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1.
Kardiologiia ; 61(8): 14-22, 2021 Aug 31.
Artigo em Russo | MEDLINE | ID: mdl-34549689

RESUMO

Aim      To study the condition of coronary vasculature by data of coronarography (CG) in patients with chronic ischemic heart disease (IHD) and arterial hypertension (AH) associated with stage 2-4 chronic kidney disease (CKD) and to evaluate the effect of a 12-week complex treatment with perindopril or with a combination of perindopril/amlodipine on changes in vascular wall stiffness, endothelial function, and structure and function parameters in this patient category after coronary stenting.Material and methodsr This study included 87 patients with chronic IHD and AH associated with stage 2-3 CKD for whom CG was performed due to ineffectiveness of the antianginal therapy. The patients were divided into three subgroups: subgroup 1 included 28 patients who received a conservative treatment with perindopril 10 mg/day; subgroup 2 consisted of 25 patients who underwent coronary stenting and were prescribed perindopril; subgroup 3 consisted of 34 patients who underwent stenting and were prescribed the perindopril/amlodipine combination. The reference group included 47 patients with IHD and AH with preserved kidney function. Anatomic and functional parameters of the heart, arterial stiffness, pulse wave velocity, cardio-ankle vascular index, augmentation index, central aortic systolic and pulse pressure, endothelium-dependent vasodilation, plasma concentration of endothelin-1 (ET-1), and plasma concentration of nitric oxide metabolites were evaluated at baseline and after 12 weeks of treatment.Results In patients with IHD, AH, and stage 2-3 CKD, arterial stiffness was more pronounced than in patients with preserved kidney function. Concentrations of ET-1 were significantly higher and levels of nitric oxide were lower in CKD. Supplementing the complex therapy with perindopril resulted in a considerable hypotensive effect in all subgroups, improvement of the kidney function, and positive dynamics of arterial stiffness and endothelial function. Changes in these parameters were more pronounced in patients after coronary stenting than in patients receiving only a conservative treatment. The use of perindopril/amlodipine following stenting exerted the most significant angioprotective and cardioprotective effect.Conclusion      Patients with IHD and AH in combination with early CKD have pronounced impairment of the condition of arterial blood vessels and the heart. Addition of perindopril to the treatment not only exerted a hypotensive effect but also beneficially influenced mechanisms of progression of this combined pathology.


Assuntos
Doença das Coronárias , Hipertensão , Insuficiência Renal Crônica , Anlodipino/farmacologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Doença das Coronárias/tratamento farmacológico , Combinação de Medicamentos , Humanos , Hipertensão/tratamento farmacológico , Perindopril , Análise de Onda de Pulso , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico
2.
Kardiologiia ; 61(7): 68-78, 2021 Jul 31.
Artigo em Russo | MEDLINE | ID: mdl-34397344

RESUMO

Arterial hypertension (AH) is one of the most important risk factors for development of myocardial infarction, chronic heart failure, stroke, cognitive disorders and dementia, and chronic kidney disease. Currently, special attention is paid to increased blood pressure variability (BPV) as a new risk factor for development of cardiovascular and cerebrovascular complications. The available evidence-based body of clinical studies demonstrates the importance of reducing not only the blood pressure itself but also the increased BPV to provide significant improvement of the prognosis and limits the risk of complications. This notion has been validated in consensus documents on the management of patients with AH. Among antihypertensive drugs, the fixed-dose combination (FC) amlodipine/perindopril has demonstrated a unique capability for reducing all types of BPV (visit-to-visit, day-to-day, during 24 h). According to current clinical guidelines, this combination belongs to first-line FCs indicated for most patients with AH. A distinctive feature of the FC amlodipine/perindopril is numerous data from real-life clinical practice, which support both its high antihypertensive efficacy and the ability to decrease high BPV. Therefore, the FC amlodipine/perindopril can be recommended for a broad range of AH patients to achieve BP control and to improve the prognosis.


Assuntos
Insuficiência Cardíaca , Hipertensão , Infarto do Miocárdio , Anlodipino/farmacologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Combinação de Medicamentos , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Hipertensão/tratamento farmacológico , Infarto do Miocárdio/tratamento farmacológico , Perindopril
3.
J Clin Hypertens (Greenwich) ; 23(7): 1335-1343, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34076333

RESUMO

This post hoc analysis of the Systolic Blood Pressure Intervention Trial (SPRINT) examined the performance of chlorthalidone (C) versus amlodipine (A) monotherapies. ANOVA was used to analyze the differences in systolic blood pressure (SBP) response between C and A. Logistic regression was used to examine monotherapy failure (adding a second antihypertensive agent or switching to a different antihypertensive agent) rates. Four hundred ninety-one participants were treated with C monotherapy (n = 210, mean dose = 22 mg/day) or A monotherapy (n = 281, mean dose = 7 mg/day). There was a significant difference in mean SBP reduction between the C and A monotherapies at the third visit (higher reduction with A, adjusted p = .018). Unadjusted analysis showed a higher failure with C in the standard treatment group. Although the average SBP at failure was higher and above the 140 mm Hg cutoff that indicated monotherapy failure with A (142.60) compared with C (138.40), more participants on C failed despite having SBP below the 140 cutoff. This was probably due to decisions made by the investigative teams to change the antihypertensive regimen, because, in their opinion, the clinical picture required it. After adjusting for baseline characteristics, C had higher failure than A only in the standard treatment group (1.64 odds ratio [OR], 95% CI 1.06-2.56, p = .028). A sub-analysis including participants who had never used antihypertensive treatment before randomization had similar results (2.57 OR, 95% CI 1.34-5.02, p = .004). Overall, in SPRINT chlorthalidone was associated with higher monotherapy failure than amlodipine in the standard treatment group because of decisions of the investigative teams.


Assuntos
Clortalidona , Hipertensão , Anlodipino/farmacologia , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Clortalidona/farmacologia , Humanos , Hipertensão/tratamento farmacológico , Resultado do Tratamento
4.
Molecules ; 26(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34070063

RESUMO

Amlodipine, a unique long-lasting calcium channel antagonist and antihypertensive drug, has weak fluorescence in aqueous solutions. In the current paper, we show that direct visualization of amlodipine in live cells is possible due to the enhanced emission in cellular environment. We examined the impact of pH, polarity and viscosity of the environment as well as protein binding on the spectral properties of amlodipine in vitro, and used quantum chemical calculations for assessing the mechanism of fluorescence quenching in aqueous solutions. The confocal fluorescence microscopy shows that the drug readily penetrates the plasma membrane and accumulates in the intracellular vesicles. Visible emission and photostability of amlodipine allow confocal time-lapse imaging and the drug uptake monitoring.


Assuntos
Anlodipino/farmacologia , Microscopia de Fluorescência , Anlodipino/química , Sobrevivência Celular/efeitos dos fármacos , Células HEK293 , Humanos , Indóis/metabolismo , Microscopia Confocal , Modelos Biológicos , Conformação Molecular , Soluções
5.
Kardiologiia ; 61(3): 36-41, 2021 Mar 30.
Artigo em Russo, Inglês | MEDLINE | ID: mdl-33849417

RESUMO

Aim        To study the psychological continuum in elderly patients with arterial hypertension associated with metabolic syndrome during the chronotherapy with a fixed combination (FC) of amlodipine, lisinopril, and rosuvastatin.Material and methods        In the inpatient conditions, 63 patients aged 60-74 years with arterial hypertension associated with metabolic syndrome were treated with chronotherapy with a FC of amlodipine, lisinopril, and rosuvastatin (5 / 10 / 10 mg/day in the evening). These patients composed the main group. The control group (58 patients aged 60-74 years with arterial hypertension associated with metabolic syndrome) was treated with the FC of amlodipine, lisinopril, and rosuvastatin at the same dose of 5 / 10 / 10 mg/day in the morning.Results   At one year, the disorders of psychological continuum were significantly decreased with the chronotherapy (evening dosing) with the antihypertensive FC of amlodipine, lisinopril, and rosuvastatin compared to the traditional treatment (morning dosing) at the same dose of 5 / 10 / 10 mg/day in both groups. With the chronotherapeutic approach, the dynamic of cognitive disorders in patients aged 60-74 years with arterial hypertension associated with metabolic syndrome was characterized by a significant increase in the Mini-Mental-State-Examination scale score from 17.8±0.3 at baseline to 23.5±0.4 with the evening dosing (р<0.001) vs. the increase from 16.9±0.3 to 20.4±0.4 (р<0.001) with the morning dosing. The situational anxiety score decreased from 40.0±2.2 to 30.6±1.8 (р<0.05) and from 40.8±2.5 to 33.5±1.9  (р<0.05), and the trait anxiety score decreased from 48.8±2.0 to 26.4±1.9 (р<0.001) and from 44.9±1.9 to 30.7±1.7  (р<0.01) with the evening and morning dosing, respectively. Depressive disorders slightly decreased with the chronotherapy by 14.1 % vs. 7.7 % with the traditional regimen; nevertheless, they were consistent with depressive spectrum disorders in both groups.Conclusion            The study results showed a higher effectiveness of the chronotherapeutic treatment compared to the traditional treatment with FC of amlodipine, lisinopril, and rosuvastatin in arterial hypertension with metabolic syndrome.


Assuntos
Hipertensão , Síndrome Metabólica , Idoso , Anlodipino/farmacologia , Anti-Hipertensivos/uso terapêutico , Ansiedade , Pressão Sanguínea , Cronoterapia , Humanos , Hipertensão/tratamento farmacológico , Lisinopril , Síndrome Metabólica/complicações , Síndrome Metabólica/tratamento farmacológico , Pessoa de Meia-Idade , Rosuvastatina Cálcica
6.
Ann Surg Oncol ; 28(9): 5400-5411, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33566246

RESUMO

BACKGROUND: The membrane transporters activated in cancer stem cells (CSCs) are the target of novel cancer therapies for gastric cancer. The present study investigated ion channel expression profiles in gastric CSCs (GCSCs). METHODS: Cells strongly expressing CD44 were separated from MKN74 cells, a human gastric cancer cell line, by fluorescence-activated cell sorting (FACS), and GCSCs were identified based on tumorsphere formation. Gene expression profiles in GCSCs were examined by a microarray analysis. RESULTS: Among MKN74 cells, CD44 messenger RNA levels were higher in CSCs than in non-CSCs. These CSCs also exhibited resistance to cisplatin. The microarray analysis revealed that the expression of several genes related to voltage-gated Ca2+ channels (VGCCs), including CACNA2D1 and CACNB4, was upregulated. The cytotoxicities of the CACNA2D1 inhibitor amlodipine and the CACNB4 inhibitor verapamil were greater at lower concentrations in CSCs than in non-CSCs, and markedly reduced tumorsphere numbers. Tumor volumes were significantly smaller in a xenograft nude mouse model treated with amlodipine or verapamil in combination with cisplatin than in that treated with cisplatin alone. CONCLUSIONS: The present results indicate that VGCCs play a role in maintaining CSCs, and demonstrated the potential of their specific inhibitors, amlodipine and verapamil, as targeted therapeutic agents against gastric cancer.


Assuntos
Anlodipino , Neoplasias Gástricas , Anlodipino/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Receptores de Hialuronatos/metabolismo , Células-Tronco Neoplásicas/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Verapamil/farmacologia
7.
Oncogene ; 40(6): 1128-1146, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33323966

RESUMO

Cancer cell expression of PD-L1 leads to T cells exhaustion by transducing co-inhibitory signal, and further understanding the regulation of PD-L1 in cancer cells may provide additional therapeutic strategies. Here by drug repurposing screen, we identified amlodipine as a potent inhibitor of PD-L1 expression in cancer cells. Further survey of calcium-associated pathways revealed calpain-dependent stabilization of the PD-L1 protein. Intracellular calcium delivered an operational signal to calpain-dependent Beclin-1 cleavage, blocking autophagic degradation of PD-L1 accumulated on recycling endosome (RE). Blocking calcium flux by amlodipine depleted PD-L1 expression and increased CD8+ T-cell infiltration in tumor tissues but not in myocardium, causing dose-dependent tumor suppression in vivo. Rescuing PD-L1 expression eliminated the effects of amlodipine, suggesting the PD-L1-dependent effect of amlodipine. These results reveal a calcium-dependent mechanism controlling PD-L1 degradation, and highlight calcium flux blockade as a potential strategy for combinatorial immunotherapy.


Assuntos
Anlodipino/farmacologia , Antineoplásicos/farmacologia , Antígeno B7-H1/genética , Neoplasias/tratamento farmacológico , Animais , Antígeno B7-H1/antagonistas & inibidores , Proteína Beclina-1/genética , Calpaína/genética , Reposicionamento de Medicamentos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia/tendências , Camundongos , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Transdução de Sinais/efeitos dos fármacos
8.
Kardiologiia ; 60(10): 132-140, 2020 Nov 12.
Artigo em Russo | MEDLINE | ID: mdl-33228516

RESUMO

Arterial hypertension (AH) and exertional headache (EHA) are comorbidities. The article presents a nonsystematic review focused on studying the AH+EHA phenotype. The authors addressed the history of studying the phenotype, several theories about its pathophysiological causes (psychosomatic, neuroanatomical, and baroreflector). The protective "hypertension-associated hypoalgesia" phenotype, a mechanism of its change in AH chronization, and difficulties of differential diagnosis are described. The AH+EHA phenotype requires further study since its incidence is quite high. This will allow developing an individualized approach in prevention and treatment of EHA attacks, decreasing the risk of life-threatening cardiovascular complications, and avoiding iatrogenic complications in patients with AH. The main way to prevent the development of AH+EHA phenotype is patient's compliance, which can be provided by using combination hypotensive drugs to reduce the number of pills and dosing. It is important to take into account possible adverse reactions of the nervous system (medication-overuse headache or EHA aggravation). Considering these conditions, the drug Triplixam can be used for prevention of complications in the AH+EHA phenotype. Triplixam is a fixed triple combination of amlodipine/indapamide/perindopril, and its individual components have low and medium risk for development of headache.


Assuntos
Hipertensão , Indapamida , Cefaleia do Tipo Tensional , Anlodipino/farmacologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Comorbidade , Combinação de Medicamentos , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Perindopril/farmacologia , Cefaleia do Tipo Tensional/tratamento farmacológico , Cefaleia do Tipo Tensional/epidemiologia
9.
J Assoc Physicians India ; 68(10): 39-43, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32978924

RESUMO

Background: Hypertension is the biggest contributor to global burden of disease and mortality. Increasing compliance with antihypertensive treatment and achieving a wide BP control in the population represents a major challenge for clinical practice. The benefits of single pill combination versus free-equivalent combination has been demonstrated in several meta-analyses and is now strongly supported by the latest 2018 ESC/ESH guidelines. The RAAS blocker with CCB and thiazide like diuretic is proposed as the optimal combination in patients inadequately controlled by two drugs. Objective: To assess the blood pressure control rate, safety, tolerability and quality of life with triple-drug SPC in patients with grade II/ III hypertension. Methods: Hypertensive patients uncontrolled (BP ≥ 140/90 mmHg) on two-drug therapy were recruited in an open-label, phase III clinical trial conducted in outpatient setting in India with 6 months treatment period. No other antihypertensive medication except the study medication was received by the patients. Results: Out of 218 evaluable patients the observed average blood pressure reduction achieved from baseline to end of study at 6 months was Systolic Blood Pressure (SBP) 28.5 mm Hg / Diastolic Blood Pressure (DBP) 13.8 mm Hg. The quality of life (QoL) questionnaire demonstrated improvement in QoL for all patients. Conclusion: This study showed the clinical efficacy, safety and acceptability of the perindopril/indapamide/amlodipine SPC in patients with grade 2/3 hypertension inadequately controlled with two-drug therapy. The clinical effectiveness was observed in more than 96 % patients. The benefit of single-pill combination (SPC) therapy in hypertension control was reconfirmed in this study.


Assuntos
Hipertensão/tratamento farmacológico , Indapamida , Anlodipino/farmacologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Combinação de Medicamentos , Humanos , Índia , Perindopril/efeitos adversos , Qualidade de Vida , Resultado do Tratamento
10.
Mol Med Rep ; 22(3): 1783-1792, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32705176

RESUMO

The aim of the present study was to explore whether the hypertrophy of H9C2 cardiomyocytes was induced by high glucose, to investigate whether the calcium channel inhibitor (Norvasc) could inhibit this process and to clarify the possible signaling pathways. The morphology of H9C2 cells was observed under an optical microscope, and the cell surface area was measured by Image Pro Plus 6.1 software. Furthermore, fluorescence spectrophotometry was used to detect intracellular calcium concentration ([Ca2+]i). ELISA was performed to detect calcineurin (CaN) activity; reverse transcription­quantitative PCR and western blotting were performed to detect the mRNA and protein expression levels of CaN Aß subunit (CnAß), nuclear factor of activated T cells 3 (NFAT3) and ß type myosin heavy chain (ß­MHC). Cell size was increased with the increase in glucose concentration of culture medium at 48 and 72 h, respectively, and decreased with the addition of Norvasc compared with those without Norvasc (P<0.05). There was no significant difference in cell size with the addition of Norvasc compared with cells cultured with 5 mM glucose (P>0.05). The average [Ca2+]i activity of single cells in the 48­ and 72­h culture groups treated with 50 mM glucose was significantly higher than cells treated with 5 mM glucose (P<0.05); and the fluorescent value of average [Ca2+]i activity of single cells was lower, following the addition of Norvasc than that without Norvasc (P<0.05). CaN activity in the 48­ and 72­h culture group treated with 50 mM glucose was markedly higher than that treated with 5 mM glucose, and the activity of CaN notably decreased with the addition of Norvasc compared with those without Norvasc. The mRNA and protein expression levels of CnAß, NFAT3 and ß­MHC in the 48­ and 72­h culture groups treated with 50 mM glucose were all significantly higher than those treated with 5 mM glucose (P<0.05). The mRNA and protein expression of CnAß, NFAT3 and ß­MHC cultured with 50 mM glucose were significantly decreased following the addition of Norvasc (P<0.05). Thus, the calcium channel inhibitor Norvasc may inhibit high glucose­induced hypertrophy of H9C2 cardiomyocytes by inhibiting the Ca2+­CaN­NFAT3 signaling pathway.


Assuntos
Anlodipino/farmacologia , Cardiotônicos/farmacologia , Glucose/efeitos adversos , Miócitos Cardíacos/citologia , Fatores de Transcrição NFATC/genética , Proteínas do Tecido Nervoso/genética , Animais , Calcineurina/genética , Calcineurina/metabolismo , Cálcio/metabolismo , Linhagem Celular , Meios de Cultura/química , Regulação da Expressão Gênica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Fatores de Transcrição NFATC/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Miosina não Muscular Tipo IIB/genética , Miosina não Muscular Tipo IIB/metabolismo , Ratos
12.
Artigo em Inglês | MEDLINE | ID: mdl-32423960

RESUMO

Mining existing agents that enhance the therapeutic potential of ergosterol biosynthesis inhibitors (EBI) is a promising approach to improve Chagas disease chemotherapy. In this study, we evaluated the effect of ravuconazole, an EBI, combined with amlodipine, a calcium channel blocker, upon Trypanosoma cruzi experimental infection. In vitro assays confirmed the trypanocidal activity of both compounds in monotherapy and demonstrated an additive effect (sum of the fractional inhibitory concentration [ΣFIC] > 0.5) of the combined treatment without additional toxicity to host cells. In vivo experiments, using a murine model of the T. cruzi Y strain in a short-term protocol, demonstrated that amlodipine, although lacking trypanocidal activity, dramatically increased the antiparasitic activity of underdosing ravuconazole regimens. Additional analysis using long-term treatment (20 days) showed that parasitemia relapse until 60 days after treatment was significatively lower in mice treated with the combination (4 out of 14 mice) than ravuconazole monotherapy (10 out of 14 mice), even in the presence of immunosuppressant pressure. Furthermore, the combined therapy was well tolerated and protected the mice from mortality. The treatments also impacted on the cellular and humoral immune response of infected animals, inducing a reduction of serum cytokine levels in all ravuconazole-treated mice. Our findings demonstrate that amlodipine is efficacious in enhancing the antiparasitic activity of ravuconazole in an experimental model of T. cruzi infection and indicates a potential strategy to be explored in Chagas disease treatment.


Assuntos
Doença de Chagas , Nitroimidazóis , Tripanossomicidas , Trypanosoma cruzi , Anlodipino/farmacologia , Anlodipino/uso terapêutico , Animais , Doença de Chagas/tratamento farmacológico , Camundongos , Nitroimidazóis/uso terapêutico , Parasitemia/tratamento farmacológico , Tiazóis , Triazóis , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico
13.
J Hypertens ; 38(8): 1593-1602, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32371763

RESUMO

OBJECTIVE: The current study was planned to formulate, characterize and evaluate the pharmacokinetics, and pharmacodynamics of a novel 'NanoFDC' comprising hydrochlorothiazide, candesartan (CNDT) and amlodipine. METHODOLOGY: The candidate drugs were loaded in poly(DL-lactide-co-glycolide) by emulsion-diffusion-evaporation method. The formulations were evaluated for their size, morphology, drug loading and in-vitro release individually. Repeat dose pharmacokinetic and pharmacodynamic study of the nano-fixed dose combination (FDC) was done in dexamethasone-induced animal model. RESULTS: The entrapment efficiencies ranged from 44 ±â€Š2.1, 32.2 ±â€Š4 and 40.5 ±â€Š2.6% for amlodipine, hydrochlorothiazide and CNDT, respectively. The nanoparticles ranged in size from 164 to 215 nm. In-vitro release profile of the nanoformulation showed unto 90% release by day 7 in simulated gastric fluid and simulated intestinal fluid, respectively. In pharmacokinetic analysis a sustained-release for 7 days was observed in nano-FDC group. Once weekly oral dosing of nano-FDC of amlodipine, CNDT and hydrochlorothiazide provided adequate antihypertensive effect which was not statistically different from daily dosing of free drugs in dexamethasone-induced animal model. CONCLUSION: Once weekly oral dosing of nano-FDC of amlodipine, CNDT and hydrochlorothiazide provided adequate antihypertensive effect and was not statistically different from daily dosing of free drugs in dexamethasone-induced animal model. This study provides proof of concept of feasibility of once weekly dosing of a nano-FDC comprising three antihypertensive drugs, which can lead to significant improvement in patient adherence to therapy.


Assuntos
Anti-Hipertensivos , Hipertensão , Nanopartículas , Anlodipino/farmacocinética , Anlodipino/farmacologia , Animais , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/farmacologia , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Compostos de Bifenilo/farmacocinética , Compostos de Bifenilo/farmacologia , Modelos Animais de Doenças , Combinação de Medicamentos , Hidroclorotiazida/farmacocinética , Hidroclorotiazida/farmacologia , Masculino , Ratos , Ratos Wistar , Tetrazóis/farmacocinética , Tetrazóis/farmacologia
14.
Curr Med Sci ; 40(2): 320-326, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32337692

RESUMO

Vascular remodeling is an adaptive response to various stimuli, including mechanical forces, inflammatory cytokines and hormones. In the present study, we investigated the role of angiotensin II type 1 receptor (AT1R) and calcium channel in carotid artery remodeling in response to increased biomechanical forces by using the transverse aortic constriction (TAC) rat model. TAC was induced on ten-week-old male Sprague-Dawley rats and these models were treated with AT1R blocker olmesartan (1 mg/kg/day) or/and calcium channel blocker (CCB) amlodipine (0.5 mg/kg/day) for 14 days. After the treatment, the right common carotid artery proximal to the band (RCCA-B) was collected for further assay. Results showed that olmesartan, but not amlodipine, significantly prevented TAC-induced adventitial hyperplasia. Similarly, olmesartan, but not amlodipine, signifcantly prevented vascular infammation, as indicated by increased tumor necrosis factor α (TNF-α) and increased p65 phosphorylation, an indicator of nuclear factor κ-light-chain-enhancer of activated B cells (NFκB) activation in RCCA-B. In contrast, both olmesartan and amlodipine reversed the decreased expression of endothelial nitric oxidase synthase (eNOS) and improved endothelium-dependent vasodilation, whereas combination of olmesartan and amlodipine showed no further synergistic protective effects. These results suggest that AT1R was involved in vascular remodeling and inflammation in response to pressure overload, whereas AT1R and subsequent calcium channel were involved in endothelial dysfunction.


Assuntos
Anlodipino/administração & dosagem , Canais de Cálcio/metabolismo , Lesões das Artérias Carótidas/tratamento farmacológico , Lesões das Artérias Carótidas/metabolismo , Imidazóis/administração & dosagem , Receptor Tipo 1 de Angiotensina/metabolismo , Tetrazóis/administração & dosagem , Anlodipino/farmacologia , Animais , Lesões das Artérias Carótidas/etiologia , Constrição Patológica , Modelos Animais de Doenças , Hiperplasia , Imidazóis/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Tetrazóis/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Remodelação Vascular
15.
Acta Med Okayama ; 74(2): 103-108, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32341583

RESUMO

This study examined whether switching from amlodipine and atorvastatin treatment using two pills to an equal dose of single-pill therapy is useful in Japanese outpatients. We retrospectively reviewed data obtained from 94 outpatients for whom treatment with two pills, namely amlodipine and atorvastatin, was switched to an equal dose of single-pill therapy in 11 hospitals. The criterion for enrollment in this study was that patients had switched their medication without changing other anti-hypertensive or anti-cholesterol drugs. Neither systolic nor diastolic blood pressure changed significantly after switching to an equal dose of single-pill therapy, whereas low-density lipoprotein (LDL) cholesterol levels significantly decreased after the medication was switched from 94±24 mg/dl to 89±17 mg/dl (p=0.015). A switch from medication with two separate pills of amlodipine and atorvastatin to an equal dose of single-pill therapy resulted in an overall decrease in LDL cholesterol. The results indicated that the switch to single-pill therapy might be a useful treatment.


Assuntos
Anlodipino/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Atorvastatina/administração & dosagem , Ácidos Heptanoicos/administração & dosagem , Pirróis/administração & dosagem , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anlodipino/farmacologia , Anticolesterolemiantes/farmacologia , Anti-Hipertensivos/farmacocinética , Atorvastatina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , LDL-Colesterol/efeitos dos fármacos , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Ácidos Heptanoicos/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Pirróis/farmacologia , Estudos Retrospectivos
16.
Life Sci ; 249: 117518, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32147432

RESUMO

AIMS: The objectives of the present study were to investigate the mechanisms of Ninj-1 regulation in TNFα-activated human endothelial cells (HEC), and to test if Amlodipine (AML) ameliorates the inflammatory stress by decreasing Ninj-1 expression. MAIN METHODS: TNFα-activated HEC with/without AML (0.1 µM and 1 µM) were used. TNFα-receptor 1 (TNFR1) was silenced and inhibitors for oxidative stress (N-acetyl cysteine), endoplasmic reticulum stress (salubrinal, 4-phenyl butyric acid), or NF-kB (Bay 11-7085) and p38 MAPK (SB203580) were used. Levels of Ninj-1, TNFR1, monocyte adhesion, endoplasmic reticulum stress (ERS) sensors, NADPH oxidase- and mitochondria-derived oxidative species were evaluated. KEY FINDINGS: The novel findings that we report here are: (i) silencing the endothelial TNFR1 leads to decreased Ninj-1 expression and diminished monocyte adhesion; (ii) increased oxidative stress, ERS and NF-kB activation enhance Ninj-1 expression and monocyte adhesion; (iii) up-regulation of endothelial Ninj-1 expression stimulates monocytes adhesion to TNFα - activated HEC; (iv) AML diminishes monocyte adhesion by reducing Ninj-1 expression through mechanisms involving the decrease of NADPH oxidase and mitochondria-dependent oxidative stress, ERS and NF-kB. In addition, AML alleviates apoptosis by reducing the pro-apoptotic CHOP expression and re-establishing the mitochondrial transmembrane potential. SIGNIFICANCE: The results of the present study suggest that Ninj-1 and the proteins involved in its regulation can be considered therapeutic targets for the alleviation of inflammation- dependent disorders. In addition, we demonstrate that some of the benefic effects of AML can be achieved through regulation of Ninj-1.


Assuntos
Anlodipino/farmacologia , Moléculas de Adesão Celular Neuronais/fisiologia , Adesão Celular/fisiologia , Monócitos/citologia , Fatores de Crescimento Neural/fisiologia , Receptores Tipo I de Fatores de Necrose Tumoral/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Regulação para Cima , Vasodilatadores/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Inativação Gênica , Células Endoteliais da Veia Umbilical Humana , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , NADPH Oxidases/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/genética
17.
Arch Gynecol Obstet ; 301(3): 845-850, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32112181

RESUMO

OBJECTIVE: To detect whether amlodipine could increase pre-ovulatory follicular blood flow, thus enhancing ovulation and creating a better chance of conception in women with PCOS. METHODS: 165 women were screened of which 124 were qualified and women were equally randomized to 62 receiving clomiphene citrate and amlodipine and 62 receiving clomiphene citrate and placebo. The primary outcome was to detect if amlodipine can improve pre-ovulatory follicle blood flow studied by colour and power Doppler Pulsatility index of ovarian arteries, with drug administration. The secondary outcomes were endometrial thickness and clinical pregnancy. RESULTS: The mean value of the ovarian arteries Pulsatility Index was significantly lower in the amlodipine group when compared to those of the placebo group (1.36 and 1.82, respectively, with P value 0.002). Mean endometrial thickness, for all women in both groups, on the day of detecting a mature follicle was significantly higher in the amlodipine group compared to the placebo group (8.99 and 7.0, respectively, with P value 0.003), and clinical pregnancy increased from 11% to 37% in the amlodipine group compared to the placebo group. CONCLUSION: Amlodipine improves ovarian blood flow and increases the chances of conception. TRIAL REGISTRATION: Pan African Clinical Trial Registry (http://www.pactr.org). Trial No: PAC TR201708002485292.


Assuntos
Anlodipino/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Clomifeno/uso terapêutico , Fármacos para a Fertilidade Feminina/uso terapêutico , Hemodinâmica/efeitos dos fármacos , Infertilidade Feminina/tratamento farmacológico , Folículo Ovariano/efeitos dos fármacos , Ovulação/efeitos dos fármacos , Adulto , Anlodipino/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Clomifeno/farmacologia , Método Duplo-Cego , Feminino , Humanos , Síndrome do Ovário Policístico/complicações , Gravidez , Estudos Prospectivos
18.
Inflammopharmacology ; 28(4): 1121-1136, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32141013

RESUMO

Amlodipine, a second-generation calcium channel blocker, exhibits documented anti-inflammatory potential. Thereby, present investigation was accomplished with an aim to explore anti-arthritic potential of amlodipine, giving a second chance to an existing drug. For validation of anti-arthritic potential of amlodipine, some in vitro models comprised of bovine serum albumin- and egg albumin-induced protein denaturation along with membrane stabilization of red blood cell was being conducted. In vivo models comprised of formaldehyde-provoked acute arthritis and CFA-instigated chronic arthritic. Paw edema, arthritic index, body weight alterations, biochemical and hematological parameters, and ankle joint histological and radiographic investigations were appraised. Moreover, RT-PCR was conducted to evaluate the levels of several inflammatory markers. Molecular docking was being conducted targeting TNF-α, IL-1ß and IL-6 to establish the correlation between experimental and theoretical results. Amlodipine provides significant protection against denaturation being provoked by heating egg albumin and BSA along with stabilizing membrane of red blood cell, thereby proving in vitro anti-arthritic effect. A significant (p < 0.001) reduction in paw swelling was being observed with amlodipine in case of formaldehyde-instigated arthritis especially at the dose of 20 mg/kg. In case of CFA-provoked arthritis, reduction in paw volume and arthritic score while preservation of body weight loss and normal hematological and biochemical parameters in comparison to arthritic control were being manifested by amlodipine at the dose of 20 mg/kg. Gene expression level of TNF-α, IL-6 and IL-1ß was significantly reduced by amlodipine while an increase in expression level of IL-4 and IL-10 was evident in animals treated with piroxicam and amlodipine. Molecular docking analysis demonstrated strong binding interaction of amlodipine with TNF-α, IL-6 and IL-1ß thus providing a good correlation between experimental and theoretical results. Thus, current study is suggestive that amlodipine exhibits strong anti-arthritic potential and thus can be considered as a candidate for drug repurposing as anti-arthritic agent.


Assuntos
Anlodipino/farmacologia , Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Albuminas/metabolismo , Animais , Artrite Experimental/diagnóstico por imagem , Artrite Experimental/genética , Artrite Experimental/metabolismo , Citocinas/biossíntese , Citocinas/genética , Reposicionamento de Medicamentos , Eritrócitos/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Ratos
19.
J Hypertens ; 38(3): 536-545, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32028517

RESUMO

BACKGROUND: ß-blockers are no longer considered as first-line antihypertensive drugs due to their lower cardioprotection. METHOD: Considering the differences in the pharmacological properties of ß-blockers, the present work compared the effects of third-generation ß-blockers - carvedilol and nebivolol - with a first-line agent - amlodipine - on hemodynamic parameters, including short-term blood pressure variability (BPV), and their ability to prevent target organ damage in spontaneously hypertensive rats (SHR). SHR rats were orally treated with carvedilol, nebivolol, atenolol, amlodipine or vehicle for 8 weeks. Wistar Kyoto rats treated with vehicle were used as normotensive group. Echocardiographic evaluation, BP, and short-term BPV measurements were performed. Left ventricle and thoracic aorta were removed for histological evaluations and to assess the expression of transforming growth factor ß (TGF-ß), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). RESULTS: Carvedilol, nebivolol or amlodipine induced a greater reduction of carotid BP, short-term BPV and echocardiography parameters than atenolol in SHR rats. Carvedilol, nebivolol and amlodipine were more effective than atenolol in the prevention of cardiac hypertrophy, and cardiac and aortic collagen deposit. Carvedilol and nebivolol, but not atenolol, reduced the expressions of fibrotic and inflammatory biomarkers - TGF-ß, TNF-α and IL-6 - in SHR rats to a similar extent to that of amlodipine. CONCLUSION: Chronic treatment with carvedilol or nebivolol attenuates carotid BP and short-term BPV, and reduces target organ damage in SHR to a greater extent than atenolol. Our findings suggest that the lower cardiovascular protection of nonvasodilating ß-blockers, as atenolol, in hypertension must not be translated to third-generation ß-blockers.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Anlodipino/farmacologia , Anti-Hipertensivos/farmacologia , Atenolol/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Antagonistas Adrenérgicos beta/efeitos adversos , Anlodipino/efeitos adversos , Animais , Aorta/efeitos dos fármacos , Atenolol/efeitos adversos , Citocinas/metabolismo , Ventrículos do Coração/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR
20.
Acta Pharmacol Sin ; 41(5): 719-728, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31932646

RESUMO

Sunitinib is an oral small molecule multitargeted tyrosine kinase inhibitor, which is currently used to treat severe cancers. Clinical research has shown that patients treated with sunitinib develop hypertension. As soon as sunitinib-induced hypertension appears, it is usual to administer anti-hypertension agent. But this treatment may cause acute blood pressure fluctuation which may lead to additional cardiovascular risk. The aim of this study is to establish a mathematical model for managing sunitinib-induced hypertension and blood pressure fluctuation. A mechanism-based PK/PD model was developed based on animal experiments. Then this model was used to perform simulations, thus to propose an anti-hypertension indication, according to which the anti-hypertension treatment might yield relative low-level AUC and fluctuation of blood pressure. The simulation results suggest that the anti-hypertension agent may yield low-level AUC and fluctuation of blood pressure when relative ET-1 level ranges from -15% to 5% and relative NO level is more than 10% compared to control group. Finally, animal experiments were conducted to verify the simulation results. Macitentan (30 mg/kg) was administered based on the above anti-hypertension indication. Compared with the untreated group, the optimized treatment significantly reduced the AUC of blood pressure; meanwhile the fluctuation of blood pressure in optimized treatment group was 70% less than that in immediate treatment group. This work provides a novel model with potential translational value for managing sunitinib-induced hypertension.


Assuntos
Anti-Hipertensivos/farmacologia , Endotelina-1/sangue , Hipertensão/tratamento farmacológico , Óxido Nítrico/sangue , Inibidores de Proteínas Quinases/efeitos adversos , Sunitinibe/antagonistas & inibidores , Administração Oral , Anlodipino/administração & dosagem , Anlodipino/farmacologia , Animais , Anti-Hipertensivos/administração & dosagem , Biomarcadores/sangue , Pressão Sanguínea/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Hipertensão/induzido quimicamente , Masculino , Modelos Moleculares , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Ratos , Ratos Wistar , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacologia , Sunitinibe/administração & dosagem , Sunitinibe/efeitos adversos
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