [M+H+3] + on IS and the effect of SIL IS purity on ivabradine were evaluated. An appropriate concentration of SIL IS was chosen to permit method selectivity and linearity of the assay over the required range. The standard curves were demonstrated to be linear in the range of 0.100 to 60.0 ng x mL(-1) for ivabradine, and 0.050 0 to 20.0 ng x mL(-1) for N-demethylivabradine. The intra and inter day precision and accuracy were within the acceptable limits for all concentrations. Besides, the interaction between IS and ivabradine did not impact the determination of analytes. This method was successfully applied to a pharmacokinetic study of hydrogen sulfate ivabradine sustained release tablets on Chinese healthy volunteers.

Ivabradine Improves Heart Rate Variability in Patients with Nonischemic Dilated Cardiomyopathy / Ivabradina Melhora a Variabilidade da Frequência Cardíaca em Pacientes com Cardiomiopatia Dilatada Não Isquêmica

Background: Ivabradine is a novel specific heart rate (HR)-lowering agent that improves event-free survival in patients with heart failure (HF). Objectives: We aimed to evaluate the effect of ivabradine on time domain indices of heart rate variability (HRV) in patients with HF. Methods: Forty-eight patients with compensated HF of nonischemic origin were included. Ivabradine treatment was initiated according to the latest HF guidelines. For HRV analysis, 24-h Holter recording was obtained from each patient before and after 8 weeks of treatment with ivabradine. Results: The mean RR interval, standard deviation of all normal to normal RR intervals (SDNN), the standard deviation of 5-min mean RR intervals (SDANN), the mean of the standard deviation of all normal-to-normal RR intervals for all 5-min segments (SDNN index), the percentage of successive normal RR intervals exceeding 50 ms (pNN50), and the square root of the mean of the squares of the differences between successive normal to normal RR intervals (RMSSD) were low at baseline before treatment with ivabradine. After 8 weeks of treatment with ivabradine, the mean HR (83.6 ± 8.0 and 64.6 ± 5.8, p < 0.0001), mean RR interval (713 ± 74 and 943 ± 101 ms, p < 0.0001), SDNN (56.2 ± 15.7 and 87.9 ± 19.4 ms, p < 0.0001), SDANN (49.5 ± 14.7 and 76.4 ± 19.5 ms, p < 0.0001), SDNN index (24.7 ± 8.8 and 38.3 ± 13.1 ms, p < 0.0001), pNN50 (2.4 ± 1.6 and 3.2 ± 2.2 %, p < 0.0001), and RMSSD (13.5 ± 4.6 and 17.8 ± 5.4 ms, p < 0.0001) substantially improved, which sustained during both when awake and while asleep. Conclusion: Our findings suggest that treatment with ivabradine improves HRV in nonischemic patients with HF. .

Fundamento: A ivabradina é um novo agente redutor específico da frequência cardíaca (FC) que melhora a sobrevida livre de eventos de pacientes com insuficiência cardíaca (IC). Objetivo: Avaliar o efeito da ivabradina nos índices temporais da variabilidade da frequência cardíaca (VFC) em pacientes com IC. Métodos: Quarenta e oito pacientes com IC compensada de etiologia não-isquêmica foram incluídos no estudo. O tratamento com ivabradina foi iniciado de acordo com as recomendações mais recentes para a IC. O Holter de 24 horas foi utilizado para analisar os índices da VFC em cada paciente antes e após 8 semanas de tratamento com ivabradina. Resultados: Todos os índices da VFC, o intervalo RR médio, o desvio padrão de todos os intervalos RR normais (DPNN), o desvio padrão de intervalos RR médios de 5 minutos (DPNNM), a média do desvio padrão de todos os intervalos RR normais para todos os segmentos de 5 minutos (índice DPNN), porcentagem de intervalos RR normais sucessivos superiores a 50 milissegundos (pNN50), e a raiz quadrada da média dos quadrados das diferenças entre intervalos RR sucessivos (RMQQD) apresentaram redução no ínicio do estudo, antes do tratamento com ivabradina. Após 8 semanas de tratamento com ivabradina, as médias das FC (83,6 ± 8,0 e 64,6 ± 5,8, p < 0,0001) e todos os índices da VFC, médias dos intervalos RR (713 ± 74 e 943 ± 101 ms, p < 0,0001), DPNN (56,2 ± 15,7 e 87,9 ± 19,4 ms, p < 0,0001), DPNNM (49,5 ± 14,7 e 76,4 ± 19,5 ms, p < 0,0001), índice DPNN (24,7 ± 8,8 e 38,3 ± 13,1 ms, p < 0,0001), pNN50 (2,4 ± 1,6 e 3,2 ± 2,2%, p < 0,0001) e RMQQD (13,5 ± 4,6 e 17,8 ± 5,4 ms , p < 0,0001), foram substancialmente melhorados, e permaneceram nestas ...

Simultaneous determination of amlodipine, benazepril and benazeprilat in human plasma by LC-HESI/MS/MS method / 药学学报

The study aims to develop a rapid, sensitive and specified method of liquid chromatography with heated electrospray ionization tandem mass spectrometry (LC-HESI/MS/MS) for simultaneous determination of amlodipine, benazepril and benazeprilat in human plasma using amlodipine-d4 and ubenimex as internal standards (ISs). Selected reaction monitoring (SRM) with heated electrospray ionization (HESI) was used in the positive mode for mass spectrometric detection. Analytes and ISs were extracted from plasma by simple protein precipitation. The reconstituted samples were chromatographed on a C18 (100 mm x 4.6 mm, 5 microm) column with mixture of methanol-acetonitrile-5 mmol.L- ammonium acetate-formic acid (30 : 30 : 40 : 0.1) as mobile phase at a flow rate of 0.6 mL.min-1. The standard curves were demonstrated to be linear in the range of 0.02 to 6.00 ng.mL-1 for amlodipine, 0.2 to 1,500 ng.mL-1 for benazepril and benazeprilat with r2>0.99 for each analyte. The lower limit of quantitation was identifiable and reproducible at 0.02, 0.2 and 0.2 ng mL-1 for amlodipine, benazepril and benazeprilat, respectively. The intra-day and inter-day precision and accuracy results were within the acceptable limit across all concentrations. The plasma samples were stable after four freeze-thaw cycles and being stored for 93 days at -20 degrees C. The method was applied to a pharmacokinetic study of a fixed-dose combination of amlodipine and benazepril on Chinese healthy volunteers.

Effectiveness of Varenicline with counseling programs on smoking cessation in a targeted clinical setting in China / 中华流行病学杂志

<p><b>OBJECTIVE</b>To evaluate the effectiveness of Varenicline for smoking cessation in a community-based smoking-cessation-clinic (SCC) in Chinese smokers.</p><p><b>METHODS</b>A prospective observational study was conducted in Beijing, China. 799 smokers (762 men and 37 women) were assessed on data gathered from structured questionnaires at baseline and follow up programs at 1, 3 and 6 months. Trained physician counselors provided free individual counseling and follow-up interviews with brief counseling for all the subjects. 272 subjects were additionally prescribed Varenicline according to their own choice and reported data were compared to those without Varenicline. Outcomes were self-reported, regarding the 7-day point prevalence on abstinence rate and continuous abstinence rates at 1, 3 and 6 month follow-up periods.</p><p><b>RESULTS</b>At 6-month and by intention-to-treat, the 7-day point prevalence on abstinence rate with Varenicline and counseling, was significantly higher than the group with counseling only (34.6% versus 23.1%; OR = 1.75, 95% CI: 1.27-2.42;P < 0.001). The 3-month continuous abstinence rate at 6 month was higher in the group with Varenicline(31.3% versus 18.2% ;OR = 2.04, 95% CI:1.46-2.86;P < 0.001). Varenicline also showed better outcomes at 1 and 3 month follow-up.</p><p><b>CONCLUSION</b>Varenicline prescription in the smoking cessation clinic appeared to be effective that doubled the rates of quitting among Chinese smokers in the practice at a community-based SCC.</p>

Angiotensin-converting enzyme inhibitors in the treatment of sarcoidosis and association with ACE gene polymorphism: Case series.

Angiotensin-converting enzyme (ACE) is used as a marker for sarcoid disease activity.1 We present an observational study of four African-American patients all of whom demonstrated improvement in their sarcoidosis after treatment with ACE inhibitors for hypertension.

Resultados de un programa multidisciplinario para el control del hábito tabáquico / Results of a multidisciplinary program to quit smoking

Background: Therapies to quit smoking are based on counseling, psychological therapy (PT), nicotine replacement therapy, bupropion or varenidine. Aim: To report the results of a multidisciplinary program to quit smoking Material and Methods: Patients agedl8years or more, motivated to quit smoking were admitted in a program based in counseling and PT, with or without pharmacological therapy. They were assessed by telephone during one year offollow up. Patients with unstable psychiatric diseases were excluded. Results were considered as "successful" when patients maintained abstinence during the year offollow up. A logistic regression analysis was done to identify factors associated with treatment success. Results: Between 2005 and 2011, 198 patients aged 45 ± 11 years (56% males), who smoked 31.5 ± 20.6 packages/year, were treated. Ofthese, 155 (78%) were treated with varenidine, 26 (13%) with bupropion and 17 (9%>) did not receive pharmacological therapy. One hundred sixty eightpatients completed the year offollow up. In 82 (49%>), treatment was successful and was negatively associated with a history of depression (odds ratio = 4 (95% confidence intervals 1.23-38.33). The main side effeets associated to varenidine and bupropion were nausea in 37 and 23%o, sleep disorders in 20 and 19%o and headache in 12 and 0%>, respectively Conclusions: A multidisciplinary program to quit smoking achieved a 49%> of abstinence during a year offollow up.

Weight Loss Drugs Recently Approved by the FDA / 임상당뇨병

There have been many advances in obesity treatment, including life-style modification and pharmacological and surgical treatments. It seems that the most remarkable advances in obesity treatment are those of pharmacological strategies. However, weight loss medications have a long history of development. The FDA has withdrawn anti-obesity drugs such as fenfluramine, dexfenfluramine, and phenylpropylamine due to unwanted side effects. Sibutramine was voluntarily withdrawn from the market, and new drugs such as rimonabant have been suspended in the middle of clinical study due to unacceptable side effects. Last year, the FDA approved two new anti-obesity drugs for the treatment of obesity. Lorcaserin is a selective 5-hydroxytryptamine receptor 2c (5-HT2c) agonist whose pharmacological mechanism of action is similar to those of fenfluramine and dexfenfluramine. However, lorcaserin is specific for 5-HT2c, which is located almost exclusively in the CNS and is not found on heart valves. Three exciting phase 3 clinical trials for lorcaserin have been published recently. Lorcaserin has been shown to successfully result in weight reduction, and the drug was not found to lead to heart disease, as is the case with some other such drugs. Furthermore, the FDA also approved controlled release phentermine/topiramate (PHEN/TPM CR), a drug composed of immediate-release phentermine and controlled-release topiramate. Weight reduction by PHEN/TPM CR is better than any other anti-obesity drugs in the world. Along with this excellent efficacy, however, come painful side effects that clinicians should consider.

Effects of chronotherapy of benazepril on the diurnal profile of RAAS and clock genes in the kidney of 5/6 nephrectomy rats / 华中科技大学学报（医学）（英德文版）

This study investigated the effects of benazepril administered in the morning or evening on the diurnal variation of renin-angiotensin-aldosterone system (RAAS) and clock genes in the kidney. The male Wistar rat models of 5/6 subtotal nephrectomy (STNx) were established. Animals were randomly divided into 4 groups: sham STNx group (control), STNx group, morning benazepril group (MB) and evening benazepril group (EB). Benazepril was intragastrically administered at a dose of 10 mg/kg/day at 07:00 and 19:00 in the MB group and EB group respectively for 12 weeks. All the animals were synchronized to the light:dark cycle of 12:12 for 12 weeks. Systolic blood pressure (SBP), 24-h urinary protein excretion and renal function were measured at 11 weeks. Blood samples and kidneys were collected every 4 h throughout a day to detect the expression pattern of renin activity (RA), angiotensin II (AngII) and aldosterone (Ald) by radioimmunoassay (RIA) and the mRNA expression profile of clock genes (bmal1, dbp and per2) by real-time PCR at 12 weeks. Our results showed that no significant differences were noted in the SBP, 24-h urine protein excretion and renal function between the MB and EB groups. There were no significant differences in average Ald and RA content of a day between the MB group and EB group. The expression peak of bmal1 mRNA was phase-delayed by 4 to 8 h, and the diurnal variation of per2 and dbp mRNA diminished in the MB and EB groups compared with the control and STNx groups. It was concluded when the similar SBP reduction, RAAS inhibition and clock gene profile were achieved with optimal dose of benazepril, morning versus evening dosing of benazepril has the same renoprotection effects.

Inhibition of peripheral NPY Y1 and Y2 receptors ameliorates the aberrant baroreceptor reflex sensitivity in streptozotocin induced diabetic rats / 生理学报

Neuropeptide Y (NPY), a sympathetic neurotransmitter, is highly associated with baroreflex dysfunction and multiple cardiac diseases such as diabetic myocardiopathy. In the present study, we aimed to explore the role of peripheral NPY Y1 receptor (Y1R) and Y2 receptor (Y2R), which are dominantly present in peripheral cardiovascular control, in baroreflex sensitivity (BRS) of streptozotocin (STZ)-induced diabetic rats. Peripheral Y1R and Y2R were antagonized by specific antagonists (BIBP 3226 and BIIE 0246, respectively) from subcutaneously implanted ALZET mini-osmotic pump in STZ-induced diabetic rats for 4 weeks. Then baseline systolic blood pressure, heart rate, cardiac function, BRS, plasma NPY and lipid levels were evaluated. We found that STZ led to increased plasma NPY and lipid level. And the STZ-increased lipid levels were reduced by BIBP 3226 and BIIE 0246. BIBP 3226 ameliorated the aberrant BRS, but had little effect on the impaired cardiac function of the STZ rats. BIIE 0246 alleviated sodium nitroprusside (SNP)-induced but not phenylephrine (PE)-induced aberrant baroreflex control of heart rate in the STZ rats. In addition, BIIE 0246 alleviated the bradycardia, but further impaired cardiac contractility in the STZ rats. These results suggest that peripheral Y1R and Y2R play different roles in STZ-induced impairment of BRS.