Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 20.572
Filtrar
1.
Pediatr Cardiol ; 41(7): 1301-1318, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32915293

RESUMO

Alterations in blood pressure are common during the perioperative period in infants and children. Perioperative hypertension may be the result of renal failure, volume overload, or activation of the sympathetic nervous system. Concerns regarding end-organ effects or postoperative bleeding may mandate regulation of blood pressure. During the perioperative period, various pharmacologic agents have been used for blood pressure control including sodium nitroprusside, nitroglycerin, ß-adrenergic antagonists, fenoldopam, and calcium channel antagonists. The following manuscript outlines the commonly used pharmacologic agents for perioperative BP including dosing regimens and adverse effect profiles. Previously published clinical trials are discussed and efficacy in the perioperative period reviewed.


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Adolescente , Antagonistas Adrenérgicos beta/efeitos adversos , Antagonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/uso terapêutico , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/farmacologia , Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Criança , Pré-Escolar , Fenoldopam/efeitos adversos , Fenoldopam/farmacologia , Fenoldopam/uso terapêutico , Humanos , Hipertensão/etiologia , Lactente , Masculino , Nitroprussiato/efeitos adversos , Nitroprussiato/farmacologia , Nitroprussiato/uso terapêutico , Período Perioperatório , Insuficiência Renal/complicações , Resultado do Tratamento
2.
BMJ Open ; 10(9): e040644, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32928868

RESUMO

OBJECTIVE: To review evidence on routinely prescribed drugs in the UK that could upregulate or downregulate ACE2 and potentially affect COVID-19 disease. DESIGN: Systematic review. DATA SOURCE: MEDLINE, EMBASE, CINAHL, the Cochrane Library and Web of Science. STUDY SELECTION: Any design with animal or human models examining a currently prescribed UK drug compared with a control, placebo or sham group, and reporting an effect on ACE2 level, activity or gene expression. DATA EXTRACTION AND SYNTHESIS: MEDLINE, EMBASE, CINAHL, the Cochrane Library, Web of Science and OpenGrey from inception to 1 April 2020. Methodological quality was assessed using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk-of-bias tool for animal studies and Cochrane risk-of-bias tool for human studies. RESULTS: We screened 3360 titles and included 112 studies with 21 different drug classes identified as influencing ACE2 activity. Ten studies were in humans and one hundred and two were in animal models None examined ACE2 in human lungs. The most frequently examined drugs were angiotensin receptor blockers (ARBs) (n=55) and ACE inhibitors (ACE-I) (n=22). More studies reported upregulation than downregulation with ACE-I (n=22), ARBs (n=55), insulin (n=8), thiazolidinedione (n=7) aldosterone agonists (n=3), statins (n=5), oestrogens (n=5) calcium channel blockers (n=3) glucagon-like peptide 1 (GLP-1) agonists (n=2) and Non-steroidal anti-inflammatory drugs (NSAIDs) (n=2). CONCLUSIONS: There is an abundance of the academic literature and media reports on the potential of drugs that could attenuate or exacerbate COVID-19 disease. This is leading to trials of repurposed drugs and uncertainty among patients and clinicians concerning continuation or cessation of prescribed medications. Our review indicates that the impact of currently prescribed drugs on ACE2 has been poorly studied in vivo, particularly in human lungs where the SARS-CoV-2 virus appears to enact its pathogenic effects. We found no convincing evidence to justify starting or stopping currently prescribed drugs to influence outcomes of COVID-19 disease.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Infecções por Coronavirus , Estrogênios/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipoglicemiantes/farmacologia , Pandemias , Peptidil Dipeptidase A/efeitos dos fármacos , Pneumonia Viral , Anti-Inflamatórios não Esteroides/farmacologia , Betacoronavirus/metabolismo , Regulação para Baixo , Peptídeo 1 Semelhante ao Glucagon/agonistas , Humanos , Insulina/farmacologia , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Peptidil Dipeptidase A/metabolismo , Tiazolidinedionas/farmacologia , Reino Unido , Regulação para Cima
3.
Life Sci ; 259: 118210, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32763289

RESUMO

AIMS: From the synthesis of 43 lipophilic dihydropyridines, the aim of this study was to verify whether the new dihydropyridines have calcium channel affinity using coupling studies and to determine antihypertensive and antioxidant properties, as well as toxicology and toxicity nifedipine and three new compounds, were chosen from the previous results. MATERIALS AND METHODS: The animals were treated for 56 days, 28 days with N (ω) -nitro-L-arginine methyl ester to induce hypertension, and then treated for another 28 days with the new di- hydropyridine and the standard drug nifedipine. Throughout the treatment the animals had their blood pressure measured and their heart rate checked by pletysmography. After treatment the animals were euthanised, blood samples were collected for creatine kinase and urea analysis, and the brain, heart and liver were collected for oxidative status analysis (quantification of reactive oxygen species, total antioxidant capacity, and lipid peroxidation). KEY FINDINGS: Compounds 2c, and 9a, and nifedipine significantly reduced blood pressure to control group levels. The tachycardia caused by the induction of hypertension was reversed by 2c and 9a compounds. Regarding oxidative stress analyzes, the compounds that had the best performances were also 2c and 9a. Overall the results demonstrate that two of the three new dihydropyridines tested demonstrated performance equal to or superior to the standard drug nifedipine. SIGNIFICANCE: In this study, for the first time, docking was applied to analyse 43 fatty dihydropyridines regarding their calcium channel binding. Afterwards, three fatty dihydropyridines were chosen and their antihypertensive and antioxidant properties.


Assuntos
Canais de Cálcio Tipo L/metabolismo , Canais de Cálcio Tipo L/ultraestrutura , Di-Hidropiridinas/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Antioxidantes/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio , Di-Hidropiridinas/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/fisiopatologia , Masculino , Nifedipino/farmacologia , Piridinas/farmacologia , Ratos , Ratos Wistar
4.
Life Sci ; 260: 118291, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32810510

RESUMO

AIMS: Despite the advanced cancer treatments, there is increased resistance to chemotherapy and subsequent mortality. In lack of reliable data in monolayer cultures and animal models, researchers are shifting to 3D cancer spheroids, which represents the in vivo robust tumour morphology. Calcium is essential in cell signalling and proliferation. It is found that T-type calcium channels (TTCCs) are overexpressed in various cancer cells, supporting their increased proliferation. Many of the TTCCs blockers available could target other channels besides TTCCs, which can cause adverse effects. Therefore, we hypothesise that TTA-A2, a highly selective blocker towards TTCCs, can inhibit the growth of cancer spheroids, and provide an anti-cancer and an adjuvant role in cancer therapy. METHODS: We studied TTA-A2 and paclitaxel (PTX-control drug) in lung adenocarcinoma cell line- A549, cancer cells and human embryonic kidney cell line- HEK 293, control cell, in their monolayer and spheroids forms for viability, proliferation, morphology change, migration, and invasion-after 48-96 h of treatment. KEY FINDINGS: Though the results varied between the monolayer and spheroids studies, we found both anti-cancer as well as adjuvant effect of TTA-A2 in both the studies. TTA-A2 was able to inhibit the growth, viability, and metastasis of the cancer cells and spheroids. Differences in the results of two modes might explain that why drugs tested successfully in monolayer culture fail in clinical trials. SIGNIFICANCE: This study establishes the role of TTA-A2, a potent TTCC blocker as an anti-cancer and adjuvant drug in reducing the viability and metastasis of the cancer cells.


Assuntos
Adenocarcinoma de Pulmão/patologia , Antineoplásicos , Benzenoacetamidas/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/efeitos dos fármacos , Neoplasias Pulmonares/patologia , Piridinas/farmacologia , Células A549 , Adenocarcinoma de Pulmão/tratamento farmacológico , Benzenoacetamidas/uso terapêutico , Canais de Cálcio Tipo T/fisiologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células HEK293 , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Invasividade Neoplásica/prevenção & controle , Piridinas/uso terapêutico
5.
ACS Chem Neurosci ; 11(15): 2145-2148, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32662982

RESUMO

Studies have shown that the calcium ion (Ca2+) plays important roles both in Alzheimer's dementia and SARS-CoV S-mediated fusion to host cell entry. An elevated level of intracellular calcium causes neuronal dysfunction, cell death, and apoptosis. Dysregulation of calcium has also been shown to increase the production of amyloid beta (Aß) protein, the hallmark of Alzheimer's dementia. Reversely, deposition of Aß is also responsible for calcium dysregulation. On the other hand, it has been well investigated that viruses can disturb host cell Ca2+ homeostasis as well as modulate signal transduction mechanisms. Viruses can also hijack the host cell calcium channels and pumps to release more intracellular Ca2+ to utilize for their life cycle. Even though evidence has not been reported on SARS-CoV-2 concerning Ca2+ regulation, however, it has been well established that Ca2+ is essential for viral entry, viral gene replication, and virion maturation and release. Recent reports suggest that SARS-CoV needs two Ca2+ ions to fuse with the host cell at the entry step. Furthermore, some calcium channel blockers (CCBs), such as nimodipine, memantine, etc., have been reported to be effective in the treatment of dementia in Alzheimer's disease (AD) as well as have shown inhibition in various virus infections.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Betacoronavirus , Bloqueadores dos Canais de Cálcio/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/metabolismo , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/psicologia , Humanos , Pandemias , Pneumonia Viral/metabolismo , Pneumonia Viral/psicologia , Resultado do Tratamento
6.
Proc Natl Acad Sci U S A ; 117(32): 19497-19506, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32719120

RESUMO

Understanding the genetics of susceptibility to infectious agents is of great importance to our ability to combat disease. Here, we show that voltage-gated calcium channels (VGCCs) are critical for cellular binding and entry of the New World arenaviruses Junín and Tacaribe virus, suggesting that zoonosis via these receptors could occur. Moreover, we demonstrate that α1s haploinsufficiency renders cells and mice more resistant to infection by these viruses. In addition to being more resistant to infection, haploinsufficient cells and mice required a lower dosage of VGCC antagonists to block infection. These studies underscore the importance of genetic variation in susceptibility to both viruses and pharmaceutics.


Assuntos
Infecções por Arenaviridae/genética , Canais de Cálcio Tipo L/genética , Resistência à Doença/genética , Animais , Infecções por Arenaviridae/tratamento farmacológico , Arenavirus do Novo Mundo/fisiologia , Agonistas dos Canais de Cálcio/farmacologia , Agonistas dos Canais de Cálcio/uso terapêutico , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Tipo L/deficiência , Canais de Cálcio Tipo L/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Heterozigoto , Humanos , Camundongos , Camundongos Mutantes , Mutação , Ligação Viral/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos
7.
Turk Kardiyol Dern Ars ; 48(4): 410-424, 2020 06.
Artigo em Inglês | MEDLINE | ID: covidwho-595169

RESUMO

OBJECTIVE: The aim of this study was to evaluate the effectiveness of plants used in the formulations of traditional Chinese medicine (TCM), which were also used in clinical trials to treat patients with the novel coronavirus COVID-19, and to assess their effects on the cardiovascular system. METHODS: A literature review of PubMed, ResearchGate, ScienceDirect, the Cochrane Library, and TCM monographs was conducted and the effects of the plants on the cardiovascular system and the mechanisms of action in COVID-19 treatment were evaluated. RESULTS: The mechanism of action, cardiovascular effects, and possible toxicity of 10 plants frequently found in TCM formulations that were used in the clinical treatment of COVID-19 were examined. CONCLUSION: TCM formulations that had been originally developed for earlier viral diseases have been used in COVID-19 treatment. Despite the effectiveness seen in laboratory and animal studies with the most commonly used plants in these formulations, the clinical studies are currently insufficient according to standard operating procedures. More clinical studies are needed to understand the safe clinical use of traditional plants.


Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Infecções por Coronavirus/terapia , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa , Pneumonia Viral/terapia , Animais , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Antiarrítmicos/toxicidade , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/toxicidade , Anticolesterolemiantes/farmacologia , Anticolesterolemiantes/uso terapêutico , Anticolesterolemiantes/toxicidade , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Anti-Hipertensivos/toxicidade , Antivirais/farmacologia , Antivirais/uso terapêutico , Antivirais/toxicidade , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Bloqueadores dos Canais de Cálcio/toxicidade , Interações Medicamentosas , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/toxicidade , Humanos , Pandemias , Inibidores da Agregação de Plaquetas/farmacologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Inibidores da Agregação de Plaquetas/toxicidade , Vasodilatadores/farmacologia , Vasodilatadores/uso terapêutico , Vasodilatadores/toxicidade
8.
Turk Kardiyol Dern Ars ; 48(4): 410-424, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32519978

RESUMO

OBJECTIVE: The aim of this study was to evaluate the effectiveness of plants used in the formulations of traditional Chinese medicine (TCM), which were also used in clinical trials to treat patients with the novel coronavirus COVID-19, and to assess their effects on the cardiovascular system. METHODS: A literature review of PubMed, ResearchGate, ScienceDirect, the Cochrane Library, and TCM monographs was conducted and the effects of the plants on the cardiovascular system and the mechanisms of action in COVID-19 treatment were evaluated. RESULTS: The mechanism of action, cardiovascular effects, and possible toxicity of 10 plants frequently found in TCM formulations that were used in the clinical treatment of COVID-19 were examined. CONCLUSION: TCM formulations that had been originally developed for earlier viral diseases have been used in COVID-19 treatment. Despite the effectiveness seen in laboratory and animal studies with the most commonly used plants in these formulations, the clinical studies are currently insufficient according to standard operating procedures. More clinical studies are needed to understand the safe clinical use of traditional plants.


Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Infecções por Coronavirus/terapia , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa , Pneumonia Viral/terapia , Animais , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Antiarrítmicos/toxicidade , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/toxicidade , Anticolesterolemiantes/farmacologia , Anticolesterolemiantes/uso terapêutico , Anticolesterolemiantes/toxicidade , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Anti-Hipertensivos/toxicidade , Antivirais/farmacologia , Antivirais/uso terapêutico , Antivirais/toxicidade , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Bloqueadores dos Canais de Cálcio/toxicidade , Interações Medicamentosas , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/toxicidade , Humanos , Pandemias , Inibidores da Agregação de Plaquetas/farmacologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Inibidores da Agregação de Plaquetas/toxicidade , Vasodilatadores/farmacologia , Vasodilatadores/uso terapêutico , Vasodilatadores/toxicidade
9.
J Interv Cardiol ; 2020: 5894586, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32508542

RESUMO

Coronary artery spasm (CAS) defined by a severe reversible diffuse or focal vasoconstriction is the most common diagnosis among INOCA (ischemia with no obstructive coronary artery disease) patients irrespective to racial, genetic, and geographic variations. However, the prevalence of CAS tends to decrease in correlation with the increasing use of medicines such as calcium channel blockers, angiotensin converting enzyme inhibitor, and statins, the controlling management of atherosclerotic risk factors, and the decreased habitude to perform a functional reactivity test in highly active cardiac catheterization centers. A wide spectrum of clinical manifestations from silent disease to sudden cardiac death was attributed to this complex entity with unclear pathophysiology. Multiple mechanisms such as the autonomic nervous system, endothelial dysfunction, chronic inflammation, oxidative stress, and smooth muscle hypercontractility are involved. Regardless of the limited benefits proffered by the newly emerged cardiac imaging modalities, the provocative test remains the cornerstone diagnostic tool for CAS. It allows to reproduce CAS and to evaluate reactivity to nitrates. Different invasive and noninvasive therapeutic approaches are approved for the management of CAS. Long-acting nondihydropyridine calcium channel blockers are recommended for first line therapy. Invasive strategies such as PCI (percutaneous coronary intervention) and CABG (coronary artery bypass graft) have shown benefits in CAS with significant atherosclerotic lesions. Combination therapies are proposed for refractory cases.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Técnicas de Imagem Cardíaca/métodos , Vasoespasmo Coronário , Revascularização Miocárdica/métodos , Vasoespasmo Coronário/etiologia , Vasoespasmo Coronário/fisiopatologia , Vasoespasmo Coronário/terapia , Humanos , Fatores de Risco
10.
Zhonghua Zhong Liu Za Zhi ; 42(6): 486-490, 2020 Jun 23.
Artigo em Chinês | MEDLINE | ID: mdl-32575945

RESUMO

Objective: To investigate the effects of targeted artery perfusion of verapamil and chemotherapy drugs on advanced non-small cell lung cancer (NSCLC). Methods: Sixty patients with advanced NSCLC who were admitted to the Central Hospital of Zhumadian from April 2016 to April 2018 were selected as the research subjects. They were divided into the observation group (26 cases) and the control group (34 cases) according to the treatment method. Patients in the observation group were treated with targeted artery perfusion of verapamil and chemotherapy drugs while the control group were treated with target artery perfusion of chemotherapy drugs alone.Both groups were treated continuously for more than 2 months. The short-term curative effect, adverse reactions, changes in immune function, levels of serum tumor markers and Karnofsky Performance Scale (KPS) scores before and after treatment as well as the prognosis were compared between the two groups. Results: The response rate and control rate in the observation group were 80.8% and 96.2%, higher than 55.9% and 76.5% in the control group (P<0.05). After treatment, CD4(+) levels and CD4(+) /CD8(+) in the observation group were (25.43±2.76)% and (0.88±0.11), lower than (27.56±2.79)% and (0.95±0.13) in the control group (P<0.05). After treatment, serum levels of CEA and CA50 in the observation group were (11.57±2.32)ng/ml and (16.62±3.28)U/ml, also lower than (15.87±2.66)ng/ml and (20.31±3.42)U/ml in the control group (P<0.05). There was no significant difference in adverse reactions between the two groups (P>0.05). After treatment, KPS score of the observation group was (81.44±2.76) points, higher than (79.62±2.38) points of the control group (P<0.05). The median survival time and progression-free median survival time of the observation group were 16.0 months and 7.5 months, respectively, significantly better than 10.0 months and 5.0 months of the control group (P<0.05). Conclusions: The treatment with target arterial perfusion of verapamil and chemotherapy drugs for advanced NSCLC can effectively improve the short-term curative effect, reduce serum levels of tumor markers, improve life quality and prolong the survival time. However, it has a certain inhibitory effect on the patient's immune function.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bloqueadores dos Canais de Cálcio/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Verapamil/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bloqueadores dos Canais de Cálcio/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Infusões Intra-Arteriais , Avaliação de Estado de Karnofsky , Neoplasias Pulmonares/patologia , Resultado do Tratamento , Verapamil/administração & dosagem , Verapamil/efeitos adversos
12.
Int J Mol Sci ; 21(11)2020 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-32521790

RESUMO

This study was undertaken to test two therapies for acute kidney injury (AKI) prevention, IGF-1, which is renal protective, and BTP-2, which is a calcium entry (SOCE) inhibitor. We utilized lipopolysaccharide (LPS) IP, as a systemic model of AKI and studied in five groups of animals. Three experiments showed that at 7 days: (1) LPS significantly reduced serum IGF-1 and intramuscular IGF-I in vivo gene therapy rescued this deficiency. (2) Next, at the 7-day time point, our combination therapy,compared to the untreated group,caused a significant increase in survival, which was noteworthy because all of the untreated animals died in 72 hrs. (3) The four pathways associated with inflammation, including (A) increase in cytosolic calcium, (B) elaboration of proinflammatory cytokines, (C) impairment of vascular integrity, and (D) cell injury, were adversely affected in renal tissue by LPS, using a sublethal dose of LPS. The expression of several genes was measured in each of the above pathways. The combined therapy of IGF-1 and BTP-2 caused a favorable gene expression response in all four pathways. Our current study was an AKI study, but these pathways are also involved in other types of severe inflammation, including sepsis, acute respiratory distress syndrome, and probably severe coronavirus infection.


Assuntos
Lesão Renal Aguda/patologia , Fator de Crescimento Insulin-Like I/genética , Lesão Renal Aguda/mortalidade , Lesão Renal Aguda/terapia , Animais , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Citocinas/genética , Citocinas/metabolismo , Citoplasma/metabolismo , Modelos Animais de Doenças , Feminino , Expressão Gênica/efeitos dos fármacos , Terapia Genética , Fator de Crescimento Insulin-Like I/análise , Fator de Crescimento Insulin-Like I/deficiência , Rim/metabolismo , Rim/patologia , Lipopolissacarídeos/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Proteína ORAI1/antagonistas & inibidores , Proteína ORAI1/metabolismo , Taxa de Sobrevida
14.
Wilderness Environ Med ; 31(3): 312-316, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32482519

RESUMO

INTRODUCTION: Cold-induced vasodilation (CIVD) is seen in the extremities during exposure to cold. A strong vasodilation response has been associated with a decreased risk of cold injury. Increasing CIVD might further decrease this risk. The calcium-channel blocker nifedipine causes vasodilation and is used to treat Raynaud's syndrome and chilblains. Nifedipine is also used for high altitude pulmonary edema and could potentially serve a dual purpose in preventing frostbite. The effects of nifedipine on CIVD have not been studied. METHODS: A double-blind crossover study comparing nifedipine (30 mg SR (sustained release) orally twice daily) to placebo was designed using 2 sessions of 4 finger immersion in 5°C water, with 24 h of medication pretreatment before each session. Finger temperatures were measured via nailbed thermocouples. The primary outcome was mean finger temperature; secondary outcomes were mean apex and nadir temperatures, first apex and nadir temperatures, subjective pain ranking, and time of vasodilation onset (all presented as mean±SD). RESULTS: Twelve volunteers (age 29±3 [24-34] y) completed the study. No significant difference in finger temperature (9.2±1.1°C nifedipine vs 9.0±0.7°C placebo, P=0.38) or any secondary outcome was found. Pain levels were similar (2.8±1.6 nifedipine vs 3.0±1.5 placebo, P=0.32). The most common adverse event was headache (32% of nifedipine trials vs 8% placebo). CONCLUSIONS: Pretreatment with 30 mg of oral nifedipine twice daily does not affect the CIVD response in healthy individuals under cold stress.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Temperatura Baixa/efeitos adversos , Dedos/fisiologia , Nifedipino/farmacologia , Vasodilatação/fisiologia , Vasodilatadores/farmacologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Utah , Vasodilatação/efeitos dos fármacos , Adulto Jovem
15.
Handb Exp Pharmacol ; 261: 193-208, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32458136

RESUMO

Pharmacological treatment of arterial hypertension in children is mainly based on individual experience, but there is evidence that blocking the angiotensin system reduces systolic and diastolic blood when compared to placebo, and these drugs are safe to use for a short duration, also in children under 6 years of age. Blocking the angiotensin system either by angiotensin-converting enzyme inhibitors or by antagonizing the angiotensin 1 receptor is effective, but did not display a consistent dose-response relationship with escalating doses, but the effective doses are known. Calcium channel antagonists are effective antihypertensives in children, but the evidence is limited. Based on small-sized studies, beta-blockers modestly reduce systolic blood pressure, but have no significant effect on diastolic blood pressure compared to placebo. They act in combination to antagonize reflex tachycardia induced by vasodilators. The most commonly used antihypertensive agents are safe to use in short-term studies.


Assuntos
Hipertensão , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/fisiologia , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Criança , Humanos
16.
Toxicol Appl Pharmacol ; 401: 115072, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32470353

RESUMO

Ochratoxin A (OTA) is a dietary mycotoxin that can cause nephrotoxicity, hepatotoxicity, neurotoxicity and carcinogenicity. We found that in mice OTA is transported by the drug transporters mouse (m)ABCB1 and/or mABCG2, mOATP1A/1B, and human (h)OATP1B3. The complete deletion of mABCB1 and mABCG2 resulted in ~2-fold higher OTA liver and kidney accumulation upon intravenous injection. Upon oral administration, absence of mOATP1A/1B led to a substantial (>3-fold) decrease in hepatic and small intestinal exposure of OTA. Furthermore, in humanized mouse strains, hepatic expression of transgenic hOATP1B3, but not hOATP1B1, partly reversed the reduced liver concentration of OTA in mOATP1A/1B knockout mice. These data indicate that transgenic hOATP1B3 can significantly transport OTA into the liver, and can at least partly compensate for the loss of the mOATP1A/1B transporters. This study shows that some ABC and OATP transporters can substantially affect the pharmacokinetics of OTA, which might have implications for its toxicity behavior.


Assuntos
Bloqueadores dos Canais de Cálcio/metabolismo , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Fígado/metabolismo , Ocratoxinas/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Humanos , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Ocratoxinas/farmacologia
18.
Cardiovasc Eng Technol ; 11(3): 316-327, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32356274

RESUMO

PURPOSE: Fibrocalcific aortic valve disease (CAVD) is caused by the deposition of calcific nodules in the aortic valve leaflets, resulting in progressive loss of function that ultimately requires surgical intervention. This process is actively mediated by the resident valvular interstitial cells (VICs), which, in response to oxidized lipids, transition from a quiescent to an osteoblast-like state. The purpose of this study was to examine if the ryanodine receptor, an intracellular calcium channel, could be therapeutically targeted to prevent this phenotypic conversion. METHODS: The expression of the ryanodine receptor in porcine aortic VICs was characterized by qRT-PCR and immunofluorescence. Next, the VICs were exposed to lysophosphatidylcholine, an oxidized lipid commonly found in low-density lipoprotein, while the activity of the ryanodine receptor was modulated with ryanodine. The cultures were analyzed for markers of cellular mineralization, alkaline phosphatase activity, proliferation, and apoptosis. RESULTS: Porcine aortic VICs predominantly express isoform 3 of the ryanodine receptors, and this protein mediates the cellular response to LPC. Exposure to LPC caused elevated intracellular calcium concentration in VICs, raised levels of alkaline phosphatase activity, and increased calcific nodule formation, but these changes were reversed when the activity of the ryanodine receptor was blocked. CONCLUSIONS: Our findings suggest blocking the activity of the ryanodine receptor can attenuate the valvular mineralization caused by LPC. We conclude that oxidized lipids, such as LPC, play an important role in the development and progression of CAVD and that the ryanodine receptor is a promising target for pharmacological intervention.


Assuntos
Valva Aórtica/efeitos dos fármacos , Calcinose/induzido quimicamente , Agonistas dos Canais de Cálcio/toxicidade , Cálcio/metabolismo , Lisofosfatidilcolinas/toxicidade , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Apoptose/efeitos dos fármacos , Calcinose/metabolismo , Calcinose/patologia , Calcinose/prevenção & controle , Bloqueadores dos Canais de Cálcio/farmacologia , Sinalização do Cálcio , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Sus scrofa
19.
PLoS One ; 15(4): e0231711, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32298357

RESUMO

Actively growing tumors are often histologically associated with Ki67 positivity, while the detection of invasiveness relies on non-quantitative pathologic evaluation of mostly advanced tumors. We recently reported that reduced expression of the Ca2+-dependent membrane-binding annexin A6 (AnxA6) is associated with increased expression of the Ca2+ activated RasGRF2 (GRF2), and that the expression status of these proteins inversely influence the growth and motility of triple negative breast cancer (TNBC) cells. Here, we establish that the reciprocal expression of AnxA6 and GRF2 is at least in part, dependent on inhibition of non-selective Ca2+ channels in AnxA6-low but not AnxA6-high TNBC cells. Immunohistochemical staining of breast cancer tissues revealed that compared to non-TNBC tumors, TNBC tumors express lower levels of AnxA6 and higher Ki67 expression. GRF2 expression levels strongly correlated with high Ki67 in pretreatment biopsies from patients with residual disease and with residual tumor size following chemotherapy. Elevated AnxA6 expression more reliably identified patients who responded to chemotherapy, while low AnxA6 levels were significantly associated with shorter distant relapse-free survival. Finally, the reciprocal expression of AnxA6 and GRF2 can delineate GRF2-low/AnxA6-high invasive from GRF2-high/AnxA6-low rapidly growing TNBCs. These data suggest that AnxA6 may be a reliable biomarker for distant relapse-free survival and response of TNBC patients to chemotherapy, and that the reciprocal expression of AnxA6 and GRF2 can reliably delineate TNBCs into rapidly growing and invasive subsets which may be more relevant for subset-specific therapeutic interventions.


Assuntos
Anexina A6/metabolismo , Canais de Cálcio/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Fatores ras de Troca de Nucleotídeo Guanina/metabolismo , Animais , Anexina A6/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Humanos , Antígeno Ki-67/metabolismo , Camundongos , Metástase Neoplásica/genética , Prognóstico , Transplante Heterólogo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidade , Fatores ras de Troca de Nucleotídeo Guanina/genética
20.
Biochim Biophys Acta Rev Cancer ; 1873(2): 188364, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32275934

RESUMO

Hyperactivation of the Mitogen Activated Protein Kinase (MAPK) pathway is prevalent in melanoma, principally due to mutations in the BRAF and NRAS genes. MAPK inhibitors are effective only short-term, and recurrence occurs due to functional redundancies or intertwined pathways. The remodeling of Ca2+ signaling is also common in melanoma cells, partly through the increased expression of T-type channels (TTCCs). Here we summarize current knowledge about the prognostic value and molecular targeting of TTCCs. Furthermore, we discuss recent evidence pointing to TTCCs as molecular switches for melanoma chemoresistance, which set the grounds for novel combined therapies against the advanced disease.


Assuntos
Antineoplásicos/uso terapêutico , Canais de Cálcio Tipo T/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Antineoplásicos/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Linhagem Celular Tumoral , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , GTP Fosfo-Hidrolases/antagonistas & inibidores , GTP Fosfo-Hidrolases/genética , Humanos , Estimativa de Kaplan-Meier , Sistema de Sinalização das MAP Quinases/genética , Melanoma/genética , Melanoma/mortalidade , Melanoma/patologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Mutação , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA