Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 94
Filtrar
1.
Anticancer Res ; 41(9): 4215-4228, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475041

RESUMO

BACKGROUND/AIM: Tyrosine kinase inhibitors (TKIs) are used for the treatment of both wild type and mutant non-small cell lung cancer (NSCLC); however, acquired resistance is a major clinical challenge. Herein, we aimed to investigate the effects of telmisartan (Tel), CFM 4.16 and sorafenib combination in rociletinib resistant NSCLC tumors. MATERIALS AND METHODS: 3D spheroid cultures and western blotting were used for evaluating cytotoxic effects and protein expression. An in vivo rociletinib resistant H1975 xenograft model of NSCLC was developed by subcutaneous injection of rociletinib resistant H1975 cells into nude mice. RESULTS: Tel, CFM 4.16 and sorafenib combination displayed superior anti-cancer effects in 3D spheroid cultures and a rociletinib resistant H1975 xenograft model of NSCLC by decreasing the protein expression of oncogenic and cancer stem cell markers (Nanog, Sox2 and Oct4). CONCLUSION: Tel facilitates effective penetration of CFM 4.16 and sorafenib in rociletinib resistant H1975 models of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Esferoides Celulares/citologia , Compostos de Espiro/administração & dosagem , Telmisartan/administração & dosagem , Tiadiazóis/administração & dosagem , Acrilamidas/farmacologia , Acrilamidas/uso terapêutico , Animais , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Nus , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Esferoides Celulares/efeitos dos fármacos , Compostos de Espiro/farmacologia , Telmisartan/farmacologia , Tiadiazóis/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Int J Mol Sci ; 22(17)2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34502342

RESUMO

Our previous studies have demonstrated that specific peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists play a fundamental role in oligodendrocyte progenitor (OP) differentiation, protecting them against oxidative and inflammatory damage. The antihypertensive drug Telmisartan (TLM) was shown to act as a PPAR-γ modulator. This study investigates the TLM effect on OP differentiation and validates its capability to restore damage in a pharmacological model of Niemann-Pick type C (NPC) disease through a PPAR-γ-mediated mechanism. For the first time in purified OPs, we demonstrate that TLM-induced PPAR-γ activation downregulates the type 1 angiotensin II receptor (AT1), the level of which naturally decreases during differentiation. Like other PPAR-γ agonists, we show that TLM promotes peroxisomal proliferation and promotes OP differentiation. Furthermore, TLM can offset the OP maturation arrest induced by a lysosomal cholesterol transport inhibitor (U18666A), which reproduces an NPC1-like phenotype. In the NPC1 model, TLM also reduces cholesterol accumulation within peroxisomal and lysosomal compartments and the contacts between lysosomes and peroxisomes, revealing that TLM can regulate intracellular cholesterol transport, crucial for myelin formation. Altogether, these data indicate a new potential use of TLM in hypomyelination pathologies such as NPC1, underlining the possible repositioning of the drug already used in other pathologies.


Assuntos
Anti-Hipertensivos/farmacologia , Diferenciação Celular , Colesterol/metabolismo , Oligodendroglia/efeitos dos fármacos , PPAR gama/metabolismo , Substâncias Protetoras/farmacologia , Telmisartan/farmacologia , Animais , Oligodendroglia/metabolismo , PPAR gama/genética , Ratos , Ratos Wistar
3.
J Clin Hypertens (Greenwich) ; 23(9): 1664-1674, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34384001

RESUMO

This multicenter, phase 4, Prospective Randomized Open, Blinded End-point (PROBE) study aimed to evaluate safety and efficacy of telmisartan/rosuvastatin single-pill combination (SPC) therapy on lowering central blood pressure (BP) compared with telmisartan monotherapy in hypertensive patients with dyslipidemia in Korea. Study was terminated earlier than planned due to COVID-19 pandemic, thus should be considered as a pilot study. Among 125 patients who met the inclusion criteria of hypertension and dyslipidemia (defined as 10-year Atherosclerotic Cardiovascular Disease risk score over 5%), 80 patients went through 4-week single-group run-in period with telmisartan 40-80 mg, then randomized to telmisartan 80 mg + rosuvastatin (10 or 20 mg) SPC group or telmisartan 80 mg monotherapy group. The central/brachial BP, brachial-ankle pulse wave velocity (baPWV), and augmentation index (AIx) were assessed at baseline and 16 weeks later. Mean brachial SBP changed from 135.80 ± 14.22 mmHg to 130.69 ± 13.23 mmHg in telmisartan/rosuvastatin group and from 134.37 ± 12.50 mmHg to 133.75 ± 12.30 mmHg in telmisartan monotherapy group without significant difference (between-group difference p = .149). Mean central SBP were reduced significantly in the telmisartan/rosuvastatin group with change from 126.72 ± 14.44 mmHg to 121.56 ± 14.56 mmHg while telmisartan monotherapy group showed no significant change (between-group difference p = .028). BaPWV changed from 1672.57 ± 371.72 m/s to 1591.75 ± 272.16 m/s in telmisartan/rosuvastatin group and from 1542.85 ± 263.70 m/s to 1586.12 ± 297.45 m/s in telmisartan group with no significance (between-group difference p = .078). Change of AIx had no significant difference (between-group difference p = .314). Both groups showed excellent compliance rate of 96.9 ± 4.5% with no significant difference in adverse rate. Telmisartan/rosuvastatin SPC therapy was more effective in lowering central BP compared with the telmisartan monotherapy. The results of this study showed benefit of additive statin therapy in hypertensive patients combined with dyslipidemia.


Assuntos
COVID-19 , Dislipidemias , Hipertensão , Índice Tornozelo-Braço , Anti-Hipertensivos/uso terapêutico , Benzoatos , Pressão Sanguínea , Combinação de Medicamentos , Dislipidemias/tratamento farmacológico , Humanos , Hipertensão/tratamento farmacológico , Pandemias , Projetos Piloto , Estudos Prospectivos , Análise de Onda de Pulso , Rosuvastatina Cálcica , SARS-CoV-2 , Telmisartan/farmacologia
4.
Gene ; 801: 145856, 2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34293449

RESUMO

Epidemiological studies have established that untreated hypertension (HTN) is a major independent risk factor for developing cardiovascular diseases (CVD), stroke, renal failure, and other conditions. Several important studies have been published to prevent and manage HTN; however, antihypertensive agents' optimal choice remains controversial. Therefore, the present study is undertaken to update our knowledge in the primary treatment of HTN, specifically in the setting of other three important diseases. MicroRNAs (miRNAs) are remarkably stable short endogenous conserved non-coding RNAs that bind to the mRNA at its (3' UTR) to regulate its gene expression by causing translational repression or mRNA degradation. Through their coordinated activities on different pathways and networks, individual miRNAs control normal and pathological cellular processes. Therefore, to identify the critical miRNA-mRNA-TF interactions, we performed systematic bioinformatics analysis. We have also employed the molecular modelling and docking approach to identify the therapeutic target that delivers novel empathies into Food and Drug Administration approved and herbal drug response physiology. Gene Expression Omnibus (GEO) was employed to identify the differentially expressed genes (DEGs) and hub genes- KNG1, HLA-DPB1, CXCL8, IL1B, and BCL2. The HTN associated feed-forward loop (FFL) network included miR-9-5p, KNG1 and AR. We employed high throughput screening to get the best interacting compounds, telmisartan and limonin, that provided a significant docking score (-13.3 and -12.0 kcal/mol) and a potential protective effect that may help to combat the impact of HTN. The present study provides novel insight into HTN etiology through the identification of mRNAs and miRNAs and associated pathways.


Assuntos
Anti-Hipertensivos/farmacologia , Redes Reguladoras de Genes , Hipertensão/genética , Mapas de Interação de Proteínas/genética , Desenvolvimento de Medicamentos/métodos , Perfilação da Expressão Gênica , Ensaios de Triagem em Larga Escala/métodos , Humanos , Hipertensão/tratamento farmacológico , Cininogênios/química , Cininogênios/genética , Limoninas/química , Limoninas/farmacologia , MicroRNAs/genética , Modelos Moleculares , Simulação de Acoplamento Molecular , Telmisartan/química , Telmisartan/farmacologia , Fatores de Transcrição/genética
5.
Int J Biol Macromol ; 183: 589-599, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-33933545

RESUMO

Consumption of marine alga-based polysaccharides as additional functional foods can endow with health benefits by diminishing the risk of chronic diseases. A polygalacto-fucopyranose characterized as [→1)-2, 4-SO3-α-Fucp-(3 → 1)-{2-SO3-α-Fucp-(3→}] with [(4 → 1)-6-OAc-ß-Galp-(4→] side chain isolated from marine alga Sargassum wightii exhibited potential antihypertensive activity. Upon treatment with studied polygalactofucan (50 mg/kg BW), serum hypertension biomarkers troponin-T (1.3 pg/mL), troponin-I (1.2 µg/dL) and angiotensin-II converting enzyme (0.18 pg/mL) were significantly recovered in hypertensive rats compared to disease control. Serum cardiovascular risk indices of diseased rats were significantly decreased (< 10%, p < 0.05) after administration of the studied galactofucan (50 mg/kg BW) related to hypertension group (> 17%), and were comparable with standard antihypertensive agent telmisartan (8.3-10.2% at 2 mg/kg BW). The studied compound was safe for consumption as obvious from the high LD50 value (>5 g/kg), and could be developed as a prospective functional food ingredient attenuating the pathophysiological attributes causing hypertension-related conditions.


Assuntos
Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Fucose/farmacologia , Hipertensão/tratamento farmacológico , Sargassum , Animais , Anti-Hipertensivos/isolamento & purificação , Anti-Hipertensivos/toxicidade , Cloreto de Cádmio , Modelos Animais de Doenças , Descoberta de Drogas , Fucose/análogos & derivados , Fucose/isolamento & purificação , Fucose/toxicidade , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Dose Letal Mediana , Masculino , Ratos Wistar , Sargassum/química , Telmisartan/farmacologia
6.
Acta Biochim Biophys Sin (Shanghai) ; 53(6): 784-795, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-33928341

RESUMO

Autoantibody against the angiotensin II type I receptor (AT1-AA) has been found in the serum of patients with diabetes mellitus (DM). However, it remains unclear whether AT1-AA induces ß-cell apoptosis and participates in the development of DM. In this study, an AT1-AA-positive rat model was set up by active immunization, and AT1-AA IgG was purified. INS-1 cells were treated with AT1-AA, and cell viability, apoptosis, and autophagy-related proteins were detected by Cell Counting Kit-8 assay, flow cytometry, and western blot analysis, respectively. Results showed that existence of AT1-AA impaired the islet function and increased the apoptosis of pancreatic islet cells in rats, and the autophagy level in rat pancreatic islet tissues tended to increase gradually with the prolongation of immunization time. AT1-AA markedly reduced INS-1 cell viability, promoted cell apoptosis, and decreased insulin secretion in vitro. In addition, the autophagy level was gradually increased along with the prolongation of AT1-AA treatment time. Meanwhile, it was determined that treatment with autophagy inhibitor 3-methyladenine and angiotensin II type 1 receptor (AT1R) blocker telmisartan could improve insulin secretion and apoptosis in vitro and in vivo. In conclusion, it is deduced that upregulation of autophagy contributed to the AT1-AA-induced ß-cell apoptosis and islet dysfunction, and AT1R mediated the signal transduction.


Assuntos
Apoptose/efeitos dos fármacos , Autoanticorpos/imunologia , Autoanticorpos/farmacologia , Autofagia/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/imunologia , Imunoglobulina G/imunologia , Imunoglobulina G/farmacologia , Células Secretoras de Insulina/metabolismo , Receptor Tipo 1 de Angiotensina/imunologia , Adenina/análogos & derivados , Adenina/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Apoptose/imunologia , Autoanticorpos/isolamento & purificação , Autofagia/imunologia , Linhagem Celular Tumoral , Sobrevivência Celular/imunologia , Imunização/métodos , Imunoglobulina G/isolamento & purificação , Secreção de Insulina/efeitos dos fármacos , Secreção de Insulina/imunologia , Masculino , Ratos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Telmisartan/farmacologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologia
7.
J Biochem Mol Toxicol ; 35(7): e22785, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33860986

RESUMO

Azilsartan is found to be more potent than other angiotensin receptor blockers in reducing blood pressure. However, its effect on the heart following myocardial infarction remains to be established. For the first time, we investigated the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonistic and cardioprotective properties of azilsartan. Computational modeling studies of interactions between azilsartan and PPAR-γ revealed azilsartan as an agonist of PPAR-γ and showed the mechanism of azilsartan in cardioprotection. Our study compared the cardioprotective potential of telmisartan to that of azilsartan in a murine model of myocardial ischemia-reperfusion injury by comparing their antioxidant, ant apoptotic, anti-inflammatory, mitogen-activated protein kinase (MAPK)-modulating ability, and PPAR-γ agonistic activity. Male Wistar rats were grouped into four to receive vehicle (dimethyl sulfoxide [0.05%] 2 ml/kg) telmisartan (10 mg/kg p.o.), azilsartan (10 mg/kg p.o.) or azilsartan with specific PPAR-γ blocker, GW 9662 for 28 days. Ischemia was induced for 45 min on the 29th day followed by 60 min of reperfusion. Telmisartan and azilsartan pretreatment significantly nearly normalized cardiac parameters and preserved structural changes. Both drugs inhibited oxidative burst, inflammation, as well as cell death by modulating apoptotic protein expression along with reduction in 4',6-diamidino-2-phenylindole/terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells. An increment in pro-survival kinase ERK paralleled with a reduction in p38 and JNK was also revealed by MAPK pathway studies, after administration of these drugs. Interestingly, the aforementioned changes induced by both drugs were reversed by administration of the specific PPAR-γ antagonist, GW9662. However, we found that azilsartan upregulated PPAR-γ to a lesser extent as compared to telmisartan and the latter may be preferred in hypertensive patients at risk of myocardial infarction.


Assuntos
Benzimidazóis/farmacologia , Cardiotônicos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica , Miocárdio , Oxidiazóis/farmacologia , Telmisartan/farmacologia , Animais , Modelos Animais de Doenças , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/metabolismo , Miocárdio/patologia , Ratos , Ratos Wistar
8.
Chem Biol Interact ; 342: 109475, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33872574

RESUMO

Endorphins are endogenous opioid neuropeptides that are mainly produced from pituitary gland in response to pain and different triggers including interleukin 1 beta (IL-1ß) and corticotropin-releasing factor (CRF). Angiotensin II (Ang II) can stimulate ß-endorphin production, but the exact molecular mechanisms involved in this effect, and the role of the released ß-endorphin in Ang II-mediated pressor response remain elusive. Male rats were injected with IL-1ß receptor antagonist (IL-1Ra, 100 µg/kg), the CRF receptor blocker, astressin (20 µg/rat) or a combination of both, prior to Ang II injection (200 µg/kg). Another group of rats was given naloxone (1.6 mg/kg) or telmisartan (5 mg/kg) before Ang II injection. Blood pressure and serum and Paraventricular nucleus (PVN) ß-endorphin were detected. Moreover, IL-1ß and CRF as well as markers of oxidative stress [malondialdehyde (MDA) and superoxide dismutase (SOD)], inflammation [C-reactive protein (CRP)] and neuronal activation (c-Fos, l-glutamate, and phosphorylated ERK) were measured in the PVN of different groups. Ang II induced a pressor response and increased serum and PVN ß-endorphin levels that were attenuated in rats pre-treated with astressin or/and IL-1Ra. Moreover, Ang II increased PVN oxidative stress, inflammation and neuronal activation. Telmisartan abolished the previous effects, while naloxone, astressin and IL-1Ra aggravated Ang II-mediated pressor response and most of the biochemical changes. These findings suggest that, Ang II can induce ß-endorphin release via increasing both IL-1ß and CRF levels which in result mitigates Ang II-mediated central responses. This study highlights ß-endorphin as a possible target for treating hypertension.


Assuntos
Angiotensina II/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , beta-Endorfina/metabolismo , Animais , Hormônio Liberador da Corticotropina/metabolismo , Hormônio Liberador da Corticotropina/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-1beta/metabolismo , Masculino , Naloxona/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Fragmentos de Peptídeos/farmacologia , Ratos , Telmisartan/farmacologia
9.
Cardiovasc Diabetol ; 20(1): 70, 2021 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-33761942

RESUMO

BACKGROUND: The prevalence of hypertension and obesity has increased significantly in recent decades. Hypertension and obesity often coexist, and both are associated with increased cardiovascular mortality. Obese hypertensive patients usually require special anti-hypertensive treatment strategy due to the increased risk of treatment resistance. Molecules that can target both obesity and hypertension underlying pathologies should get more attention. Herein, we evaluated the therapeutic effects of telmisartan, with special interest in visceral adipose tissue dysfunction, in obesity-related hypertension rat model. METHODS: Thirty male Wistar rats weighing 150-200 g were equally divided into: 1-Control group (fed normal laboratory diet for 24 weeks), 2-Diet-induced obesity group (DIO, fed high fat diet for 24 weeks), and 3-Diet-induced obesity treated with telmisartan group (DIO + Tel, fed high fat diet and received telmisartan for 24 weeks). At the end of the study, anthropometrical parameters were evaluated. Systolic blood pressure and heart rate were measured. Blood samples were collected for the measurement of serum lipids, adipokines, cardiac, renal, inflammatory, and oxidative stress biomarkers. Kidneys were removed and used for histopathological studies, and visceral adipose tissue was utilized for histopathological, immunohistochemical and RT-PCR studies. RESULTS: High fat diet resulted in obesity-related changes in anthropometrical parameters, elevation of blood pressure, increase in heart rate, higher serum levels of cardiac, inflammatory and kidney function biomarkers, with altered serum lipids, adipokines and oxidative stress markers. Morphological changes (H&E and PAS-stained sections) were noticed in kidneys and visceral adipose tissue. Immunohistochemistry and RT-PCR studies confirmed adipose tissue dysfunction and over-expression of inflammatory and oxidative stress proteins. Telmisartan countered obesity-induced alterations in cardiovascular, renal, and adipose tissue functions. CONCLUSION: Adipose tissue dysfunction could be the core pathophysiology of obesity-related hypertension. Besides its anti-hypertensive effect, telmisartan had profound actions on visceral adipose tissue structure and function. Attention should be given to polymodal molecules targeting adipose tissue-related disorders.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Gordura Intra-Abdominal/efeitos dos fármacos , Obesidade/complicações , Telmisartan/farmacologia , Adiposidade/efeitos dos fármacos , Animais , Biomarcadores/sangue , Modelos Animais de Doenças , Hipertensão/sangue , Hipertensão/etiologia , Hipertensão/fisiopatologia , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/fisiopatologia , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/fisiopatologia , Masculino , Obesidade/sangue , Obesidade/fisiopatologia , Ratos Wistar
10.
Eur J Med Chem ; 216: 113285, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33662676

RESUMO

The development of resistance poses a serious problem in the therapy of cancer due to the necessity of a multiple-drug and unlimited treatment of affected patients. In chronic myeloid leukemia (CML), the introduction of imatinib has revolutionized the therapy. The persistence of an untreatable cancer stem cell pool and other resistance-causing factors, however, also impede the cure of this malignancy. New therapeutic approaches are therefore essential to overcome current treatment drawbacks. In this regard, an intervention in the STAT5 signaling pathway can significantly improve drug response, as this central signaling node induces the formation of highly resistant CML cells. In the present study, we continued the design of efficient chemosensitizers derived from the partial PPARγ agonist telmisartan. The developed 2-carbonitriles or 2-carboxymethyl esters showed improved potency in sensitizing K562-resistant cells to imatinib treatment, even at concentrations, which are considered patient-relevant. At 5 µM, for instance, 2d sensitized the cells in such a manner that the resistance was fully overcome and the recovered efficacy of imatinib resulted in >76% cell death. Importantly, all compounds were non-cytotoxic per se. A transactivation experiment showed that only the carbonitriles are partial agonists of PPARγ, which does not seem to be involved in the mode of action. Yet, immunoassays revealed a suppression of the STAT5 phosphorylation status by co-application of the most active derivatives with imatinib. This mechanism consequently resulted in reduced cell proliferation and induction of cell death in resistant CML cells.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Nitrilas/química , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Células COS , Linhagem Celular Tumoral , Chlorocebus aethiops , Desenho de Fármacos , Regulação da Expressão Gênica , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Nitrilas/farmacologia , PPAR gama/genética , PPAR gama/metabolismo , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT5/antagonistas & inibidores , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Telmisartan/química , Telmisartan/farmacologia , Ativação Transcricional/efeitos dos fármacos , Proteínas Supressoras de Tumor/antagonistas & inibidores , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
11.
Adv Ther ; 38(1): 304-315, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33108624

RESUMO

INTRODUCTION: We investigate the safety and efficacy of telmisartan plus S-amlodipine single-pill combination in a real-world population. METHODS: A total of 44,715 patients who had hypertension and received a telmisartan/S-amlodipine single-pill combination at least once were included for safety and efficacy evaluation from 2852 primary to tertiary hospitals in Korea from August 2013 to December 2019. They were followed up for 3-6 months in terms of safety and efficacy of blood pressure (BP) lowering. RESULTS: A total of 44,715 patients were included for safety analysis and 41,579 for efficacy analysis. Mean duration of taking the drug was 175.86 ± 48.45 days. A total of 28,096 (62.8%) patients were on telmisartan 40 mg plus S-amlodipine 2.5 mg combination followed by 80/2.5 mg (8664, 19.4%) and 40/5 mg of the drug (7136, 16.0%). Adverse events, total adverse drug reactions, and serious adverse drug reactions were found in 808 patients (1.81%), 352 (0.79%), and 1 (0.002%), respectively. Dizziness and headache were most common (134 [0.30%] and 81 [0.18%]) among all adverse events. Total edema and leg edema were rarely reported, 38 (0.08%) and 25 (0.06%), respectively. Systolic BP (SBP) and diastolic BP (DBP) was lowered from 143.1 ± 16.1/88.1 ± 11.8 mmHg to 129.6 ± 11.4/80.1 ± 9.0 mmHg (difference - 13.5/- 7.9 mmHg, P < 0.0001 for both). Target BP goal attainment rate defined as SBP < 140 mmHg and DBP < 90 mmHg was 74.6% (95% confidence interval [CI] 74.2-75.0) and BP response rate (defined as SBP < 140 mmHg or ≥ 20 mmHg reduction; DBP < 90 mmHg or ≥ 10 mmHg reduction) was 94.5% (95% CI 94.3-94.7). CONCLUSION: Telmisartan plus S-amlodipine single-pill combination was safe and effective in patients with hypertension in a large real-world population.


Assuntos
Anti-Hipertensivos , Hipertensão , Anlodipino/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Benzoatos/efeitos adversos , Pressão Sanguínea , Combinação de Medicamentos , Quimioterapia Combinada , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , República da Coreia , Telmisartan/farmacologia , Telmisartan/uso terapêutico , Resultado do Tratamento
13.
Diabetes ; 70(3): 759-771, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33310740

RESUMO

The causes of the increased risk of severe coronavirus disease 2019 (COVID-19) in people with diabetes are unclear. It has been speculated that renin-angiotensin system (RAS) blockers may promote COVID-19 by increasing ACE2, which severe acute respiratory syndrome coronavirus 2 uses to enter host cells, along with the host protease TMPRSS2. Taking a reverse translational approach and by combining in situ hybridization, primary cell isolation, immunoblotting, quantitative RT-PCR, and liquid chromatography-tandem mass spectrometry, we studied lung and kidney ACE2 and TMPRSS2 in diabetic mice mimicking host factors linked to severe COVID-19. In healthy young mice, neither the ACE inhibitor ramipril nor the AT1 receptor blocker telmisartan affected lung or kidney ACE2 or TMPRSS2, except for a small increase in kidney ACE2 protein with ramipril. In contrast, mice with comorbid diabetes (aging, high-fat diet, and streptozotocin-induced diabetes) had heightened lung ACE2 and TMPRSS2 protein levels and increased lung ACE2 activity. None of these parameters were affected by RAS blockade. ACE2 was similarly upregulated in the kidneys of mice with comorbid diabetes compared with aged controls, whereas TMPRSS2 (primarily distal nephron) was highest in telmisartan-treated animals. Upregulation of lung ACE2 activity in comorbid diabetes may contribute to an increased risk of severe COVID-19. This upregulation is driven by comorbidity and not by RAS blockade.


Assuntos
Enzima de Conversão de Angiotensina 2/genética , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica , Rim/metabolismo , Pulmão/metabolismo , Serina Endopeptidases/genética , Fatores Etários , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Enzima de Conversão de Angiotensina 2/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , COVID-19 , Immunoblotting , Hibridização In Situ , Rim/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Masculino , Camundongos , Ramipril/farmacologia , Receptores de Coronavírus/efeitos dos fármacos , Receptores de Coronavírus/genética , Receptores de Coronavírus/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , SARS-CoV-2 , Serina Endopeptidases/efeitos dos fármacos , Serina Endopeptidases/metabolismo , Telmisartan/farmacologia
14.
Biomed Res Int ; 2020: 8872479, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33282956

RESUMO

Copper nanoparticles (Cu-Nps) are one of the promising materials for the advancement of nanoscience and technology. In this work, we synthesized telmisartan copper nanoparticles and 2-pyrimidinamines via Biginelli reaction using telmisartan copper nanoparticles (Cu-Nps) as a reusable catalyst. The synthesis of 2-pyrimidinamine derivatives (1a-c) was achieved in water and under solvent-free condition (Green chemistry approach). Synthesis of 2-pyrimidinamine with telmisartan copper nanoparticle (Cu-Nps-Pyr) unexpected product was also isolated from synthesis of 2-pyrimidinamine preparation. Antioxidant and cytotoxic activities were carried out both in 2-pyrimidinamine (1a-1c) and 2-pyrimidinamine with telmisartan copper nanoparticles (Cu-Nps-Pyr). The synthesized 2-pyrimidinamine derivatives (1a-c) were characterized from FT-IR, 1H and 13C NMR spectroscopy, mass and elemental analyses. The synthesized telmisartan copper nanoparticles (Cu-Nps) were characterized from UV spectroscopy, XRD, SEM, EDX, AFM (atomic force microscopy), profile, waviness, and roughness analyses. Antioxidant activity was screened based on ABTS·+ radical scavenging and linoleic acid peroxidation performance. Cu-Nps-Pyr-1b showed substantial antioxidant (97.2%) activity against ABTS·+ assay and 91.2% activity against AAPH assays compared with Trolox. Cytotoxicity was evaluated using HepG2, HeLa, and MCF-7 cell lines, the Cu-Nps-Pyr-1a is high in toxicities (GI50 = 0.01 µm) against the HeLa cancel cell line compared with doxorubicin. The developed copper NPs with 2-pyrimidinamine (Cu-Nps-Pyr) could provide promising advances as antioxidant activities; this nanocomposition could be considered an anticancer treatment in future investigations.


Assuntos
Antioxidantes/farmacologia , Cobre/farmacologia , Nanopartículas Metálicas/química , Pirimidinas/farmacologia , Telmisartan/farmacologia , Benzotiazóis/química , Catálise , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sequestradores de Radicais Livres/química , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Nanopartículas Metálicas/ultraestrutura , Tamanho da Partícula , Pós , Pirimidinas/síntese química , Pirimidinas/química , Espectrometria por Raios X , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Ácidos Sulfônicos/química , Telmisartan/química , Termogravimetria , Difração de Raios X
15.
Res Vet Sci ; 133: 150-156, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32992126

RESUMO

Renal proteinuria is associated with promoted renal dysfunction and a shorter survival period in dogs with chronic kidney disease (CKD). Renin angiotensin- aldosterone system inhibitors are primarily used to treat renal proteinuria. In this retrospective, open-label study, we aimed to evaluate the anti-proteinuric and anti-hypertensive effects of telmisartan (angiotensin II receptor blocker) in dogs with proteinuric CKD. A total of 28 dogs with proteinuric CKD were included in the study, all dogs received telmisartan 1 mg/kg q24h, PO. The urine protein-to-creatinine ratio (UPC), urine albumin-to-creatinine ratio (UAC) and systolic blood pressure (SBP) decreased significantly after telmisartan administration (P < 0.05). The median rate of change in UPC, UAC and SBP at Day 120 were - 65.1%, -75.9% and - 9.7%. Ten dogs (36.7%) achieved UPC < 1.0 at Day 120, of which six dogs had UPC < 0.5. A reduction of UPC to ≥50% was achieved in 10 dogs (36%) at Day 45 and 17 dogs (61%) at Day 120. Seventeen dogs (61%) had hypertension at baseline, of which 10 dogs (59%) had SBP < 160 mmHg at Day 120. Two-way repeated measures analysis of variance did not attribute the observed changes in SBP, UPC or UAC to feeding with a renal diet. In conclusion, telmisartan therapy provides anti-proteinuric and anti-hypertensive effects in dogs with proteinuric CKD.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Doenças do Cão/tratamento farmacológico , Proteinúria/veterinária , Insuficiência Renal Crônica/veterinária , Telmisartan/farmacologia , Telmisartan/uso terapêutico , Animais , Cães , Feminino , Masculino , Proteinúria/complicações , Proteinúria/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Estudos Retrospectivos , Resultado do Tratamento
16.
J Stroke Cerebrovasc Dis ; 29(12): 105255, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32992165

RESUMO

BACKGROUND: Inflammatory response is a critical contributor to cerebral ischaemia injuries and blood-brain barrier (BBB) dysfunction. Early growth response-1 (Egr-1), an oxygen-sensing transcription factor which is rapidly and markedly triggered in ischaemic events, acts as a master switch coordinating the upregulation of multiple target proinflammatory genes. Here, we explored whether peroxisome proliferator-activated receptor-gamma (PPARγ) activation by telmisartan can modulate Egr-1 expression and the subsequent inflammatory responses in a rat model of cerebral ischaemia. METHODS: Cerebral ischaemia was induced in rats by middle cerebral artery occlusion (MCAO). Brain injury was evaluated by brain water content, infarct volume, and Evans blue dye extravasation. Egr-1 and claudin-5 levels were assessed by western blot and real-time polymerase chain reaction. RESULTS: MCAO-provoked Egr-1 expression was time dependent, peaking at 24 h and continuing to 72 h. The elevation in Egr-1 was coupled with a reduction in claudin-5. Telmisartan treatment significantly corrected the alterations of Egr-1 and claudin-5, alleviated the neurological deficits, and reduced brain water content, infarct volume, and Evans blue dye extravasation 24 h after MCAO. However, all the benefits of telmisartan were reversed by antagonising PPARγ with GW9662. CONCLUSION: Egr-1, a proinflammatory factor, is positively associated with post-ischaemic inflammation and the associated BBB dysfunction. PPARγ serves as an upstream transcription factor of the Egr-1 cascade. Targeting Egr-1 may emerge as a potential strategy to suppress inflammatory responses following ischaemic stroke.


Assuntos
Anti-Inflamatórios/farmacologia , Encéfalo/efeitos dos fármacos , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , PPAR gama/agonistas , Telmisartan/farmacologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Claudina-5/metabolismo , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Masculino , PPAR gama/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais
17.
Cancer Lett ; 493: 31-40, 2020 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-32763272

RESUMO

Hypoxic tumour cells are radiation-resistant and are associated with poor therapeutic outcome. A poorly understood source of tumour hypoxia is unstable perfusion, which exposes tumour cells to varying oxygen tensions over time creating "transiently" hypoxic cells. Evidence suggests that angiotensin II type 1 receptor blockers (ARBs) can improve tumour perfusion by reducing collagen deposition from cancer associated fibroblasts (CAFs). However, the influence of ARBs on transient hypoxia and tumour radiation response is unknown. We tested how the ARBs losartan and telmisartan affected the solid tumour microenvironment, using fluorescent perfusion dyes and positron emission tomography to quantify tumour perfusion, and a combination of hypoxia markers and the hemorheological agent pentoxifylline to assess transient tumour hypoxia. We found CAF-containing tumours have reduced collagen I levels in response to telmisartan, but not losartan. Telmisartan significantly increased tumour blood flow, stabilized microregional tumour perfusion, and decreased tumour hypoxia by reducing the development of transient hypoxia. Telmisartan-treated tumours were more responsive to radiation, indicating that telmisartan reduces a therapeutically important population of transiently hypoxic tumour cells. Our findings indicate telmisartan is capable of modifying the tumour microenvironment to stabilize tumour perfusion, reduce transient hypoxia, and improve tumour radiation response.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Neoplasias/terapia , Radiossensibilizantes/administração & dosagem , Telmisartan/administração & dosagem , Hipóxia Tumoral/efeitos dos fármacos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/metabolismo , Linhagem Celular Tumoral , Colágeno Tipo I/metabolismo , Corantes Fluorescentes/administração & dosagem , Humanos , Losartan/administração & dosagem , Losartan/farmacologia , Camundongos , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Pentoxifilina/administração & dosagem , Tomografia por Emissão de Pósitrons , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Radioterapia , Telmisartan/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Virology ; 548: 250-260, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32791353

RESUMO

Chikungunya has re-emerged as an epidemic with global distribution and high morbidity, necessitating the need for effective therapeutics. We utilized already approved drugs with a good safety profile used in other diseases for their new property of anti-chikungunya activity. It provides a base for a fast and efficient approach to bring a novel therapy from bench to bedside by the process of drug-repositioning. We utilized an in-silico drug screening with FDA approved molecule library to identify inhibitors of the chikungunya nsP2 protease, a multifunctional and essential non-structural protein required for virus replication. Telmisartan, an anti-hypertension drug, and the antibiotic novobiocin emerged among top hits on the screen. Further, SPR experiments revealed strong in-vitro binding of telmisartan and novobiocin to nsP2 protein. Additionally, small angle x-ray scattering suggested binding of molecules to nsP2 and post-binding compaction and retention of monomeric state in the protein-inhibitor complex. Protease activity measurement revealed that both compounds inhibited nsP2 protease activity with IC50 values in the low micromolar range. More importantly, plaque formation assays could show the effectiveness of these drugs in suppressing virus propagation in host cells. We propose novobiocin and telmisartan as potential inhibitors of chikungunya replication. Further research is required to establish the molecules as antivirals of clinical relevance against chikungunya.


Assuntos
Antivirais/farmacologia , Febre de Chikungunya/virologia , Vírus Chikungunya/efeitos dos fármacos , Novobiocina/farmacologia , Telmisartan/farmacologia , Febre de Chikungunya/tratamento farmacológico , Vírus Chikungunya/genética , Vírus Chikungunya/fisiologia , Avaliação Pré-Clínica de Medicamentos , Humanos , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos
19.
Mol Med Rep ; 22(2): 1063-1071, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32626983

RESUMO

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract. The angiotensin II type 1 receptor blockers, telmisartan and candesartan, are widely used antihypertensive drugs that inhibits cancer cell proliferation; however, its underlying mechanisms in mesenchymal tumors, including GIST, remains unknown. The present study aimed to investigate the effect of telmisartan on GIST­T1 cells and its underlying mechanism. Telmisartan and candesartan inhibited the proliferation of these cells by blocking the G0 to G1 cell cycle transition, which was accompanied by a decrease in cell cycle­related proteins such as cyclin D1. Furthermore, telmisartan exposure significantly altered microRNA expression in vitro. In conclusion, telmisartan suppressed human GIST cell proliferation by inducing cell cycle arrest in vitro.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Anti-Hipertensivos/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/metabolismo , Telmisartan/farmacologia , Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Indutores da Angiogênese/metabolismo , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ciclina D1/efeitos dos fármacos , Ciclina D1/metabolismo , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , MicroRNAs/efeitos dos fármacos , MicroRNAs/metabolismo , Análise Serial de Tecidos
20.
Oncol Rep ; 44(1): 339-348, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32627043

RESUMO

Gastric cancer is one of the most common malignancies diagnosed worldwide. Telmisartan, an angiotensin receptor blocker (ARB), suppresses the proliferation of cancer cells and the growth of tumors through an unknown mechanism. To identify the mechanism, the present study was designed to evaluate the effects of telmisartan on gastric cancer cell lines and tumors in vitro and in vivo and the associated signaling molecules were identified. It was shown here that telmisartan suppressed the proliferation of the cultured human gastric cancer cell lines MKN74, MKN1 and MKN45 as detected in the CCK­8 assay. In a mouse xenograft model of gastric cancer, telmisartan suppressed tumor growth by arresting the cell cycle at the G0/G1 phase through inhibition of the expression of cyclin D1, the catalytic subunit of cyclin dependent kinase 4 (CDK4), as well as the phosphorylation of the tumor suppressor retinoblastoma (pRb) protein as detected by western blotting. Notably, telmisartan did not induce apoptosis, as indicated by consistent levels of caspase­cleaved keratin 18 in MKN74 cells. Furthermore, telmisartan inhibited the phosphorylation of epidermal growth factor receptor (EGFR) and increased the levels of the angiogenesis­related protein tissue inhibitor of metalloproteinase­1 (TIMP­1). Analyses of microarrays revealed that telmisartan altered the expression of miRNAs in MKN74 cells. In conclusion, telmisartan suppressed the proliferation of human gastric cancer cells by inducing cell cycle arrest.


Assuntos
Ciclina D1/genética , Quinase 4 Dependente de Ciclina/genética , Proteína do Retinoblastoma/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Telmisartan/administração & dosagem , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Reposicionamento de Medicamentos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , MicroRNAs/genética , Fosforilação/efeitos dos fármacos , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Telmisartan/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...