RESUMO
Angiotensin II-type 1 receptor stimulation is recognised to promote inflammation, a state central to the development and maintenance of rheumatoid arthritis. Herein we examined the use of losartan, an angiotensin II-type 1 receptor antagonist, on vascular reactivity, knee joint diameter and behavioural assessment of pain in a Freund's complete adjuvant (FCA) mouse model of joint inflammation. Monoarthritis was induced via FCA in the presence or absence of losartan with naive mice serving as controls. Knee joint swelling, joint pain (assessed by dynamic weight bearing of limb use), knee joint artery reactivity (assessed ex vivo) and blood perfusion of the knee joint (assessed in vivo) were determined. FCA mediated a significant increase in knee joint diameter and reduced weight-bearing (a surrogate for pain sensation) of the affected limb. Notably, these phenomena were substantially reduced when mice were prophylactically treated with losartan. Assessment of arterial relaxation and blood perfusion with acetylcholine stimulation revealed that FCA resulted in significant vascular dysfunction, which was resolved to naïve levels with losartan treatment. Through the actions of losartan, these findings indicate that the angiotensin II-type 1 receptor is a likely therapeutic target of importance in the development of the physical changes, pain sensation and vascular dysfunction found in inflammatory arthritis.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Losartan/farmacologia , Acetilcolina/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Animais , Artérias/efeitos dos fármacos , Artralgia/induzido quimicamente , Artralgia/tratamento farmacológico , Circulação Sanguínea/efeitos dos fármacos , Citocinas/sangue , Adjuvante de Freund/toxicidade , Injeções Intraperitoneais , Articulação do Joelho/efeitos dos fármacos , Losartan/administração & dosagem , Masculino , Camundongos Endogâmicos C57BL , Nitroprussiato/farmacologia , Suporte de CargaRESUMO
BACKGROUND: Worldwide, hypertension is an important public health challenge because of its high prevalence and the concomitant risks of cardiovascular disease. It induces half of the coronary heart disease and approximately two-thirds of the cerebrovascular disease burden. Vascular endothelial dysfunction has important roles in the pathophysiology of essential hypertension. Types I and II hypertension can be treated with sang-qi granules (SQG), a Chinese herbal formula. Several experimental studies on animals have shown that SQG can lower blood pressure and myocardial fibrosis by suppressing inflammatory responses. However, no standard clinical trial has confirmed this. Whether SQG can improve endothelial cell function is unknown. METHODS/DESIGN: In this randomized double-blind double-simulation controlled trial, 300 patients with stage I or II hypertension will be recruited and randomly allocated in a 1:1:1 ratio to group A (treatment with SQG and placebo instead of Losartan), group B (treatment with Losartan and placebo instead of SQG), and group C (treatment with SQG and Losartan). In this study, 10 g of SQG (or its placebo) will be administrated twice a day and 50 mg of Losartan (or its placebo) will be administrated once in the morning. The primary endpoint is the drug efficiency for each of the three groups. The secondary endpoints are the change in average systolic and diastolic blood pressure during the day and the night, the change in the rate at which blood pressure drops at night, assessment of target organ damage (heart rate variability, ankle-brachial pressure index, and pulse wave velocity), assessment of any improvement in symptoms (Hypertension Symptom Scale, syndrome integral scale in traditional Chinese medicine, Pittsburgh Sleep Quality Index Scale, Self-Rating Anxiety Scale, Self-Rating Depression Scale, and the 36-Item Short Form Health Survey), blood lipids, serum indicators of vascular function (changes in serum levels of ET-1, TXA2, NO, and PGI2), and safety indicators. DISCUSSION: This study aims to provide clinical evidence on the efficacy and safety of SQG in the treatment of hypertension. Moreover, the possible mechanism by which SQG may lower blood pressure will be explored by observing the protective effect of SQG on vascular endothelial function, as well as its effect on related clinical symptoms, risk factors, and the target organs of hypertension. TRIAL REGISTRATION: Chinese Clinical Trials Registry, ChiCTR1800016427. Registered on 1 June 2018.
Assuntos
Anti-Hipertensivos/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Endotélio Vascular/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Losartan/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Determinação da Pressão Arterial , China , Método Duplo-Cego , Esquema de Medicação , Medicamentos de Ervas Chinesas/efeitos adversos , Endotélio Vascular/fisiopatologia , Humanos , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Losartan/efeitos adversos , Placebos/administração & dosagem , Placebos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
An abnormal tumor growth induces solid stress in tumors, thus reducing blood perfusion. As a result, the impaired blood perfusion, with dense interstitial matrix in tumors significantly reduces the penetration and efficacy of nanotherapeutics. In this study, we have developed a losartan-loaded polydopamine nanoparticle (PLST) for the enhanced delivery of nanoparticles to tumors and improved photothermal cancer therapy. Losartan, an angiotensin inhibitor, is also able to alleviate the solid stress in tumors. It was laden on polydopamine nanoparticles via π-π stacking and was released upon tumor extracellular acidity. PLST reduced collagen production in vitro along with the lowered expression of profibrotic factors of TGF-ß1, CCN2, and TIMP-1. The in vivo studies reveal that PLST reduced solid stress in tumors, and the amount of PLST accumulated in tumors was enhanced. The efficiency of the photothermal ablation of tumors was significantly enhanced by using PLST.
Assuntos
Angiotensinas/antagonistas & inibidores , Neoplasias da Mama/terapia , Indóis/química , Losartan/administração & dosagem , Fototerapia/métodos , Polímeros/química , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Colágeno/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Hipertermia Induzida/métodos , Losartan/química , Losartan/farmacologia , Melaninas/química , Camundongos , Nanopartículas , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Background/aim: Losartan, an antihypertensive drug, is highly preferred in patients with diabetes mellitus (DM) and hypertension because of its retarding effect on diabetic nephropathy. In this study, we investigated the potential therapeutic effect of different doses of losartan on hepatic damage in a streptozotocin (STZ, 50 mg/kg)-induced DM model in rats. Materials and methods: In this study, five different groups were formed: control, DM, low-dose losartan (5 mg/kg), mid-dose losartan (20 mg/kg), and high-dose losartan (80 mg/kg). Liver tissues of experimental groups were evaluated immunohistochemically for TUNEL, iNOS, eNOS, VEGF, and NF-κB pathways. In addition to immunohistochemical analysis, analyses of SOD and MDA, which are oxidative stress markers, were also performed and the results were evaluated together. Results: When biochemical and immunohistochemical findings were evaluated together, it was found that the results obtained from the mid-dose losartan group were closer to those of the control than the other groups. Conclusion: This study indicated that mid-dose losartan administration may have a therapeutic effect by inhibiting apoptosis and regulating iNOS, eNOS, VEGF, and NF-κB protein expressions in DM-induced hepatic damage.
Assuntos
Anti-Hipertensivos/administração & dosagem , Complicações do Diabetes/prevenção & controle , Diabetes Mellitus Experimental/metabolismo , Hepatopatias/prevenção & controle , Losartan/administração & dosagem , NF-kappa B/biossíntese , NF-kappa B/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/biossíntese , Óxido Nítrico Sintase Tipo III/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/biossíntese , Óxido Nítrico Sintase Tipo II/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/biossíntese , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Animais , Masculino , Ratos , Ratos WistarRESUMO
Identification of renin-angiotensin system in the interplay of hypertension and neurodegeneration has paved the way for the repurposing of antihypertensive drugs against Parkinsonism. Losartan carboxylic acid (LCA), the potent AT1 blocker metabolite of losartan, suffers from poor bioavailability and brain access. Since ascorbate transporters have earlier shown enough flexibility as carriers, we have conjugated losartan carboxylic acid to ascorbic acid with the aim of achieving higher oral/brain availability. Ester of LCA and ascorbic acid (FED) was developed keeping in view the substrate specificity of ascorbate transporters. Oral/brain bioavailability was assessed using in vivo pharmacokinetic model. Effect on central nervous system (CNS) and protection against Parkinsonism was evaluated using in vivo models. FED enhanced bioavailability of LCA. The higher brain availability of LCA enabled CNS protection as evident from the increase in locomotor activity, improved motor coordination, and protection against drug-induced catatonia. In conclusion, FED offers an approach to repurpose LCA against Parkinsonism. This can encourage further investigation to simultaneously address hypertension and neurodegeneration.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Ácido Ascórbico/administração & dosagem , Losartan/administração & dosagem , Transtornos Parkinsonianos/prevenção & controle , Sistema Renina-Angiotensina/efeitos dos fármacos , Administração Oral , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacocinética , Animais , Ácido Ascórbico/química , Comportamento Animal/efeitos dos fármacos , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Haloperidol/administração & dosagem , Haloperidol/toxicidade , Humanos , Losartan/química , Losartan/farmacocinética , Masculino , Transtornos Parkinsonianos/induzido quimicamente , Ratos , Ratos WistarRESUMO
Morning hypertension is an independent risk for cerebrovascular and cardiovascular events. Although the prevalence of morning hypertension increases with age, treatment of morning hypertension has not been established, particularly in Very-Elderly patients. We compared the safety and efficacy of a losartan/hydrochlorothiazide (HCTZ) combination in controlling morning hypertension between Very-Elderly (≥75 years) and Young/Elderly patients (<75 years). This study was a subanalysis of the Morning Hypertension and Angiotensin Receptor Blocker/Hydrochlorothiazide Combination Therapy study, in which patients with morning hypertension (≥135/85 mmHg) received a 50-mg losartan/12.5-mg HCTZ combination tablet (combination therapy) or 100-mg losartan (high-dose therapy) for 3 months. High adherence rates and few adverse effects were observed in Very-Elderly patients receiving combination (n = 32) and high-dose (n = 34) therapies and in Young/Elderly patients receiving combination (n = 69) and high-dose (n = 66) therapies. Baseline morning systolic BP (SBP) was similar in both age groups receiving either therapy. Morning SBP was reduced by 20.2 and 18.1 mmHg with combination therapy and by 7.1 and 9.1 mmHg with high-dose therapy in the Very-Elderly and Young/Elderly patients, respectively. Morning BP target (<135/85 mmHg) was achieved in 40.6% and 55.1% by combination therapy and in 14.7% and 24.2% by high-dose therapy in the Very-Elderly and Young/Elderly patients, respectively. Neither therapy changed renal function and serum potassium in Very-Elderly patients. In conclusion, the losartan/HCTZ combination was safe and effective in controlling morning hypertension in Very-Elderly as well as Young/Elderly patients. In addition, combination therapy was also superior to high-dose therapy for lowering morning SBP in Very-Elderly patients.
Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Diuréticos/uso terapêutico , Hidroclorotiazida/uso terapêutico , Hipertensão/tratamento farmacológico , Losartan/uso terapêutico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Diuréticos/efeitos adversos , Combinação de Medicamentos , Feminino , Humanos , Hidroclorotiazida/efeitos adversos , Rim/efeitos dos fármacos , Rim/fisiologia , Losartan/administração & dosagem , Losartan/efeitos adversos , Masculino , Pessoa de Meia-Idade , Potássio/sangue , Fatores de Tempo , Resultado do TratamentoRESUMO
We investigated botanical drug-pharmaceutical drug interactions between DW1029M (a botanical extract of Morus alba linne root bark and Puerariae radix) and metformin, losartan, and linagliptin in the steady state. Three studies were conducted as randomized, open-label, 2-period, 2-treatment, multiple-dose, 2-way crossover designs. Eligible subjects received metformin (500 mg twice daily), losartan (50 mg once daily), or linagliptin (5 mg once daily) with DW1029M (300 mg × 2T twice daily) every 12 hours on days 1 through 6 and a single dose on the morning of day 7. Coadministration of DW1029M with metformin, losartan, or linagliptin had no clinically relevant effects based on the area under the plasma concentration-time curve (AUCτ ) geometric least-squares mean ratio (GMR) - AUCτ GMR, 89.7; 90% confidence interval (CI), 81.0-99.4 for metformin; AUCτ GMR, 96.2; 90%CI, 86.3-107.1 for losartan; and AUCτ GMR, 89.7; 90%CI, 83.2-96.6 for linagliptin. In addition, coadministration of DW1029M did not have any clinically meaningful effect on the maximum plasma concentration (Cmax,ss ) - Cmax,ss GMR, 87.3; 90%CI, 76.2-100.0 for metformin; Cmax,ss GMR, 90.5; 90%CI, 78.3-104.6 for losartan; and Cmax,ss GMR, 81.4; 90%CI, 69.5-95.3 for linagliptin. Coadministration of DW1029M with metformin, losartan, or linagliptin was well tolerated.
Assuntos
Linagliptina/farmacocinética , Losartan/administração & dosagem , Metformina/farmacocinética , Morus/química , Extratos Vegetais/farmacocinética , Pueraria/química , Adulto , Área Sob a Curva , Estudos Cross-Over , Esquema de Medicação , Interações Medicamentosas , Voluntários Saudáveis , Humanos , Linagliptina/administração & dosagem , Losartan/farmacocinética , Masculino , Metformina/administração & dosagem , Pessoa de Meia-Idade , Extratos Vegetais/administração & dosagem , Adulto JovemRESUMO
AIMS: We assessed the drug interaction profile of fermented red ginseng with respect to the activity of major cytochrome (CYP) P450 enzymes and of a drug transporter protein, P-glycoprotein (P-gp), in healthy volunteers. METHODS: This study was an open-label crossover study. The CYP probe cocktail drugs caffeine, losartan, dextromethorphan, omeprazole, midazolam and fexofenadine were administered before and after 2 weeks of fermented red ginseng administration. Plasma samples were collected, and tolerability was assessed. Pharmacokinetic parameters were calculated, and the 90% confidence intervals (CIs) of the geometric mean ratios of the parameters were determined from logarithmically transformed data. Values were compared between before and after fermented red ginseng administration using analysis of variance (anova). RESULTS: Fifteen healthy male subjects were evaluated, none of whom were genetically defined as a poor CYP2C9, CYP2C19 or CYP2D6 metabolizer based on genotyping. Before and after fermented red ginseng administration, the geometric least-square mean metabolic ratio (90% CI) was 0.901 (0.830-0.979) for caffeine (CYP1A2) to paraxanthine, 0.774 (0.720-0.831) for losartan (CYP2C9) to EXP3174, 1.052 (0.925-1.197) for omeprazole (CYP2C19) to 5-hydroxyomeprazole, 1.150 (0.860-1.538) for dextromethorphan (CYP2D6) to dextrorphan, and 0.816 (0.673-0.990) for midazolam (CYP3A4) to 1-hydroxymidazolam. The geometric mean ratio of the area under the curve of the last sampling time (AUClast ) for fexofenadine (P-gp) was 1.322 (1.112-1.571). CONCLUSION: No significantly different drug interactions were observed between fermented red ginseng and the CYP probe substrates following the two-week administration of concentrated fermented red ginseng. However, the inhibition of P-gp was significantly different between fermented red ginseng and the CYP probe substrates. The use of fermented red ginseng requires close attention due to the potential for increased systemic exposure when it is used in combination with P-gp substrate drugs.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/metabolismo , Alimentos Fermentados , Panax , Preparações Farmacêuticas/metabolismo , Adulto , Cafeína/administração & dosagem , Cafeína/farmacocinética , Estudos Cross-Over , Interações Medicamentosas , Voluntários Saudáveis , Humanos , Losartan/administração & dosagem , Losartan/farmacocinética , Masculino , Midazolam/administração & dosagem , Midazolam/farmacocinética , Pessoa de Meia-Idade , Omeprazol/administração & dosagem , Omeprazol/farmacocinética , Preparações Farmacêuticas/administração & dosagem , Terfenadina/administração & dosagem , Terfenadina/análogos & derivados , Terfenadina/farmacocinética , Adulto JovemRESUMO
Red ginseng (RG) is one of the top selling herbal medicines in Korea, but is not recommended in hypertensive patients. In this study, the pharmacokinetic (PK) interaction between RG and losartan, an antihypertensive drug, was examined. RG was orally administered for 2 wk to male Sprague-Dawley (S-D) rats at either control (0), 0.5, 1, or 2 g/kg/d for 2 wk. After the last administration of RG and 30 min later, all animals were treated with 10 mg/kg losartan by oral route. In addition, some S-D rats were administered RG orally for 21 d at 2 g/kg followed by losartan intravenously (iv) at 10 mg/kg/d. Post losartan administration, plasma samples were collected at 5, 15, and 30 min and 1, 1.5, 2, 3, 6, 12, and 24 h. Plasma concentrations of losartan and E-3174, the active metabolite of losartan, were analyzed by a high-pressure liquid chromatography-tandem mass spectrometer system (LC-MS/MS). Oral losartan administration showed dose-dependent pharmacokinetics (PK) increase with time to maximum plasma, but this was not significant between different groups. There was no significant change in tmax with E-3174 PK. With iv losartan, pharmacokinetics showed elevation of area under the plasma concentration-time curve from time zero extrapolated to infinitity. There was not a significant change in AUCinf with E-3174 PK. Therefore, RG appeared to interfere with biotransformation of losartan, as RG exerted no marked effect on E-3174 PK in S-D rats. Data demonstrated that oral or iv treatment with losartan in rats pretreated with RG for 2 wk showed that losartan PK was affected but E-3174 PK remained unchanged among different dose groups. These results suggested that RG induces negligible influence on losartan and E-3174 PK in rats.
Assuntos
Anti-Hipertensivos/farmacocinética , Imidazóis/farmacocinética , Losartan/farmacocinética , Panax/química , Tetrazóis/farmacocinética , Administração Intravenosa , Administração Oral , Animais , Anti-Hipertensivos/administração & dosagem , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Imidazóis/administração & dosagem , Losartan/administração & dosagem , Masculino , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Tetrazóis/administração & dosagemRESUMO
OBJECTIVE: Chronic kidney disease (CKD) amplifies atherosclerosis, which involves renin-angiotensin system (RAS) regulation of macrophages. RAS influences peroxisome proliferator-activated receptor-γ (PPARγ), a modulator of atherogenic functions of macrophages, however, little is known about its effects in CKD. We examined the impact of combined therapy with a PPARγ agonist and angiotensin receptor blocker on atherogenesis in a murine uninephrectomy model. METHODS: Apolipoprotein E knockout mice underwent uninephrectomy (UNx) and treatment with pioglitazone (UNx + Pio), losartan (UNx + Los), or both (UNx + Pio/Los) for 10 weeks. Extent and characteristics of atherosclerotic lesions and macrophage phenotypes were assessed; RAW264.7 and primary peritoneal mouse cells were used to examine pioglitazone and losartan effects on macrophage phenotype and inflammatory response. RESULTS: UNx significantly increased atherosclerosis. Pioglitazone and losartan each significantly reduced the atherosclerotic burden by 29.6% and 33.5%, respectively; although the benefit was dramatically augmented by combination treatment which lessened atherosclerosis by 55.7%. Assessment of plaques revealed significantly greater macrophage area in UNx + Pio/Los (80.7 ± 11.4% vs. 50.3 ± 4.2% in UNx + Pio and 57.2 ± 6.5% in UNx + Los) with more apoptotic cells. The expanded macrophage-rich lesions of UNx + Pio/Los had more alternatively activated, Ym-1 and arginine 1-positive M2 phenotypes (Ym-1: 33.6 ± 8.2%, p < 0.05 vs. 12.0 ± 1.1% in UNx; arginase 1: 27.8 ± 0.9%, p < 0.05 vs. 11.8 ± 1.3% in UNx). In vitro, pioglitazone alone and together with losartan was more effective than losartan alone in dampening lipopolysaccharide-induced cytokine production, suppressing M1 phenotypic change while enhancing M2 phenotypic change. CONCLUSION: Combination of pioglitazone and losartan is more effective in reducing renal injury-induced atherosclerosis than either treatment alone. This benefit reflects mitigation in macrophage cytokine production, enhanced apoptosis, and a shift toward an anti-inflammatory phenotype.
Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Doenças da Aorta/tratamento farmacológico , Aterosclerose/tratamento farmacológico , Losartan/uso terapêutico , Macrófagos/efeitos dos fármacos , Insuficiência Renal Crônica/complicações , Tiazolidinedionas/uso terapêutico , Antagonistas de Receptores de Angiotensina/administração & dosagem , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Doenças da Aorta/etiologia , Doenças da Aorta/genética , Doenças da Aorta/patologia , Apolipoproteínas E/deficiência , Apoptose/efeitos dos fármacos , Aterosclerose/etiologia , Aterosclerose/genética , Aterosclerose/patologia , Linhagem Celular , Citocinas/biossíntese , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Hiperlipidemias/complicações , Hiperlipidemias/genética , Inflamação , Losartan/administração & dosagem , Losartan/farmacologia , Macrófagos/classificação , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nefrectomia , PPAR gama/agonistas , Fenótipo , Pioglitazona , Sistema Renina-Angiotensina/efeitos dos fármacos , Tiazolidinedionas/administração & dosagem , Tiazolidinedionas/farmacologiaRESUMO
In order to investigate whether Yinchenhao decoction (YCHD) attenuates hepatic fibrogenesis in the bile duct ligation (BDL) model via recovering and restoring the self-regulation and balance of the renin-angiotensin system (RAS), 33 specific-pathogen-free (SPF) male Sprague-Dawley rats with common BDL and scission were randomly divided into five groups as follows: G1, the sham group (n=4); G2, BDL 7-day group (n=5); G3, BDL+YCHD 430 mg/mL (n=8); G4, BDL+losartan 0.65 mg/mL (ARB group, n=8); G5, model group (BDL without any treatment, n=8). YCHD and losartan (10 mL·kg(-1)·day(-1)) were given by gastric gavage for 16 days following BDL in G3 and G4 groups, respectively. The effect of YCHD on liver fibrosis and the detailed molecular mechanisms were assessed by liver function including total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IDBIL), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Histological changes were observed by transmission electron microscopy (TEM) and Masson trichrome staining. Western blotting was used to detect the protein expression level of the renin-angiotensin system (RAS) components including angiotensin converting enzyme (ACE), angiotensin II type 1 receptor (AT1R), ACE2, angiotensin II (AngII) as well as transforming growth factor ß1 (TGFß1). The experimental data were analyzed by principle component analytical method of pattern recognition. The results showed that biochemically, serum TBIL, DBIL, IDBIL, ALT and AST levels were markedly increased following BDL as compared with the sham group (P<0.05). Serum TBIL, IDBIL and DBIL levels in G3 group were dramatically decreased as compared with G5 and G4 groups (P<0.05). Serum AST level in G3 was significantly lowered than in G5 group (P<0.05), but there was no significant difference in ALT among G3, G4 and G5 groups (P>0.05). Histologically, livers in G3 group showed less hepatocytes necrosis, less bile duct hyperplasia and less collagen formation than in G4 and G5 groups. The protein expression levels of ACE2, ACE, AngII, AT1R and TGFß1 in G2, G3 and G4 groups were significantly higher than in sham group (P<0.05), and lower than in G5 group (P<0.05). However, the differences among G2, G3 and G4 groups were not significant (P>0.05). ACE2 protein expression in G3 group was significantly higher than in G2 group (P<0.05) and there was no significant difference in comparison with G4 group (P>0.05). Moreover, the protein expression of TGFß1 in G3 group was significantly lower than in G5 and G4 groups (P<0.05). Our findings suggest that the antifibrotic effects of YCHD may be associated with the decreased classical RAS pathway components and TGFß1 downexpression so as to recover and rebuild self-regulation of the RAS by elevating the protein expression of ACE2.
Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Cirrose Hepática/prevenção & controle , Fígado/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Testes de Função Hepática , Losartan/administração & dosagem , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Recent data have highlighted shortcomings of the usual blood pressure (BP) hypothesis in several populations, and emphasized the importance of visit-to-visit variability of BP in predicting cardiovascular events. Herein, we aimed at assessing the association between visit-to-visit BP variability and outcomes in chronic heart failure (CHF) patients enrolled in the Heart failure Endpoint evaluation of Angiotensin II Antagonist Losartan (HEAAL). METHODS AND RESULTS: The HEAAL study randomized 3834 patients with HF and reduced ejection fraction administered 150 mg or 50mg losartan daily in a double blind, randomized, controlled trial. The patients were followed up for up to 6.8 years after randomization, and BP was measured at 3 time points in the first year and at semi-annual visits in the years thereafter. Three measures of visit-to-visit BP variability were computed for each subject: the standard deviation, the coefficient of variation and the average absolute visit-to-visit variation. Cox proportional hazard models were used to investigate the relationship between variations in systolic blood pressure, baseline covariates and the time to death or heart failure hospitalization (i.e. primary outcome). In multivariate analyses stratified on baseline BP, the patients with higher visit-to visit BP variability exhibited poorer outcomes (average absolute difference in SBP in mmHg:hazard ratio: 1.023 [95% CI (1.013, 1.034), P<0.0001]), independent from high dose losartan (still beneficial). CONCLUSIONS: For the first time, visit-to-visit BP variability was found elevated in CHF patients with reduced ejection fraction, and associated with poorer cardiovascular outcomes. Such assessments should be prioritized for testing prevention strategies in CHF. CLINICAL TRIAL REGISTRATION: This study is registered with the ClinicalTrials.gov, number NCT00090259.
Assuntos
Determinação da Pressão Arterial/métodos , Pressão Sanguínea/fisiologia , Insuficiência Cardíaca/fisiopatologia , Losartan/administração & dosagem , Visita a Consultório Médico/estatística & dados numéricos , Função Ventricular Esquerda/fisiologia , Idoso , Idoso de 80 Anos ou mais , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Insuficiência Cardíaca/dietoterapia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Volume Sistólico , Fatores de Tempo , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
OBJECTIVES: This study investigated the dose-related effect of losartan on changes in renal function using data from the HEAAL (Heart failure Endpoint evaluation of Angiotensin II Antagonist Losartan) trial. BACKGROUND: Angiotensin receptor blockers adversely affect renal function in patients with heart failure (HF). The time course and dose dependency of this time course, as well as the clinical implications of these changes in renal function, are not well described. METHODS: Subjects in the HEAAL dataset (n = 3,843) were studied. Changes in estimated glomerular filtration rate (eGFR) over time were compared between dose groups. The association between the timing of incident increases in serum creatinine (SCr) >0.3 mg/dl and clinical outcomes was explored. RESULTS: Compared with 50 mg, 150 mg losartan led to a greater reduction in eGFR across time (mean difference:-3.76 ml/min/1.73 m(2); p < 0.0001). This difference was driven by early changes, and differences in eGFRafter 4 months were not significant (mean difference: 0.42 ml/min/1.73 m(2); p = 0.15) [corrected]. Although an increase in SCr >0.3 mg/dl from baseline was associated with increased risk of death or hospitalization for HF (hazard ratio [HR]: 1.36; p < 0.0001), the relationship was not significant if the change occurred before 4 months (HR: 1.09; p = 0.20). Despite increased risk of worsening renal function, 150 mg losartan was associated with reduced risk of death or hospitalization for HF compared with 50 mg (HR: 0.85; p < 0.0001). CONCLUSIONS: Compared with 50 mg, 150 mg losartan is associated with an increased risk of acute rise in SCr, as well as with greater long-term reductions in eGFR. Despite these effects, high-dose losartan retains its net clinical benefit and is associated with reduced risk of death or hospitalization for HF. (Study to Evaluate Potential Decrease in Hospitalization Events, Time Between Events, and Increasing Longevity in Patients With Symptomatic Heart Failure; NCT00090259).
Assuntos
Antagonistas de Receptores de Angiotensina/administração & dosagem , Taxa de Filtração Glomerular/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Rim/fisiopatologia , Losartan/administração & dosagem , Relação Dose-Resposta a Droga , Seguimentos , Insuficiência Cardíaca/fisiopatologia , Humanos , Rim/efeitos dos fármacos , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
Tamoxifen (TAM) is a standard adjuvant endocrine therapy in postmenopausal breast cancer patients, but innate or acquired TAM resistance has remained to be a therapeutic challenge for clinicians. The aim of this study was to explore the possible participation of renin-angiotensin system (RAS) in the acquisition of TAM resistance and try to prevent and regress the resistance using an angiotensin II receptor type-1 (AGTR1) blocker, losartan. Establishment of TAM-resistant (TAM-R) cells was accomplished by continuous exposure of MCF-7 cells to 1 µmol/L TAM. MTT (3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay was performed to determine cell growth. Moreover, messenger RNA (mRNA) expression levels of AGTR1 and angiotensin II receptor type-2 (AGTR2) were measured by quantitative real-time polymerase chain reaction. A significant increase of AGTR1 and AGTR2 transcripts was observed in TAM-R cells compared to MCF-7 cells. Interestingly, losartan-TAM combination effectively resensitized TAM-R cells to tamoxifen treatment by inducing cell death. Therefore, our findings suggest an important role of RAS in acquired TAM resistance and targeting of RAS by losartan may overcome TAM resistance phenomenon and provide a novel avenue for treatment of resistant breast cancers.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Losartan/administração & dosagem , Receptor Tipo 1 de Angiotensina/genética , Tamoxifeno/administração & dosagem , Antagonistas de Receptores de Angiotensina/administração & dosagem , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptor alfa de Estrogênio/genética , Feminino , Humanos , Células MCF-7 , Sistema Renina-Angiotensina/genéticaRESUMO
OBJECTIVE: We analyzed the efficacy and safety of combination therapy of high-dose losartan (100 mg/day) and hydrochlorothiazide (HCTZ, 12.5 mg/day) compared with those of the combination of high-dose telmisartan (80 mg/day) and HCTZ (12.5 mg/day). METHODS: Forty hypertensive patients who received a combination of high-dose telmisartan and HCTZ were enrolled. We applied a changeover strategy with switching from a combination of high-dose telmisartan and HCTZ to high-dose losartan and HCTZ. We divided the patients into two groups; those who achieved the target blood pressure (controlled group) and those who did not reach the target blood pressure (uncontrolled group) before the changeover and performed further analysis. RESULTS: The uncontrolled group showed a significant decrease in systolic blood pressure (SBP) (143±12 mmHg to 126±11 mmHg at three months). In addition, serum uric acid significantly decreased in all subjects, and in each of the controlled and uncontrolled groups. There were no significant changes in other biochemical parameters, such as potassium and hemoglobin A1c, at three months after the changeover in all subjects. CONCLUSION: Combination therapy with high-dose losartan and HCTZ was superior to the combination of telmisartan and HCTZ with respect to significant decreases in systolic blood pressure and serum uric acid in hypertensive patients.
Assuntos
Anti-Hipertensivos/uso terapêutico , Hidroclorotiazida/uso terapêutico , Hipertensão/tratamento farmacológico , Losartan/uso terapêutico , Idoso , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Creatinina/urina , Diástole/efeitos dos fármacos , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Hemoglobinas Glicadas/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hidroclorotiazida/administração & dosagem , Hidroclorotiazida/efeitos adversos , Hidroclorotiazida/farmacologia , Hipertensão/sangue , Hipertensão/fisiopatologia , Hipertensão/urina , Losartan/administração & dosagem , Losartan/efeitos adversos , Losartan/farmacologia , Masculino , Potássio/sangue , Sístole/efeitos dos fármacos , Resultado do Tratamento , Ácido Úrico/sangue , Ácido Úrico/urinaRESUMO
BACKGROUND AND OBJECTIVES: Once-daily losartan reduces BP in a dose-dependent manner and is well tolerated in hypertensive children aged 6-16 years. This study assessed the dose-response relationship, safety, and tolerability of losartan in hypertensive children aged 6 months to 6 years. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a 12-week, randomized, open-label, dose-ranging study, with a 2-year extension. Patients were randomized to losartan at the following dosages: 0.1 mg/kg per day (low), 0.3 mg/kg per day (medium), or 0.7 mg/kg per day (high). Losartan was titrated to the next dose level (to a 1.4 mg/kg per day maximum dosage, not exceeding 100 mg/d, which was not one of the three original doses offered at randomization) at weeks 3, 6, and 9 for patients who did not attain their goal BP and were not taking the highest dose. Dose response was evaluated by analyzing the slope of change in sitting systolic BP (SBP; primary end point) and diastolic BP (DBP; secondary end point) after 3 weeks compared with baseline. Adverse events (AEs) were recorded throughout. RESULTS: Of the 101 patients randomized, 99 were included in the analysis (low dose, n=32; medium dose, n=34; and high dose, n=33). Mean sitting BP decreased from baseline in the low-, medium-, and high-dose groups by 7.3, 7.6, and 6.7 mmHg, respectively, for SBP and 8.2, 5.1, and 6.7 mmHg, respectively, for DBP after 3 weeks. No dose-response relationship was established by the slope analysis on SBP (P=0.75) or DBP (P=0.64). The BP-lowering effect was observed throughout the 2-year extension. The incidence of AEs was low and comparable between groups. CONCLUSIONS: Hypertensive children aged 6 months to 6 years treated with losartan 0.1-0.7 mg/kg per day had clinically significant decreases from baseline in SBP and DBP, yet no dose-response relationship was evident. Losartan, at a dosage up to 1.4 mg/kg per day, was well tolerated.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Losartan/administração & dosagem , Fatores Etários , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Lactente , Losartan/efeitos adversos , Masculino , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Angiotensin receptor antagonists (ARBs) improve outcomes in patients with heart failure (HF) with reduced left ventricular ejection fraction, but may induce hyperkalemia (HK) and/or a worsening of renal function (WRF). METHODS AND RESULTS: The incidence and risk factors of HK and its inter-relationship with WRF, as well as associations with clinical outcome (death or admission for HF i.e. the primary outcome) in 3846 HF patients enrolled in the double blind HEAAL trial (losartan 150 mg/d vs. 50 mg/d) were assessed. Worsening of renal function was defined as a decrease in eGFR >20% from baseline and HK as serum K >5.5 or >5 mmol/L. Higher dose of losartan increased serum potassium. Episodes of HK >5 mmol/L or WRF occurred at least once in about half of the patients. WRF was associated with higher occurrence of HK (HR 1.19 (1.06-1.34)) and vice versa (HR 1.35 (1.19-1.53)), but preceded HK in only about half of the events. High dose losartan improved outcome despite more frequent WRF and HK, both being independently associated with adverse outcomes in multivariate analyses. CONCLUSIONS: HK and WRF are common in HF patients. Both can be predicted from baseline risk factors and are therefore potentially preventable. Although associated with worse outcome, occurrence of any does not hinder the efficacy of high dose losartan. HK was associated with WRF and worse outcomes. Whether therapy targeting specifically HK may maximize the survival benefit derived from renin angiotensin aldosterone inhibitor use should be appropriately tested in future trials.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/epidemiologia , Hiperpotassemia/tratamento farmacológico , Hiperpotassemia/epidemiologia , Volume Sistólico/fisiologia , Método Duplo-Cego , Sistemas de Liberação de Medicamentos/métodos , Feminino , Seguimentos , Insuficiência Cardíaca/diagnóstico , Humanos , Hiperpotassemia/diagnóstico , Incidência , Internacionalidade , Losartan/administração & dosagem , Masculino , Insuficiência Renal/diagnóstico , Insuficiência Renal/tratamento farmacológico , Insuficiência Renal/epidemiologia , Fatores de Risco , Volume Sistólico/efeitos dos fármacosRESUMO
BACKGROUND: Given the well-documented adverse side effects of sorafenib, many sorafenib-treated patients may need the reduced initial dose of the compound, and an alternative sorafenib-based therapy, which exerts similar clinical benefit, is anticipated. An angiostatic therapy with sorafenib is considered one of the promising approaches for chemoprevention of hepatocellular carcinoma. The aim of the current study was to elucidate the combination effect of low dose of sorafenib and angiotensin-II receptor blocker (ARB) on hepatocarcinogenesis, especially in conjunction with angiogenesis. METHODS: The chemopreventive effect on the development of liver preneoplastic lesions, angiogenesis, and several indices was elucidated in rats. We also performed several sets of in vitro experiments to examine the mechanisms involved. RESULTS: Using a non-diabetic rat model of steatohepatitis with choline deficient L-amino acid-defined diet, sorafenib demonstrated marked inhibition of preneoplastic lesions in a dose dependent manner. Combined treatment with ARB (losartan) at a clinically comparable dose and half dose of sorafenib resulted in the inhibitory effect equivalent to that of common dose of sorafenib along with suppression of hepatic neovascularization and potent angiogenic factor, vascular endothelial growth factor. Furthermore, similar combined inhibitory outcomes were observed in several sets of in vitro studies. CONCLUSION: Since the combinatorial treatment using low doses of sorafenib and ARB could sufficiently induce inhibitory effect on the development of preneoplastic lesions at the magnitude similar to the conventional dose of sorafenib, this regimen may provide new strategy for patients intolerant of the usual dose of sorafenib in the future.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/prevenção & controle , Neoplasias Hepáticas Experimentais/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/complicações , Lesões Pré-Cancerosas/prevenção & controle , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Animais , Anticarcinógenos/administração & dosagem , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Células Hep G2 , Humanos , Neoplasias Hepáticas Experimentais/etiologia , Neoplasias Hepáticas Experimentais/patologia , Losartan/administração & dosagem , Masculino , Neovascularização Patológica/patologia , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Hepatopatia Gordurosa não Alcoólica/patologia , Compostos de Fenilureia/administração & dosagem , Lesões Pré-Cancerosas/etiologia , Lesões Pré-Cancerosas/patologia , Ratos Endogâmicos F344 , SorafenibeRESUMO
Losartan is an effective anti-hypotension drug frequently used in clinic. Compound danshen tablet (CDST) is an important traditional Chinese multiherbal formula composed of Danshen, Sanqi and Bingpian, which is widely used for the treatment of cardiovascular and cerebrovascular diseases in China. More often, losartan and CDST are simultaneously used for the treatment of anti-hypertension in the clinic. The aim of this study was to compare the pharmacokinetics of losartan and EXP3174 after oral administration of single losartan and both losartan and CDST, and to investigate the influence of CDST on the pharmacokinetics of losartan and its metabolite EXP3174. Male Sprague-Dawley rats were randomly assigned to two groups: a losartan-only group and a losartan and CDST group. Plasma concentrations of losartan and EXP3174 were determined by LC-MS at designated points after drug administration, and the main pharmacokinetic parameters were estimated. It was found that there were significant differences (p < 0.05) between the pharmacokinetic parameters of losartan and EXP3174, which showed that CDST influenced the metabolism and excretion of losartan in vivo. The result could be used for clinical medication guidance of losartan and CDST to avoid the occurrence of adverse reactions.
Assuntos
Cromatografia Líquida/métodos , Medicamentos de Ervas Chinesas/farmacologia , Interações Ervas-Drogas , Imidazóis/farmacocinética , Losartan/farmacocinética , Espectrometria de Massas/métodos , Tetrazóis/farmacocinética , Animais , Estabilidade de Medicamentos , Medicamentos de Ervas Chinesas/administração & dosagem , Imidazóis/sangue , Losartan/administração & dosagem , Losartan/sangue , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Salvia miltiorrhiza , Sensibilidade e Especificidade , Tetrazóis/sangueRESUMO
Timing can greatly affect the response to a stimulus, including antihypertensive medications. Herein, we assess the response of 30 patients to losartan/hydrochlorothiazide (L/H), administered for at least 1 month at a given circadian stage to each patient, this stage being changed during consecutive spans to cover six treatment times from awakening to bedtime at approximately 3-hour intervals. At the end of each stage, each patient underwent a 7-day around-the-clock ambulatory blood pressure (BP) profile, analyzed chronobiologically. A larger reduction of the midline estimating statistic of rhythm (MESOR; a rhythm-adjusted mean) of diastolic BP was achieved by L/H administration in the early morning for more patients (P < .05), while treatment upon awakening was the best choice for most patients to reduce the circadian amplitude of BP the most (P < .01). The optimal treatment time varied considerably among patients, however. Special attention should be given to the effect on the circadian amplitude since treatment can increase it above a threshold, beyond which there is a marked increase in cardiovascular disease risk. The results indicate the desirability to individualize the optimization of the antihypertensive effect of L/H by timing along the circadian scale.