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1.
N Engl J Med ; 382(17): 1608-1618, 2020 04 23.
Artículo en Inglés | MEDLINE | ID: mdl-32227756

RESUMEN

BACKGROUND: Clinical trials that have assessed the effect of revascularization in patients with stable coronary disease have routinely excluded those with advanced chronic kidney disease. METHODS: We randomly assigned 777 patients with advanced kidney disease and moderate or severe ischemia on stress testing to be treated with an initial invasive strategy consisting of coronary angiography and revascularization (if appropriate) added to medical therapy or an initial conservative strategy consisting of medical therapy alone and angiography reserved for those in whom medical therapy had failed. The primary outcome was a composite of death or nonfatal myocardial infarction. A key secondary outcome was a composite of death, nonfatal myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. RESULTS: At a median follow-up of 2.2 years, a primary outcome event had occurred in 123 patients in the invasive-strategy group and in 129 patients in the conservative-strategy group (estimated 3-year event rate, 36.4% vs. 36.7%; adjusted hazard ratio, 1.01; 95% confidence interval [CI], 0.79 to 1.29; P = 0.95). Results for the key secondary outcome were similar (38.5% vs. 39.7%; hazard ratio, 1.01; 95% CI, 0.79 to 1.29). The invasive strategy was associated with a higher incidence of stroke than the conservative strategy (hazard ratio, 3.76; 95% CI, 1.52 to 9.32; P = 0.004) and with a higher incidence of death or initiation of dialysis (hazard ratio, 1.48; 95% CI, 1.04 to 2.11; P = 0.03). CONCLUSIONS: Among patients with stable coronary disease, advanced chronic kidney disease, and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of death or nonfatal myocardial infarction. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA-CKD ClinicalTrials.gov number, NCT01985360.).


Asunto(s)
Angiografía Coronaria , Puente de Arteria Coronaria , Isquemia Miocárdica/tratamiento farmacológico , Isquemia Miocárdica/cirugía , Intervención Coronaria Percutánea , Insuficiencia Renal Crónica/complicaciones , Antagonistas Adrenérgicos beta/uso terapéutico , Anciano , Bloqueadores de los Canales de Calcio/uso terapéutico , Prueba de Esfuerzo , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/prevención & control , Isquemia Miocárdica/complicaciones , Isquemia Miocárdica/mortalidad , Factores de Riesgo
2.
Med Sci Monit ; 26: e923696, 2020 Apr 14.
Artículo en Inglés | MEDLINE | ID: mdl-32285846

RESUMEN

BACKGROUND This study evaluated the impact of clinical features and concomitant conditions on the clinical selection of different renin-angiotensin system (RAS) inhibitors in patients with hypertension, and built a renin-angiotensin inhibitors selection model (RAISM) to provide a reference for clinical decision making. MATERIAL AND METHODS We included 213 hypertensive patients in the study cohort; patients were divided into two groups: the angiotensin-converting enzyme inhibitor (ACEI) combined with calcium channel blocker (CCB) group (ACEI+CCB group) and the angiotensin receptor antagonist (ARB) combined with CCB group (ARB+CCB group). Basic demographic characteristics and concomitant conditions of the patients were compared. Single-factor and multi-factor analysis was performed by adopting logistic regression model. The RAISM was established by utilizing the nomograph technology. C-index and calibration curve were used to evaluate the model's efficacy. RESULTS In the study, 34.27% of the patients used ACEI+CCB and 65.73% of patients used ARB+CCB. The difference in age, body mass index (BMI), elderly patient, diabetes, renal dysfunction, and hyperlipidemia between the 2 groups determined medication selection. To be specific, compared to the group using ARB+CCB, the odds ratios and 95% confidence interval (CI) of the aforementioned factors for the ACEI+CCB group were 0.476 (0.319-0.711), 1.274 (1.001-1.622), 0.365 (0.180-0.743), 0.471 (0.203-1.092), 0.542 (0.268-1.094), and 0.270 (0.100-0.728), respectively; The C-index of RAISM acquired from the model construction parameters was 0.699, and the correction curve demonstrated that the model has good discriminative ability. CONCLUSIONS The outcome of our study suggests that independent discriminating factors that influence the clinical selection of different RAS inhibitors were elderly patient, renal insufficiency, and hyperlipidemia; and the RAISM constructed in this study has good predictability and clinical benefit.


Asunto(s)
Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Hipertensión/tratamiento farmacológico , Adulto , Anciano , Toma de Decisiones Clínicas , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Teóricos , Sistema Renina-Angiotensina
3.
Internist (Berl) ; 61(3): 270-276, 2020 Mar.
Artículo en Alemán | MEDLINE | ID: mdl-32030435

RESUMEN

BACKGROUND: The treatment of polyneuropathy includes symptomatic therapy of sensory, motor and autonomic dysfunctions. AIM: This article provides an overview of the current treatment recommendations for polyneuropathy, focusing on pain. METHODS: Current treatment guidelines will be discussed based on a literature research. RESULTS: Calcium-channel anticonvulsants gabapentin/pregabalin as well as antidepressants duloxetine and amitriptyline are recommended as first line therapeutics. Alternatively, topical therapeutics can be used in the case of localized disorders. In individual cases, opioids or other antidepressants/anticonvulsants may be effective. Pharmacological treatment is often limited due to adverse events, which affect the central nervous system in particular. DISCUSSION: In general, treatment for polyneuropathy should follow a multimodal concept and include the treatment of other symptoms. When choosing pain medication, comorbidities, patient's age and adverse events need to be taken into consideration. Phenotype-based stratification may support specialized pain therapy and achieve the best medical treatment.


Asunto(s)
Anticonvulsivantes/uso terapéutico , Antidepresivos/uso terapéutico , Neuralgia/tratamiento farmacológico , Polineuropatías/tratamiento farmacológico , Amitriptilina/uso terapéutico , Analgésicos/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Humanos , Pregabalina/uso terapéutico
4.
Mol Pharmacol ; 97(4): 250-258, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32015008

RESUMEN

Phenytoin is a hydantoin derivative that is used clinically for the treatment of epilepsy and has been reported to have antiarrhythmic actions on the heart. In a failing heart, the elevated diastolic Ca2+ leak from the sarcoplasmic reticulum can be normalized by the cardiac ryanodine receptor 2 (RyR2) inhibitor, dantrolene, without inhibiting Ca2+ release during systole or affecting Ca2+ release in normal healthy hearts. Unfortunately, dantrolene is hepatotoxic and unsuitable for chronic long-term administration. Because phenytoin and dantrolene belong to the hydantoin class of compounds, we test the hypothesis that dantrolene and phenytoin have similar inhibitory effects on RyR2 using a single-channel recording of RyR2 activity in artificial lipid bilayers. Phenytoin produced a reversible inhibition of RyR2 channels from sheep and human failing hearts. It followed a hyperbolic dose response with maximal inhibition of ∼50%, Hill coefficient ∼1, and IC50 ranging from 10 to 20 µM. It caused inhibition at diastolic cytoplasmic [Ca2+] but not at Ca2+ levels in the dyadic cleft during systole. Notably, phenytoin inhibits RyR2 from failing human heart but not from healthy heart, indicating that phenytoin may selectively target defective RyR2 channels in humans. We conclude that phenytoin could effectively inhibit RyR2-mediated release of Ca2+ in a manner paralleling that of dantrolene. Moreover, the IC50 of phenytoin in RyR2 is at least threefold lower than for other ion channels and clinically used serum levels, pointing to phenytoin as a more human-safe alternative to dantrolene for therapies against heart failure and cardiac arrythmias. SIGNIFICANCE STATEMENT: We show that phenytoin, a Na channel blocker used clinically for treatment of epilepsy, is a diastolic inhibitor of cardiac calcium release channels [cardiac ryanodine receptor 2 (RyR2)] at doses threefold lower than its current therapeutic levels. Phenytoin inhibits RyR2 from failing human heart and not from healthy heart, indicating that phenytoin may selectively target defective RyR2 channels in humans and pointing to phenytoin as a more human-safe alternative to dantrolene for therapies against heart failure and cardiac arrhythmias.


Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Cardiotónicos/farmacología , Insuficiencia Cardíaca/prevención & control , Miocitos Cardíacos/efectos de los fármacos , Fenitoína/farmacología , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Potenciales de Acción/efectos de los fármacos , Animales , Arritmias Cardíacas/tratamiento farmacológico , Arritmias Cardíacas/patología , Calcio/metabolismo , Bloqueadores de los Canales de Calcio/uso terapéutico , Cardiotónicos/uso terapéutico , Dantroleno/farmacología , Dantroleno/uso terapéutico , Relación Dosis-Respuesta a Droga , Vesículas Extracelulares , Insuficiencia Cardíaca/patología , Humanos , Membrana Dobles de Lípidos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Fenitoína/uso terapéutico , Retículo Sarcoplasmático/efectos de los fármacos , Retículo Sarcoplasmático/metabolismo , Ovinos
6.
High Blood Press Cardiovasc Prev ; 27(1): 43-49, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31916208

RESUMEN

INTRODUCTION: Albuminuria is an early marker of kidney disease and reduction of albuminuria translates into a decreased occurrence of cardiovascular and renal outcomes. AIMS: To evaluate the changes in the prevalence of albuminuria in diabetic hypertensive patients treated with several combinations of renin-angiotensin aldosterone system with calcium channel blockers. METHODS: We analysed data from 668 unselected patients from the PAIT survey (mean age 60.4 ± 10.2 years, prevalence of males 38%), with and without albuminuria, maintained for 6 months with the previous treatment with amlodipine-valsartan, amlodipine perindopril, lercanidipine-enalapril, verapamil-trandolapril, nitrendipine-enalapril and felodipine-ramipril Albuminuria was assessed, as urinary albumin-creatinine ratio, using a Multistic-Clinitek device analyzer. Microalbuminuria was defined as a loss of 3.4-33.9 mg albumin/mmol creatinine (30-300 mg/g) and macroalbuminuria as a loss of > 33.9 mg albumin/mmol creatinine (> 300 mg/g). Blood pressure was measured with a validated digital device. RESULTS: At baseline, albuminuria was present in 310 subjects (46.4%) (microalbuminuria in 263 (84.8%), macroalbuminuria in 15.2%), and normoalbuminuria in 53.6% 358. After 6 months, the prevalence of subjects with albuminuria was significantly lowered (p < 0.01) by 23.5% (microalbuminuria - 23.9%, p < 0.01 and macroalbuminuria - 21.3%). The prevalence of subjects with microalbuminuria was reduced with all treatments: amlodipine-valsartan - 15.6%, amlodipine-perindopril - 11.8%, lercanidipine-enalapril - 41.3% and verapamil-trandolapril - 19.2%. Data with nitrendipine-enalapril and felodipine-ramipril were not analyzed, due to the low number of patients. The frequency of patients with normoalbuminuria was significantly higher (p < 0.01) with lercanidipine-enalapril compared with any other treatment. Blood pressure was significantly (p < 0.01) reduced, with a similar effect between treatments. CONCLUSIONS: The treatments decrease the prevalence of subjects with albuminuria, showing a significant difference among the different drug combinations, favoring the use of new dihydropyridine calcium channel blockers, such as lercanidipine, combined with RAAS inhibitors, to control albuminuria in diabetic hypertensive patients.


Asunto(s)
Albuminuria/prevención & control , Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Diabetes Mellitus/epidemiología , Nefropatías Diabéticas/epidemiología , Hipertensión/tratamiento farmacológico , Insuficiencia Renal Crónica/epidemiología , Anciano , Albuminuria/diagnóstico , Albuminuria/epidemiología , Albuminuria/fisiopatología , Presión Sanguínea/efectos de los fármacos , Estudios Transversales , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/fisiopatología , Nefropatías Diabéticas/diagnóstico , Nefropatías Diabéticas/fisiopatología , Quimioterapia Combinada , Europa (Continente)/epidemiología , Femenino , Encuestas de Atención de la Salud , Humanos , Hipertensión/diagnóstico , Hipertensión/epidemiología , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Prevalencia , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/fisiopatología , Sistema Renina-Angiotensina/efectos de los fármacos , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento
7.
Curr Cardiol Rep ; 22(3): 12, 2020 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-31997014

RESUMEN

PURPOSE OF REVIEW: To examine the current clinical evidence behind the use of calcium channel blockers (CCB) and beta-blockers (BB) for the treatment of patients with stable coronary artery disease (SCAD) and their effect on mortality. RECENT FINDINGS: Current evidence suggests that BB use as a first line antianginal medication is associated with lower 5-year all-cause mortality only in patients who had MI within a year. This could be driven due to their effects reducing the sympathetic neuro-hormonal activation of more acutely ill patients. The use of CCB as an antianginal therapy, although proven effective in multiple trials both as monotherapy and combined with other agents, has not shown mortality benefit. Both BB and CCB are effective antianginals, and the selection among them depends on the patient clinical presentation and comorbidities. BB are the only ones that have shown survival benefit in SCAD, particularly the first year post-MI.


Asunto(s)
Antagonistas Adrenérgicos beta/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Fármacos Cardiovasculares/uso terapéutico , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/mortalidad , Humanos , Infarto del Miocardio
8.
Proc Natl Acad Sci U S A ; 117(1): 448-453, 2020 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-31871187

RESUMEN

Voltage-gated calcium 3.1 (CaV3.1) channels are absent in healthy mouse ß cells and mediate minor T-type Ca2+ currents in healthy rat and human ß cells but become evident under diabetic conditions. Whether more active CaV3.1 channels affect insulin secretion and glucose homeostasis remains enigmatic. We addressed this question by enhancing de novo expression of ß cell CaV3.1 channels and exploring the consequent impacts on dynamic insulin secretion and glucose homeostasis as well as underlying molecular mechanisms with a series of in vitro and in vivo approaches. We now demonstrate that a recombinant adenovirus encoding enhanced green fluorescent protein-CaV3.1 subunit (Ad-EGFP-CaV3.1) efficiently transduced rat and human islets as well as dispersed islet cells. The resulting CaV3.1 channels conducted typical T-type Ca2+ currents, leading to an enhanced basal cytosolic-free Ca2+ concentration ([Ca2+]i). Ad-EGFP-CaV3.1-transduced islets released significantly less insulin under both the basal and first phases following glucose stimulation and could no longer normalize hyperglycemia in recipient rats rendered diabetic by streptozotocin treatment. Furthermore, Ad-EGFP-CaV3.1 transduction reduced phosphorylated FoxO1 in the cytoplasm of INS-1E cells, elevated FoxO1 nuclear retention, and decreased syntaxin 1A, SNAP-25, and synaptotagmin III. These effects were prevented by inhibiting CaV3.1 channels or the Ca2+-dependent phosphatase calcineurin. Enhanced expression of ß cell CaV3.1 channels therefore impairs insulin release and glucose homeostasis by means of initial excessive Ca2+ influx, subsequent activation of calcineurin, consequent dephosphorylation and nuclear retention of FoxO1, and eventual FoxO1-mediated down-regulation of ß cell exocytotic proteins. The present work thus suggests an elevated expression of CaV3.1 channels plays a significant role in diabetes pathogenesis.


Asunto(s)
Canales de Calcio Tipo T/metabolismo , Diabetes Mellitus Experimental/metabolismo , Secreción de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Adolescente , Adulto , Animales , Células COS , Bloqueadores de los Canales de Calcio/farmacología , Bloqueadores de los Canales de Calcio/uso terapéutico , Canales de Calcio Tipo T/genética , Núcleo Celular/metabolismo , Chlorocebus aethiops , Citosol/metabolismo , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/tratamiento farmacológico , Exocitosis/efectos de los fármacos , Estudios de Factibilidad , Femenino , Proteínas Fluorescentes Verdes/genética , Células HEK293 , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/trasplante , Masculino , Persona de Mediana Edad , Fosforilación , Cultivo Primario de Células , Ratas , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Estreptozocina/toxicidad , Proteínas de Transporte Vesicular/metabolismo , Adulto Joven
9.
Urologiia ; (5): 48-52, 2019 Dec.
Artículo en Ruso | MEDLINE | ID: mdl-31808632

RESUMEN

OBJECTIVE: to evaluate the nephroprotective effect of lercanidipine, its effect on the dynamics of creatinine clearance and blood cytokine levels in patients with nephrolithiasis with obstructive uropathy during renal drainage. MATERIAL AND METHODS: 66 patients were included in the study with concretions of the pelvic segment and the presence of obstruction according to instrumental methods of examination. In order to prevent the occurrence of infectious complications before lithotripsy patients the first stage was performed installation of nephrostomic drainage, followed by antibacterial, anti-inflammatory therapy. Patients were divided into 2 groups: the first (33 patients) received standard therapy, the second (33 people) additionally received lercanidipine at a dose of 10 mg per day for 1 month. Determined the concentration of IL-8, VEGF, MCP-1, G-CSF and GM-CSF in the blood serum by the method of solid-phase ELISA. The glomerular filtration rate was calculated using the CKD-EPI formula. All studies were performed at the preoperative stage, on 7, 14, 21 and 28 days after renal drainage. RESULTS: In the appointment of lercanidipine, there was a more rapid decrease in levels of IL-8, VEGF, MS-1, GM-CSF in serum (21 days), and an improvement in renal function, compared with the group that did not receive nephroprotective therapy. CONCLUSION: The administration of lercanidipine may contribute to a more rapid recovery of renal function and normalization of blood cytokine levels. This drug can be used in the complex treatment of patients with nephrolithiasis with obstructive uropathy.


Asunto(s)
Bloqueadores de los Canales de Calcio/uso terapéutico , Citocinas/sangre , Dihidropiridinas/uso terapéutico , Riñón/efectos de los fármacos , Nefrolitiasis/cirugía , Fármacos Neuroprotectores/uso terapéutico , Urolitiasis/cirugía , Antibacterianos/uso terapéutico , Antiinflamatorios/uso terapéutico , Bloqueadores de los Canales de Calcio/administración & dosificación , Dihidropiridinas/administración & dosificación , Tasa de Filtración Glomerular , Humanos , Fármacos Neuroprotectores/administración & dosificación , Resultado del Tratamiento
10.
Handb Exp Pharmacol ; 260: 161-186, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31820179

RESUMEN

A large series of different ion channels have been identified and investigated as potential targets for new medicines for the treatment of a variety of human diseases, including pain. Among these channels, the voltage gated calcium channels (VGCC) are inhibited by drugs for the treatment of migraine, neuropathic pain or intractable pain. Transient receptor potential (TRP) channels are emerging as important pain transducers as they sense low pH media or oxidative stress and other mediators and are abundantly found at sites of inflammation or tissue injury. Low pH may also activate acid sensing ion channels (ASIC) and mechanical forces stimulate the PIEZO channels. While potent agonists of TRP channels due to their desensitizing action on pain transmission are used as topical applications, the potential of TRP antagonists as pain therapeutics remains an exciting field of investigation. The study of ASIC or PIEZO channels in pain signaling is in an early stage, whereas antagonism of the purinergic P2X3 channels has been reported to provide beneficial effects in chronic intractable cough. The present chapter covers these intriguing channels in great detail, highlighting their diverse mechanisms and broad potential for therapeutic utility.


Asunto(s)
Bloqueadores del Canal Iónico Sensible al Ácido/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Neuralgia/tratamiento farmacológico , Manejo del Dolor , Canales Receptores Transitorios de Potencial/antagonistas & inhibidores , Canales Iónicos Sensibles al Ácido , Canales de Calcio , Humanos , Inflamación
11.
Lancet ; 394(10211): 1816-1826, 2019 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-31668726

RESUMEN

BACKGROUND: Uncertainty remains about the optimal monotherapy for hypertension, with current guidelines recommending any primary agent among the first-line drug classes thiazide or thiazide-like diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, dihydropyridine calcium channel blockers, and non-dihydropyridine calcium channel blockers, in the absence of comorbid indications. Randomised trials have not further refined this choice. METHODS: We developed a comprehensive framework for real-world evidence that enables comparative effectiveness and safety evaluation across many drugs and outcomes from observational data encompassing millions of patients, while minimising inherent bias. Using this framework, we did a systematic, large-scale study under a new-user cohort design to estimate the relative risks of three primary (acute myocardial infarction, hospitalisation for heart failure, and stroke) and six secondary effectiveness and 46 safety outcomes comparing all first-line classes across a global network of six administrative claims and three electronic health record databases. The framework addressed residual confounding, publication bias, and p-hacking using large-scale propensity adjustment, a large set of control outcomes, and full disclosure of hypotheses tested. FINDINGS: Using 4·9 million patients, we generated 22 000 calibrated, propensity-score-adjusted hazard ratios (HRs) comparing all classes and outcomes across databases. Most estimates revealed no effectiveness differences between classes; however, thiazide or thiazide-like diuretics showed better primary effectiveness than angiotensin-converting enzyme inhibitors: acute myocardial infarction (HR 0·84, 95% CI 0·75-0·95), hospitalisation for heart failure (0·83, 0·74-0·95), and stroke (0·83, 0·74-0·95) risk while on initial treatment. Safety profiles also favoured thiazide or thiazide-like diuretics over angiotensin-converting enzyme inhibitors. The non-dihydropyridine calcium channel blockers were significantly inferior to the other four classes. INTERPRETATION: This comprehensive framework introduces a new way of doing observational health-care science at scale. The approach supports equivalence between drug classes for initiating monotherapy for hypertension-in keeping with current guidelines, with the exception of thiazide or thiazide-like diuretics superiority to angiotensin-converting enzyme inhibitors and the inferiority of non-dihydropyridine calcium channel blockers. FUNDING: US National Science Foundation, US National Institutes of Health, Janssen Research & Development, IQVIA, South Korean Ministry of Health & Welfare, Australian National Health and Medical Research Council.


Asunto(s)
Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Adolescente , Adulto , Anciano , Antagonistas de Receptores de Angiotensina/efectos adversos , Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/efectos adversos , Bloqueadores de los Canales de Calcio/efectos adversos , Bloqueadores de los Canales de Calcio/uso terapéutico , Niño , Estudios de Cohortes , Investigación sobre la Eficacia Comparativa/métodos , Bases de Datos Factuales , Diuréticos/efectos adversos , Diuréticos/uso terapéutico , Medicina Basada en la Evidencia/métodos , Femenino , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/prevención & control , Humanos , Hipertensión/complicaciones , Masculino , Persona de Mediana Edad , Infarto del Miocardio/etiología , Infarto del Miocardio/prevención & control , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & control , Adulto Joven
13.
Rev Cardiovasc Med ; 20(3): 139-151, 2019 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-31601088

RESUMEN

Effective therapy of hypertension represents a key strategy for reducing the burden of cardiovascular disease and its associated mortality. The significance of voltage dependent L-type Ca²âº channels to Ca²âº influx, and of their regulatory mechanisms in the development of heart disease, is well established. A wide variety of L-type Ca²âº channel inhibitors and Ca²âº antagonists have been found to be beneficial not only in the treatment of hypertension, but also in myocardial infarction and heart failure. Over the past two decades, another class of Ca²âº channel - the voltage independent store-operated Ca²âº channel - has been implicated in the regulation and fine tuning of Ca²âº entry in both cardiac and smooth muscle cells. Store-operated Ca²âº channels are activated by the depletion of Ca²âº stores within the endoplasmic/sarcoplasmic reticulum, or by low levels of cytosolic Ca²âº, thereby facilitating agonist-induced Ca²âº influx. Store-operated Ca²âº entry through this pivotal pathway involves both stromal interaction molecule (STIM) and Orai channels. Different degrees of changes in these proteins are considered to promote Ca²âº entry and hence contribute to the pathogenesis of cardiovascular dysfunction. Several blockers of store-operated Ca²âº channels acting at the level of both STIM and Orai channels have been shown to depress Ca²âº influx and lower blood pressure. However, their specificity, safety, and clinical significance remain to be established. Thus, there is an ongoing challenge in the development of selective inhibitors of store-operated Ca²âº channels that act in vascular smooth muscles for the improved treatment of hypertension.


Asunto(s)
Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/uso terapéutico , Canales de Calcio Activados por la Liberación de Calcio/antagonistas & inhibidores , Hipertensión/tratamiento farmacológico , Músculo Liso Vascular/efectos de los fármacos , Moléculas de Interacción Estromal/antagonistas & inhibidores , Vasodilatadores/uso terapéutico , Animales , Antihipertensivos/efectos adversos , Bloqueadores de los Canales de Calcio/efectos adversos , Canales de Calcio Tipo L/efectos de los fármacos , Canales de Calcio Tipo L/metabolismo , Canales de Calcio Activados por la Liberación de Calcio/metabolismo , Señalización del Calcio/efectos de los fármacos , Humanos , Hipertensión/metabolismo , Hipertensión/fisiopatología , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Moléculas de Interacción Estromal/metabolismo , Resultado del Tratamiento , Vasodilatadores/efectos adversos
14.
Undersea Hyperb Med ; 46(4): 483-494, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31509904

RESUMEN

The aim of this study was to establish the effect of combined therapy with hyperbaric oxygen (HBO2) therapy and verapamil, amlodipine or nicorandil on functional recovery and oxidative stress markers after ischemia in the isolated rat heart. The study included 48 rats (Wistar albino, male gender, eight weeks old, body weight 200±50g). All animals were exposed to HBO2 treatment over 14 days. Isolated heart rats were perfused by the Langendorff retrograde method at a constant coronary pressure of 70 cm H2O. After stabilization period the hearts were divided into the following groups: HBO2 group (animals exposed to only HBO2 preconditioning); HBO2 + verapamil; HBO2 + amlodipine; andHBO2 + nicorandil (animals pretreated with HBO2 and appropriate pharmacological agent). Afterward, the hearts in all groups were subjected to 20-minute global ischemia and 30-minute reperfusion. Parameters of heart function were registered, including maximum and minimum rate of pressure development, systolic and diastolic left ventricular pressure, heart rate and coronary flow. Levels of pro-oxidants such as index of lipid peroxidation, measured as thiobarbituric acid-reactive substances, nitrites, levels of superoxide anion radicals and hydrogen peroxide were determined in coronary venous effluent. Changes in cardiac tissue were evaluated by hematoxylin and eosin staining. Obtained results clearly indicate that blockage of calcium channel or the activation of adenosine triphosphate-sensitive potassium (KATP) in combination with HBO2 prevented ischemia/reperfusion-induced cardiac deleterious effects, thus contributing to improvement of functional recovery of the heart. However, future studies are certainly necessary for better understanding the mechanisms through which combination of these two maneuvers of preconditioning triggers cardioprotection.


Asunto(s)
Bloqueadores de los Canales de Calcio/uso terapéutico , Oxigenación Hiperbárica , Precondicionamiento Isquémico Miocárdico/métodos , Isquemia Miocárdica/terapia , Daño por Reperfusión Miocárdica/prevención & control , Bloqueadores de los Canales de Potasio/uso terapéutico , Amlodipino/uso terapéutico , Animales , Presión Sanguínea/efectos de los fármacos , Terapia Combinada/métodos , Circulación Coronaria , Corazón , Frecuencia Cardíaca/efectos de los fármacos , Precondicionamiento Isquémico Miocárdico/efectos adversos , Peroxidación de Lípido , Masculino , Miocardio/patología , Nicorandil/uso terapéutico , Estrés Oxidativo , Ratas , Ratas Wistar , Recuperación de la Función , Verapamilo/uso terapéutico
15.
Int J Mol Sci ; 20(18)2019 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-31540416

RESUMEN

We investigated whether magnesium sulfate (MgSO4) mitigated pulmonary hypertension progression in rats. Pulmonary hypertension was induced by a single intraperitoneal injection of monocrotaline (60 mg/kg). MgSO4 (100 mg/kg) was intraperitoneally administered daily for 3 weeks, from the seventh day after monocrotaline injection. Adult male rats were randomized into monocrotaline (MCT) or monocrotaline plus MgSO4 (MM) groups (n = 15 per group); control groups were maintained simultaneously. For analysis, surviving rats were euthanized on the 28th day after receiving monocrotaline. The survival rate was higher in the MM group than in the MCT group (100% versus 73.3%, p = 0.043). Levels of pulmonary artery wall thickening, α-smooth muscle actin upregulation, right ventricular systolic pressure increase, and right ventricular hypertrophy were lower in the MM group than in the MCT group (all p < 0.05). Levels of lipid peroxidation, mitochondrial injury, inflammasomes and cytokine upregulation, and apoptosis in the lungs and right ventricle were lower in the MM group than in the MCT group (all p < 0.05). Notably, the mitigation effects of MgSO4 on pulmonary artery wall thickening and right ventricular hypertrophy were counteracted by exogenous calcium chloride. In conclusion, MgSO4 mitigates pulmonary hypertension progression, possibly by antagonizing calcium.


Asunto(s)
Bloqueadores de los Canales de Calcio/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológico , Sulfato de Magnesio/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Progresión de la Enfermedad , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/patología , Masculino , Monocrotalina , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/patología , Ratas , Ratas Sprague-Dawley
16.
Drug Des Devel Ther ; 13: 2427-2436, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31413542

RESUMEN

Background: Mortality rates increase due to iron deposition in the cardiac muscles of thalassemia major (TM) patients. Iron overload cardiomyopathy could be treated with a combination therapy of an iron chelator and an L-type calcium channel blocker. We designed a randomized controlled study to assess the potential of amlodipine, alongside chelation, in reducing myocardial iron concentration in TM patients compared with a placebo. Objectives: This study aims to estimate the change in myocardial iron concentration (MIC) determined by magnetic resonance imaging after 6 months of treatment with amlodipine, as well as measuring the changes in the secondary outcomes (liver iron concentration (LIC), serum ferritin level (SF), and left ventricle ejection fraction (LVEF)) of study participants. Methods: A single, randomized, placebo-controlled trial was performed in 40 ß-Thalassemia major patients aged between 6 and 20 years old, who received either oral amlodipine 2.5-5 mg/day or a placebo, in addition to a Deferasirox chelation regimen in a 1:1 allocation ratio. Results: After 6 months, a significant reduction was noted in the MIC of patients receiving amlodipine (n=20), compared with the patients receiving the placebo (n=20). At baseline, the mean was 0.76±0.11 mg/g dry weight, while at 6 months, the mean was 0.51±0.07 mg/g dry weight (p<0.001). Also, there was a significant change in the myocardial T2* after 6 months; the amlodipine increased the myocardial T2* from 40.63±5.45 ms at baseline to 43.25±5.35 ms (p<0.001). However, amlodipine did not significantly affect the secondary outcomes by the end of the study. Conclusion: The addition of amlodipine to the standard chelation therapy in transfusion-dependent thalassemia major patients improves myocardial iron overload without increasing the adverse effects.


Asunto(s)
Amlodipino/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Quelantes del Hierro/uso terapéutico , Sobrecarga de Hierro/tratamiento farmacológico , Talasemia beta/tratamiento farmacológico , Adolescente , Adulto , Amlodipino/administración & dosificación , Bloqueadores de los Canales de Calcio/administración & dosificación , Niño , Femenino , Humanos , Hierro/análisis , Quelantes del Hierro/administración & dosificación , Imagen por Resonancia Magnética , Masculino , Estudios Prospectivos , Adulto Joven
17.
Int J Clin Pharmacol Ther ; 57(10): 483-488, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31426904

RESUMEN

AIM: The aim of this study was to investigate the potential association between antihypertensive therapy and the incidence of Parkinson's disease (PD) in patients followed in general practices in Germany. MATERIALS AND METHODS: This study included patients aged ≥ 40 who had received initial diagnoses of PD in 1,203 general practices in Germany between January 2013 and December 2017 (index date). After applying similar inclusion criteria, PD cases were matched to non-PD controls using propensity scores based on age, sex, and treating physician. The primary outcome of the study was the incidence of PD as a function of the use of antihypertensive drugs (diuretics, ß-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers). Logistic regression models were conducted to study the association between the use of antihypertensive drugs and the incidence of PD after adjusting for codiagnoses and antihypertensive cotherapy. RESULTS: The present study included 9,127 patients with PD and 9,127 patients without PD (mean age: 75.8 years; 48.4% women). The at-least-once use of diuretics (44.8% versus 38.4%; odds ratio (OR) = 1.23 (1.15-1.32)) was associated with an increased incidence of PD. However, this effect was not maintained for a therapy duration of at least 3 years, and no association was observed between the diuretic therapy duration and PD incidence. For all other antihypertensive drug classes, we found no significant associations with PD incidence. CONCLUSION: No association was found between antihypertensive therapy duration and PD incidence. Further epidemiological studies are needed to compare the effects of subclasses of antihypertensives on PD.


Asunto(s)
Antihipertensivos/efectos adversos , Hipertensión/tratamiento farmacológico , Enfermedad de Parkinson/complicaciones , Antagonistas Adrenérgicos beta/efectos adversos , Antagonistas Adrenérgicos beta/uso terapéutico , Anciano , Antagonistas de Receptores de Angiotensina/efectos adversos , Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/uso terapéutico , Bloqueadores de los Canales de Calcio/efectos adversos , Bloqueadores de los Canales de Calcio/uso terapéutico , Diuréticos/efectos adversos , Diuréticos/uso terapéutico , Femenino , Medicina General , Alemania , Humanos , Hipertensión/complicaciones , Incidencia , Masculino
18.
High Blood Press Cardiovasc Prev ; 26(5): 399-404, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31463886

RESUMEN

INTRODUCTION: Polytherapy is often required to treat the comorbidity of hypertension and hyperlipidemia. Fixed-dose co-formulation, rather than free combinations, simplifies medication taking and also improves adherence to medication, which is the key for a successful management of these conditions. AIM: To determine the number of patients potentially eligible for treatment with triple fixed-dose atorvastatin/perindopril/amlodipine (CTAPA), and to estimate if an unmet medical need exists among CTAPA free combination treated patients. METHODS: This observational retrospective study was based on administrative databases of 3 Italian Local Health Units. The cohort comprised adult patients with at least one prescription of amlodipine and perindopril (either as free combination or co-formulated) and atorvastatin during 2014. Follow-up period started on the date of prescription of the 3 molecules (index date) and lasted 1 year. Adherence to CTAPA was analyzed during follow-up, by using the proportion of days covered (PDC). RESULTS: 2292 patients (9.1 per 10,000 beneficiaries) had a prescription for CTAPA as free combination. Only 1249 (54.5%) were adherent to the therapy (PDC ≥ 80%); among them, a small percentage required dosage modification. The number of patients with CTAPA increased during the study period. Discontinuation of drugs prescribed the year before interested 582 patients in 2014, and 522 in 2015. Considering the Italian national population (n = 60,782,668), it was estimated that 69,542 hypertensive patients could be eligible for fixed-dose CTAPA during 2014. CONCLUSIONS: Real-world analysis among patients with free combination therapy can be applied to estimate the eligible population for fixed combination, and to evaluate the appropriateness of their prescriptions. Moreover, fixed-dose CTAPA could effectively improve adherence, which was calculated to be low in the free combination cohort.


Asunto(s)
Amlodipino/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/uso terapéutico , Atorvastatina/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/uso terapéutico , Dislipidemias/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipertensión/tratamiento farmacológico , Perindopril/uso terapéutico , Anciano , Biomarcadores/sangre , Bases de Datos Factuales , Quimioterapia Combinada , Dislipidemias/sangre , Dislipidemias/diagnóstico , Femenino , Humanos , Hipertensión/diagnóstico , Hipertensión/fisiopatología , Italia , Lípidos/sangre , Masculino , Cumplimiento de la Medicación , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento
19.
J Physiol Pharmacol ; 70(2)2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31443094

RESUMEN

Urocortin 2 (Ucn2) - corticotropin-releasing hormone receptor 2 signalling has favourable effects in the cardiovascular system, including vasodilation, lowering of blood pressure and systemic peripheral resistance, increase in cardiac output and cardiac contractility, as well as cardioprotection against ischemia-reperfusion injury. Vasodilation and lowering of blood pressure seem to be very interesting and important effects, but their mechanism and interaction with the antihypertensive drugs have not been evaluated. The aim of the present study was to assess the relationship between Ucn2 concentration and antihypertensive therapy in patients with primary hypertension. We examined a group of 65 patients with primary hypertension receiving at least 3 antihypertensive drugs. In all of them plasma level of Ucn2, anthropometric measurements, biochemical tests, ambulatory blood pressure monitoring (ABPM), and echocardiography were performed. There were no differences in Ucn2 level related to beta-blockers, calcium channel blockers or diuretics, but we observed that in patients treated with angiotensin converting enzyme inhibitors (ACEI) (n = 52) serum Ucn2 levels were significantly higher than in patients treated with angiotensin-receptor blockers (ARBs) (n = 13) (10.93 versus 5.56 ng/mL; P < 0.05). Moreover, we did not observe any differences in terms of blood pressure on ABPM, biochemical measurements, left ventricular mass index, or presence of diabetes. In addition, in a small subgroup receiving alpha-blockers we also found a lower level of Ucn2, with coexisting higher systolic blood pressure at night, higher left ventricle mass index (LVMI) and more frequent occurrences of diabetes compared to non-alpha-blockers. Our findings suggest that the hypotensive action of renin-angiotensin-aldosterone system blockade may be related to the urocortin system. Ucn2 may be an important element in the mosaic of blood pressure-lowering factors in patients treated for essential hypertension.


Asunto(s)
Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/uso terapéutico , Hormona Liberadora de Corticotropina/metabolismo , Hipertensión/tratamiento farmacológico , Urocortinas/metabolismo , Presión Sanguínea/efectos de los fármacos , Monitoreo Ambulatorio de la Presión Arterial/métodos , Bloqueadores de los Canales de Calcio/uso terapéutico , Femenino , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Humanos , Hipertensión/metabolismo , Masculino , Persona de Mediana Edad , Sistema Renina-Angiotensina/efectos de los fármacos , Resistencia Vascular/efectos de los fármacos
20.
Hypertension ; 74(3): 614-622, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31327267

RESUMEN

Selection of antihypertensive treatment according to self-defined ethnicity is recommended by some guidelines but might be better guided by individual genotype rather than ethnicity or race. We compared the extent to which variation in blood pressure response across different ethnicities may be explained by genetic factors: genetically defined ancestry and gene variants at loci known to be associated with blood pressure. We analyzed data from 5 trials in which genotyping had been performed (n=4696) and in which treatment responses to ß-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blocker, thiazide or thiazide-like diuretic and calcium channel blocker were available. Genetically defined ancestry for proportion of African ancestry was computed using the 1000 genomes population database as a reference. Differences in response to the thiazide diuretic hydrochlorothiazide, the ß-blockers atenolol and metoprolol, the angiotensin-converting enzyme inhibitor lisinopril, and the angiotensin receptor blocker candesartan were more closely associated to genetically defined ancestry than self-defined ethnicity in admixed subjects. A relatively small number of gene variants related to loci associated with drug-signaling pathways (KCNK3, SULT1C3, AMH, PDE3A, PLCE1, PRKAG2) with large effect size (-3.5 to +3.5 mm Hg difference in response per allele) and differing allele frequencies in black versus white individuals explained a large proportion of the difference in response to candesartan and hydrochlorothiazide between these groups. These findings suggest that a genomic precision medicine approach can be used to individualize antihypertensive treatment within and across populations without recourse to surrogates of genetic structure such as self-defined ethnicity.


Asunto(s)
Afroamericanos/genética , Antihipertensivos/uso terapéutico , Grupo de Ascendencia Continental Europea/genética , Sitios Genéticos/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Hipertensión/genética , Antagonistas Adrenérgicos beta/uso terapéutico , Adulto , Anciano , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/farmacología , Bloqueadores de los Canales de Calcio/uso terapéutico , Ensayos Clínicos como Asunto , Femenino , Variación Genética/efectos de los fármacos , Humanos , Hidroclorotiazida/uso terapéutico , Hipertensión/etnología , Masculino , Persona de Mediana Edad , Pronóstico , Resultado del Tratamiento , Estados Unidos
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