RESUMEN

Chronic Chagas cardiomyopathy (CCC) has unique pathogenic and clinical features with worse prognosis than other causes of heart failure (HF), despite the fact that patients with CCC are often younger and have fewer comorbidities. Patients with CCC were not adequately represented in any of the landmark HF studies that support current treatment guidelines. PARACHUTE-HF (Prevention And Reduction of Adverse outcomes in Chagasic Heart failUre Trial Evaluation) is an active-controlled, randomized, phase IV trial designed to evaluate the effect of sacubitril/valsartan 200 mg twice daily vs enalapril 10 mg twice daily added to standard of care treatment for HF. The study aims to enroll approximately 900 patients with CCC and reduced ejection fraction at around 100 sites in Latin America. The primary outcome is a hierarchical composite of time from randomization to cardiovascular death, first HF hospitalization, or relative change from baseline to week 12 in NT-proBNP levels. PARACHUTE-HF will provide new data on the treatment of this high-risk population. (Efficacy and Safety of Sacubitril/Valsartan Compared With Enalapril on Morbidity, Mortality, and NT-proBNP Change in Patients With CCC [PARACHUTE-HF]; NCT04023227).

Asunto(s)

Aminobutiratos , Antagonistas de Receptores de Angiotensina , Compuestos de Bifenilo , Cardiomiopatía Chagásica , Combinación de Medicamentos , Enalapril , Insuficiencia Cardíaca , Tetrazoles , Valsartán , Humanos , Compuestos de Bifenilo/uso terapéutico , Aminobutiratos/uso terapéutico , Enalapril/uso terapéutico , Antagonistas de Receptores de Angiotensina/uso terapéutico , Cardiomiopatía Chagásica/tratamiento farmacológico , Insuficiencia Cardíaca/tratamiento farmacológico , Tetrazoles/uso terapéutico , Volumen Sistólico/fisiología , Fragmentos de Péptidos/sangre , Enfermedad Crónica , Péptido Natriurético Encefálico/sangre , Masculino , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Femenino , Resultado del Tratamiento

RESUMEN

BACKGROUND: To characterize the use of sacubitril/valsartan in a group of patients with heart failure in Colombia. RESEARCH DESIGN AND METHODS: Follow-up study of patients with heart failure who started sacubitril/valsartan and were affiliated with the Colombian health system between 2019 and 2021. Sociodemographic, clinical, and pharmacological variables and adherence and persistence of use were identified. RESULTS: A total of 514 patients were identified, with a mean age of 65.7 years, 73.7% of whom started sacubitril/valsartan at low doses, and only 12.5% reached the maximum dose. Adherence was 78.2% and persistence was 56.8% at 1 year of follow-up. The increase in systolic blood pressure (odds ratio (OR): 1.01; 95% CI: 1.00-1.03) and the use of ß-blockers (OR: 2.63; 95% CI: 1.42-4.85) were correlated with a greater persistence, while receiving furosemide (OR: 0.59; 95% CI: 0.39-0.89) and not having received renin - angiotensin - aldosterone system inhibitors in the 3 months before starting sacubitril/valsartan (OR: 0.48; 95% CI: 0.31-0.76) were associated with lower persistence. CONCLUSIONS: The persistence of treatment 1 year after starting sacubitril/valsartan was not high, and a small proportion of patients reached the target dose of the drug. Nontitration of the drug dose was common.

Asunto(s)

Insuficiencia Cardíaca , Tetrazoles , Humanos , Anciano , Estudios de Seguimiento , Tetrazoles/uso terapéutico , Volumen Sistólico/fisiología , Antagonistas de Receptores de Angiotensina/uso terapéutico , Resultado del Tratamiento , Valsartán/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Aminobutiratos/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Combinación de Medicamentos

RESUMEN

AIM: The win ratio can incorporate different types of outcomes and enhance statistical power, making it a useful method for analysing composite outcomes in cardiovascular trials. The application of this approach to the PARADISE-MI trial provides an additional perspective into understanding the effects of sacubitril/valsartan in patients with acute myocardial infarction. METHODS AND RESULTS: We conducted a post-hoc analysis of the PARADISE-MI trial, which randomly assigned patients with acute myocardial infarction complicated by a reduced left ventricular ejection fraction, pulmonary congestion, or both to receive either sacubitril/valsartan (97 mg of sacubitril and 103 mg of valsartan twice daily) or ramipril (5 mg twice daily) in addition to guideline-recommended therapy. The principal composite outcome was analysed in the hierarchical order of death due to cardiovascular causes, first hospitalization for heart failure, and first outpatient episode of symptomatic heart failure. We included events confirmed by the clinical events classification (CEC) committee as well as events identified by investigators that did not meet study definitions. Results were analysed by the unmatched win-ratio method. A win ratio that exceeds 1.00 reflects a better outcome. A total of 5661 patients underwent randomization; 2830 were assigned to receive sacubitril/valsartan and 2831 to receive ramipril. The hierarchical analysis of the principal composite outcome demonstrated a larger number of wins (1 265 767 [15.7%]) than losses (1 079 502 [13.4%]) in the sacubitril/valsartan group (win ratio of 1.17, 95% confidence interval [CI] 1.03-1.33; p = 0.015). Sensitivity analyses using alternative definitions of the composite outcome showed results similar to those of the principal analysis, except for analysis restricted to events that met CEC definitions (win ratio of 1.11, 95% CI 0.96-1.30; p = 0.16). CONCLUSION: In this post-hoc analysis of the PARADISE-MI trial using the win ratio and including investigator-identified events not having CEC confirmation, sacubitril/valsartan was superior to ramipril among high-risk survivors of acute myocardial infarction.

Asunto(s)

Insuficiencia Cardíaca , Infarto del Miocardio , Humanos , Ramipril/uso terapéutico , Ramipril/farmacología , Volumen Sistólico , Antagonistas de Receptores de Angiotensina , Neprilisina , Tetrazoles/uso terapéutico , Función Ventricular Izquierda , Aminobutiratos/uso terapéutico , Valsartán/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Combinación de Medicamentos , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/complicaciones

RESUMEN

Chagas cardiomyopathy is the most prevalent non-ischaemic cardiomyopathy in Latin America, with high morbidity and mortality even today. Treatment of these patients is based on the use of medications for heart failure. This study evaluated a case series of patients with Chagas heart disease who used sacubitril/valsartan at a referral hospital for this disease in Brazil. After 6 months, there was a symptomatic improvement in these individuals assessed by the New York Heart Association (NYHA) functional class, with a 44.3% reduction in the absolute number of patients classified as III-IV in the period (P = 0.035), but without changes in the parameters on the echocardiogram for reverse ventricular remodelling. There was a high mortality rate and number of hospitalizations. These results emphasize the importance of studying the use of sacubitril/valsartan in Chagas heart disease to better describe its effectiveness considering the particularities of these individuals.

Asunto(s)

Insuficiencia Cardíaca , Tetrazoles , Aminobutiratos/uso terapéutico , Antagonistas de Receptores de Angiotensina/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Combinación de Medicamentos , Ecocardiografía , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Volumen Sistólico , Tetrazoles/uso terapéutico , Resultado del Tratamiento , Valsartán

RESUMEN

In the present work, the anti-inflammatory and antiasthmatic potential of biseugenol, isolated as the main component from n-hexane extract from leaves of Nectandra leucantha and chemically prepared using oxidative coupling from eugenol, was evaluated in an experimental model of mixed-granulocytic asthma. Initially, in silico studies of biseugenol showed good predictions for drug-likeness, with adherence to Lipinski's rules of five (RO5), good Absorption, Distribution, Metabolism and Excretion (ADME) properties and no alerts for Pan-Assay Interference Compounds (PAINS), indicating adequate adherence to perform in vivo assays. Biseugenol (20 mg·kg-1) was thus administered intraperitoneally (four days of treatment) and resulted in a significant reduction in both eosinophils and neutrophils of bronchoalveolar lavage fluid in ovalbumin-sensitized mice with no statistical difference from dexamethasone (5 mg·kg-1). As for lung function parameters, biseugenol (20 mg·kg-1) significantly reduced airway and tissue damping in comparison to ovalbumin group, with similar efficacy to positive control dexamethasone. Airway hyperresponsiveness to intravenous methacholine was reduced with biseugenol but was inferior to dexamethasone in higher doses. In conclusion, biseugenol displayed antiasthmatic effects, as observed through the reduction of inflammation and airway hyperresponsiveness, with similar effects to dexamethasone, on mixed-granulocytic ovalbumin-sensitized mice.

Asunto(s)

Antiasmáticos/uso terapéutico , Antiinflamatorios/uso terapéutico , Asma/tratamiento farmacológico , Granulocitos/patología , Éteres Fenílicos/farmacología , Animales , Antiasmáticos/química , Antiasmáticos/farmacología , Antiinflamatorios/farmacología , Asma/complicaciones , Asma/fisiopatología , Disponibilidad Biológica , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Compuestos de Bifenilo/uso terapéutico , Simulación por Computador , Modelos Animales de Enfermedad , Granulocitos/efectos de los fármacos , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Lignanos/química , Lignanos/farmacología , Lignanos/uso terapéutico , Modelos Lineales , Masculino , Ratones Endogámicos BALB C , Éteres Fenílicos/química , Éteres Fenílicos/uso terapéutico , Pruebas de Función Respiratoria , Hipersensibilidad Respiratoria/complicaciones , Hipersensibilidad Respiratoria/tratamiento farmacológico , Hipersensibilidad Respiratoria/fisiopatología

RESUMEN

OBJECTIVES: The purpose of this study was to investigate the effect of sacubitril/valsartan therapy on sudden cardiac death (SCD) according to the use of and eligibility for an implantable cardioverter-defibrillator (ICD), stratified by heart failure cause. BACKGROUND: SCD still accounts for a significant proportion of overall mortality in heart failure with reduced ejection fraction (HFrEF). METHODS: Patients enrolled in the PARADIGM-HF (Prospective Comparison of ARNI with an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial (n = 8,399) were evaluated to assess patterns of ICD implantation and eligibility according to clinical guidelines. The impact of ICD (adjusted for propensity of ICD implantation) and sacubitril/valsartan therapy on SCD was evaluated by using cause-specific Cox models and competing risk analysis. RESULTS: At baseline, of the 7,145 patients (85%) eligible for ICD implantation, only 1,243 (15%) had an ICD. Use of ICD varied by region with the highest rates in North America (56%) and lowest in Asia-Pacific (1.7%). In a propensity score-adjusted analysis, use of an ICD was associated with a 56% lower risk of SCD in ICD-eligible patients, in both patients with ischemic (p < 0.001) and nonischemic cardiomyopathy (p = 0.02). Sacubitril/valsartan reduced SCD risk in patients with an ICD (hazard ratio [HR]: 0.49; 95% confidence interval [CI]: 0.25 to 0.99) and in those who were eligible for but did not receive an ICD (HR: 0.81; 95% CI: 0.67 to 0.98). This effect was particularly evident in nonischemic cardiomyopathy (p < 0.05), although interaction with the cause of HF was not significant (p = 0.11 in subjects using an ICD and p = 0.25 in eligible nonusers). CONCLUSIONS: Use of an ICD was associated with lower rates of SCD, regardless of HF cause but was underused in most regions of the world in the PARADIGM-HF study. Sacubitril/valsartan reduced SCD risk regardless of use of an ICD or eligibility, particularly in ICD users and nonischemic cardiomyopathy.

Asunto(s)

Aminobutiratos , Compuestos de Bifenilo , Muerte Súbita Cardíaca , Desfibriladores Implantables , Insuficiencia Cardíaca , Valsartán , Aminobutiratos/uso terapéutico , Antagonistas de Receptores de Angiotensina , Compuestos de Bifenilo/uso terapéutico , Combinación de Medicamentos , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , América del Norte , Estudios Prospectivos , Volumen Sistólico , Tetrazoles , Valsartán/uso terapéutico

RESUMEN

Previously the effects (0.01-3.0 mg/kg) of post-training SB-699551 (a 5-HT5A receptor antagonist) were reported in the associative learning task of autoshaping, showing that SB-699551 (0.1 mg/kg) decreased lever-press conditioned responses (CR) during short-term (STM; 1.5-h) or (3.0 mg/kg) long-term memory (LTM; 24-h); relative to the vehicle animals. Moreover, as pro-cognitive efficacy of SB-699551 was reported in the ketamine-model of schizophrenia. Hence, firstly aiming improving performance (conditioned response, CR), in this work autoshaping lever-press vs. nose-poke response was compared; secondly, new set of animals were randomly assigned to SB-699551 plus forgetting or amnesia protocols. Results show that the nose-poke operandum reduced inter-individual variance, increased CR and produced a progressive CR until 48-h. After one week of no training/testing sessions (i.e., interruption of 216 h), the forgetting was observed; i.e., the CR% of control-saline group significantly decreased. In contrast, SB-699551 at 0.3 and 3.0 mg/kg prevents forgetting. Additionally, as previously reported the non-competitive NMDA receptor antagonist dizocilpine (0.2 mg/kg) or the non-selective cholinergic antagonist scopolamine (0.3 mg/kg) decreased CR in STM. SB-699551 (0.3 mg/kg) alone also produced amnesia-like effect. Co-administration of SB-699551-dizocilpine or SB-699551-scopolamine reversed the SB-699551 induced-amnesic effects in LTM (24-h). Nose-poke seems to be a reliable operandum. The anti-amnesic and anti-forgetting mechanisms of amnesic SB-699551-dose remain unclear. The present findings are consistent with the notion that low doses of 5-HT5A receptor antagonists might be useful for reversing memory deficits associated to forgetting and amnesia. Of course, further experiments are necessary.

Asunto(s)

Amnesia/metabolismo , Memoria/fisiología , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/uso terapéutico , Amnesia/inducido químicamente , Amnesia/tratamiento farmacológico , Análisis de Varianza , Animales , Compuestos de Bifenilo/uso terapéutico , Antagonistas Colinérgicos/toxicidad , Condicionamiento Clásico/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Modelos Animales de Enfermedad , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Conducta Exploratoria/efectos de los fármacos , Extinción Psicológica/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Ratas , Ratas Wistar , Escopolamina/toxicidad

RESUMEN

Basal cell carcinoma (BCC) is the most prevalent malignant tumor in humans and the local destruction of tissue that can result from excision has a significant impact on well-being. Treating BCC is costly for health care systems given the high incidence of this tumor, especially in older patients. Standard treatment involves either resection with histologic assessment of margins or Mohs micrographic surgery. Surgery is sometimes contraindicated, however, due to the presence of significant comorbidity or high cosmetic expectations. For such patients, nonsurgical treatments have become available. These alternatives can offer good local control of disease, preserve function, and achieve excellent cosmetic results.

Asunto(s)

Carcinoma Basocelular/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Administración Cutánea , Aminoquinolinas/administración & dosificación , Aminoquinolinas/uso terapéutico , Anilidas/efectos adversos , Anilidas/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Compuestos de Bifenilo/efectos adversos , Compuestos de Bifenilo/uso terapéutico , Carcinoma Basocelular/etiología , Carcinoma Basocelular/patología , Ensayos Clínicos como Asunto , Fluorouracilo/administración & dosificación , Fluorouracilo/uso terapéutico , Humanos , Imiquimod , Interferones/uso terapéutico , Metaanálisis como Asunto , Terapia Molecular Dirigida , Invasividad Neoplásica , Fotoquimioterapia , Piridinas/efectos adversos , Piridinas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Medición de Riesgo , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/patología

RESUMEN

Obesity has emerged as a major contributing risk factor for overactive bladder (OAB), but no study examined urethral smooth muscle (USM) dysfunction as a predisposing factor to obesity-induced OAB. This study investigated the USM relaxant machinery in obese mice and whether soluble guanylyl cyclase (sGC) activation with BAY 60-2770 [acid 4-({(4-carboxybutyl) [2-(5-fluoro-2-{[4-(trifluoromethyl) biphenyl-4-yl] methoxy} phenyl) ethyl] amino} methyl) benzoic] rescues the urethral reactivity through improvement of sGC-cGMP (cyclic guanosine monophosphate) signaling. Male C57BL/6 mice were fed for 12 weeks with a high-fat diet to induce obesity. Separate groups of animals were treated with BAY 60-2770 (1 mg/kg per day for 2 weeks). Functional assays and measurements of cGMP, reactive-oxygen species (ROS), and sGC protein expression in USM were determined. USM relaxations induced by NO (acidified sodium nitrite), NO donors (S-nitrosoglutathione and glyceryl trinitrate), and BAY 41-2272 [5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine] (sGC stimulator) were markedly reduced in obese compared with lean mice. In contrast, USM relaxations induced by BAY 60-2770 (sGC activator) were 43% greater in obese mice (P < 0.05), which was accompanied by increases in cGMP levels. Oxidation of sGC with ODQ [1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one] (10 µM) potentiated BAY 60-2770-induced USM responses in the lean group. Long-term oral BAY 60-2770 administration fully prevented the impairment of USM relaxations in obese mice. Reactive-oxygen species (ROS) production was enhanced, but protein expression of ß1 second guanylate cyclase subunit was reduced in USM from obese mice, both of which were restored by BAY 60-2770 treatment. In conclusion, impaired USM relaxation in obese mice is associated with ROS generation and down-regulation of sGC-cGMP signaling. Prevention of sGC degradation by BAY 60-2770 ameliorates the impairment of urethral relaxations in obese mice.

Asunto(s)

Benzoatos/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Activadores de Enzimas/uso terapéutico , Guanilato Ciclasa/metabolismo , Hidrocarburos Fluorados/uso terapéutico , Óxido Nítrico/metabolismo , Obesidad/tratamiento farmacológico , Receptores Citoplasmáticos y Nucleares/metabolismo , Uretra/efectos de los fármacos , Animales , Benzoatos/administración & dosificación , Compuestos de Bifenilo/administración & dosificación , Relación Dosis-Respuesta a Droga , Activación Enzimática , Activadores de Enzimas/administración & dosificación , Hidrocarburos Fluorados/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , Relajación Muscular/efectos de los fármacos , Tono Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/enzimología , Músculo Liso/metabolismo , Obesidad/complicaciones , Obesidad/enzimología , Obesidad/fisiopatología , Especies Reactivas de Oxígeno/metabolismo , Guanilil Ciclasa Soluble , Uretra/enzimología , Uretra/metabolismo , Vejiga Urinaria Hiperactiva/enzimología , Vejiga Urinaria Hiperactiva/etiología , Vejiga Urinaria Hiperactiva/fisiopatología , Vejiga Urinaria Hiperactiva/prevención & control

RESUMEN

PURPOSE: Activators of soluble guanylyl cyclase are of potential interest as treatment for cardiovascular diseases but to our knowledge they have never been proposed to treat overactive bladder. We evaluated the effects of the soluble guanylyl cyclase activator BAY 60-2270 on voiding dysfunction and detrusor overactivity in a mouse model of obesity associated overactive bladder. MATERIALS AND METHODS: C57BL/6 male mice fed for 10 weeks with standard chow or a high fat diet were treated with 1 mg/kg BAY 60-2770 per day for 2 weeks via gavage. Cystometric evaluations were done and responses to contractile agents in isolated bladders were determined. RESULTS: Obese mice showed an irregular micturition pattern characterized by significant increases in voiding and nonvoiding contractions, which were normalized by BAY 60-2770. Carbachol, KCl and CaCl2 produced concentration dependent contractions in isolated bladder strips, which were markedly greater in obese than in lean mice. BAY 60-2770 normalized bladder contractions in the obese group. A 78% increase in reactive oxygen species generation in the bladder tissue of obese mice was observed, which was unaffected by BAY 60-2770. Treatment with BAY 60-2770 generated a tenfold increase in cyclic guanosine monophosphate in the bladders of obese mice without affecting the nucleotide level in the lean group. Protein expression of the soluble guanylyl cyclase α1 and ß1 subunits was decreased 40% in the bladder tissue of obese mice but restored by BAY 60-2770. CONCLUSIONS: Two-week BAY 60-2770 therapy increased cyclic guanosine monophosphate and rescued expression of the soluble guanylyl cyclase α1 and ß1 subunits in bladder tissue, resulting in great amelioration of bladder dysfunction.

Asunto(s)

Benzoatos/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Activadores de Enzimas/uso terapéutico , Guanilato Ciclasa/efectos de los fármacos , Hidrocarburos Fluorados/uso terapéutico , Obesidad/epidemiología , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Animales , Benzoatos/farmacología , Compuestos de Bifenilo/farmacología , Western Blotting , Hidrocarburos Fluorados/farmacología , Síntomas del Sistema Urinario Inferior/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos C57BL , Especies Reactivas de Oxígeno , Vejiga Urinaria Hiperactiva/epidemiología , Vejiga Urinaria Hiperactiva/prevención & control

RESUMEN

This study assessed blood pressure (BP) goal maintenance in patients controlled with olmesartan monotherapy after switching to another angiotensin type II receptor blocker (ARB). Hypertensive patients prescribed olmesartan monotherapy were identified from GE Healthcare's Centricity electronic medical record between 2007 and 2011. After documentation of BP goal (<140/90 mm Hg) attainment, patients were placed into the continuation cohort if olmesartan monotherapy was maintained or into the switch cohort if they were changed to irbesartan, losartan, or valsartan. Follow-up assessments were the first BP measurement 28 to 390 days after attaining BP goal (continuation cohort) or after prescribing an alternative ARB (switch cohort). Of 3412 patients included (3027 continuation cohort, 385 switch cohort), 52% were women and mean age was 58.0 years. In the switch cohort, 310 (80.5%) were switched to losartan (n=236), irbesartan (n=58), or valsartan (n=16) monotherapy and 75 (19.5%) were switched to combination antihypertensive therapy. Mean baseline and follow-up BP were 122.5/75.8 mm Hg and 126.6/77.6 mm Hg, respectively, in the continuation cohort (P<.001) and 123.5/75.4 mm Hg and 129.6/78.5 mm Hg, respectively, in the switch cohort (P<.001). BP goal maintenance was 78.7% and 72.2% in the continuation and switch cohort, respectively (odds ratio, 0.707; 95% confidence interval, 0.555-0.899). Patients who continued on olmesartan monotherapy after attaining BP goal had a higher percentage of BP goal maintenance than patients who switched therapy.

Asunto(s)

Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Imidazoles/uso terapéutico , Tetrazoles/uso terapéutico , Adulto , Anciano , Compuestos de Bifenilo/uso terapéutico , Sustitución de Medicamentos , Femenino , Estudios de Seguimiento , Humanos , Hipertensión/fisiopatología , Irbesartán , Losartán/uso terapéutico , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , Valina/análogos & derivados , Valina/uso terapéutico , Valsartán

RESUMEN

AIMS: The present study analyzed the potential antinociceptive effect of the antimigraine drugs sumatriptan, dihydroergotamine or methysergide in rats submitted to the formalin test. Moreover, by using selective antagonists, the role of 5-HT1B/1D serotonergic receptors was investigated in the antinociception induced by these antimigraine drugs. MAIN METHODS: The formalin test was used to assess the nociceptive activity. Overt pain-like behavior (flinching, 1h) and evoked nociception (long-lasting secondary mechanical allodynia and hyperalgesia, 6 days) were determined in the same rat. KEY FINDINGS: Ipsilateral, but not contralateral, pre-treatment (in µg/paw) with sumatriptan (10-300), methysergide (1-30) or dihydroergotamine (1-30) significantly prevented flinching behavior (at 1h) as well as secondary allodynia and hyperalgesia (at day 6) induced by formalin. Interestingly, the antinociceptive (flinching), antiallodynic and antihyperalgesic effects of sumatriptan were completely prevented by peripheral pre-treatment with selective antagonists at the 5-HT1B (SB 224289; 100) or 5-HT1D (BRL 15572; 100) receptors. In contrast, the acute antinociceptive effects of methysergide and dihydroergotamine were partially prevented by SB 224289 and BRL 15572. The antiallodynic and antihyperalgesic effects of both drugs were completely prevented by BRL 15572 and partially prevented by SB 224289. Given alone, SB 224289 or BRL 15572 did not modify per se the long-lasting secondary allodynia and hyperalgesia. SIGNIFICANCE: The above findings suggest that: (i) the antimigraine drugs sumatriptan, methysergide and dihydroergotamine reduce the acute and chronic nociception induced by formalin; and (ii) this antinociceptive effect results from activation of peripheral 5-HT1B/1D serotonergic receptors.

Asunto(s)

Hiperalgesia/metabolismo , Dolor Nociceptivo/tratamiento farmacológico , Receptor de Serotonina 5-HT1B/fisiología , Receptor de Serotonina 5-HT1D/fisiología , Antagonistas de la Serotonina/uso terapéutico , Dolor Agudo , Animales , Compuestos de Bifenilo/uso terapéutico , Dolor Crónico , Dihidroergotamina/uso terapéutico , Modelos Animales de Enfermedad , Quimioterapia Combinada , Femenino , Formaldehído/toxicidad , Hiperalgesia/inducido químicamente , Metisergida/uso terapéutico , Dolor Nociceptivo/inducido químicamente , Dolor Nociceptivo/metabolismo , Piperazinas/uso terapéutico , Piperidonas/uso terapéutico , Ratas , Ratas Wistar , Compuestos de Espiro/uso terapéutico , Sumatriptán/uso terapéutico

RESUMEN

BACKGROUND: ß-Adrenoceptor agonists are effective in animal models of bladder dysfunction, and the human bladder primarily expresses the ß3 receptor subtype. OBJECTIVE: To evaluate the efficacy and tolerability of the highly selective and potent ß3-adrenoceptor agonist solabegron in a clinical proof-of-concept study in incontinent women with overactive bladder (OAB). DESIGN, SETTING, AND PARTICIPANTS: This was a randomized, double-blind trial in adult women with OAB (one or more 24-h incontinence episodes and eight or more average 24-h micturitions). INTERVENTIONS: Solabegron 50 mg (n=88), solabegron 125 mg (n=85), or placebo (n=85)-all twice daily-were administered. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary efficacy end point was percentage change from baseline to week 8 in the number of incontinence episodes over 24 h. Secondary end points included actual change and percentage change from baseline to week 4 and week 8 in micturitions per 24 h, urgency episodes per 24 h, and volume voided per micturition. Adverse events (AEs) were assessed, as well. RESULTS AND LIMITATIONS: Solabegron 125 mg produced a statistically significant difference in percent change from baseline to week 8 in incontinence episodes over 24h when compared with placebo (p=0.025). Solabegron 125 mg treatment also showed statistically significant reductions from baseline to weeks 4 and 8 in micturitions over 24 h and a statistically significant increase from baseline to week 8 in urine volume voided. Solabegron was well tolerated, with a similar incidence of AEs in each treatment group. There were no significant treatment differences for mean changes from baseline to week 8 in systolic blood pressure (BP), diastolic BP, mean arterial pressure (MAP), or heart rate during the 24-h ambulatory measurement. CONCLUSIONS: Solabegron significantly reduced the symptoms of OAB in women with moderate to severe OAB. Solabegron was safe, well tolerated, and did not demonstrate significant differences in AEs as compared to placebo. ß3-Adrenoceptor agonists may represent a new therapeutic approach for treating OAB symptoms.

Asunto(s)

Agonistas de Receptores Adrenérgicos beta 3/uso terapéutico , Compuestos de Anilina/uso terapéutico , Benzoatos/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Vejiga Urinaria/efectos de los fármacos , Incontinencia Urinaria/tratamiento farmacológico , Agonistas de Receptores Adrenérgicos beta 3/administración & dosificación , Agonistas de Receptores Adrenérgicos beta 3/efectos adversos , Adulto , Anciano , Compuestos de Anilina/administración & dosificación , Compuestos de Anilina/efectos adversos , Argentina , Australia , Benzoatos/administración & dosificación , Benzoatos/efectos adversos , Compuestos de Bifenilo/administración & dosificación , Compuestos de Bifenilo/efectos adversos , Método Doble Ciego , Esquema de Medicación , Europa (Continente) , Femenino , Humanos , Modelos Lineales , Persona de Mediana Edad , Nueva Zelanda , República de Corea , Sudáfrica , Taiwán , Factores de Tiempo , Resultado del Tratamiento , Vejiga Urinaria/fisiopatología , Vejiga Urinaria Hiperactiva/fisiopatología , Incontinencia Urinaria/fisiopatología , Micción/efectos de los fármacos , Urodinámica/efectos de los fármacos , Adulto Joven

RESUMEN

BACKGROUND: Angiotensin II (Ang II) has been shown to contribute to the pathogenesis of hypertension and insulin resistance. In addition, administration of selective Ang II type-1 receptor blockers has been shown to improve insulin sensitivity. However, only a few studies have addressed the molecular mechanisms involved in this association. OBJECTIVE AND DESIGN: The current study was undertaken to determine whether an Ang II receptor blocker (irbesartan) is effective in improving insulin resistance in adipose tissue from obese Zucker rats, a model of metabolic syndrome. METHODS: Ten-week-old male obese Zucker rats (fa/fa) were treated daily with either vehicle or 50 mg/kg irbesartan for 6 months, and their age-matched lean (+/?) (lean Zucker rats) was used as a control. We determined systolic blood pressure (SBP), together with plasma levels of insulin, triglycerides, cholesterol and glucose. In addition, we evaluated insulin signaling through the insulin receptor/insulin receptor substrate-1/phosphatidylinositol 3 kinase/Akt/glucose transporter 4 pathway as well as the inflammatory status of adipose tissue. RESULTS: Obese Zucker rats displayed hyperglycemia, hypertriglyceridemia, hyperinsulinemia and hypercholesterolemia and increased SBP together with decreased activation of insulin signaling through the insulin receptor/insulin receptor substrate-1/phosphatidylinositol 3 kinase/Akt pathway in adipose tissue as well as increased adipocytes size, macrophage infiltration and augmented levels of inflammatory mediators such tumor necrosis factor-alpha, monocyte chemoattractant protein-1 and Ang II. Chronic irbesartan treatment resulted in an improvement of all alterations. CONCLUSION: The present study provides substantial information that demonstrates that long-term selective Ang II blockade ameliorates insulin resistance in adipose tissue from a model of metabolic syndrome via a mechanism that could involve the modulation of insulin signaling.

Asunto(s)

Adipocitos/efectos de los fármacos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Resistencia a la Insulina/fisiología , Síndrome Metabólico/prevención & control , Obesidad/tratamiento farmacológico , Tetrazoles/uso terapéutico , Adipocitos/metabolismo , Adipocitos/patología , Animales , Glucemia/análisis , Presión Sanguínea/efectos de los fármacos , Modelos Animales de Enfermedad , Transportador de Glucosa de Tipo 4/metabolismo , Insulina/sangre , Proteínas Sustrato del Receptor de Insulina/metabolismo , Irbesartán , Lípidos/sangre , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Síndrome Metabólico/genética , Síndrome Metabólico/metabolismo , Obesidad/genética , Obesidad/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Ratas , Ratas Zucker , Transducción de Señal

RESUMEN

The convenience to count with a safe and effective pharmacological wealth for atrial fibrillation treatment had conduced, in a way, to a deep depuration of the vast array of antiarrhythmic drugs, keeping only a very restricted number of compounds with a widely proved anti-atrial activity. On the other hand, it had lead to the discovery of the pathophysiological concepts that point to novel therapeutic targets. Within these objectives is that new antiarrhythmic drugs with preferential, even selective, activity on myocardial atrium ion channels had been developed. Among these new antiarrhythmics, dofetilide, and AVE0118, are taken into account. In addition, new possibilities are opened based on the knowledge of the cardioprotective-antiarrhythmic qualities of the opioidergic system.

Asunto(s)

Antiarrítmicos/uso terapéutico , Fibrilación Atrial/tratamiento farmacológico , Compuestos de Bifenilo/uso terapéutico , Fenetilaminas/uso terapéutico , Bloqueadores de los Canales de Potasio/uso terapéutico , Sulfonamidas/uso terapéutico , Administración Oral , Antiarrítmicos/administración & dosificación , Antiarrítmicos/efectos adversos , Antiarrítmicos/farmacología , Fibrilación Atrial/fisiopatología , Compuestos de Bifenilo/administración & dosificación , Compuestos de Bifenilo/farmacología , Electrofisiología , Atrios Cardíacos/efectos de los fármacos , Humanos , Canales Iónicos/efectos de los fármacos , Fenetilaminas/administración & dosificación , Fenetilaminas/farmacología , Bloqueadores de los Canales de Potasio/administración & dosificación , Bloqueadores de los Canales de Potasio/farmacología , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptores Opioides/efectos de los fármacos , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacología , Factores de Tiempo

RESUMEN

Renin-angiotensin-aldosterone system (RAAS) hyperactivity is implicated in the development of hypertension and progressive damage in target organs. Chronic inhibition of the RAAS or use of thiazide-type diuretics may trigger an aldoster-one escape. The aim of this study was to assess this phenomenon in hypertensive patients treated with thiazide-type diuretics (hydrochlorothiazide [HCTZ]) or single or double blockade of the RAAS (irbesartan [IRBE], quinapril [QUIN], and IRBE+QUIN). Blood pressure levels were obtained by 24-hour ambulatory blood pressure monitoring. Plasma renin activity and aldosterone levels were determined by immunoradiometric assay. Blood pressure level was normalized in the 4 treatment groups; the HCTZ and IRBE+QUIN groups showed an increased plasma aldosterone level after 12 weeks (9.1+/-2.2 to 14.1+/-1.4 and 6.9+/-1.9 to 12.9+/-2.3 ng/dL, respectively; P<.05), whereas plasma renin activity was increased only in the HCTZ group (0.9+/-0.2-1.7+/-0.2 ng/mL/h; P<.05). The increase in plasma aldosterone level after 12 weeks of HCTZ and IRBE+QUIN therapy suggests early aldosterone escape.

Asunto(s)

Aldosterona/sangre , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Hipertensión/tratamiento farmacológico , Tetrahidroisoquinolinas/uso terapéutico , Tetrazoles/uso terapéutico , Diuréticos/uso terapéutico , Quimioterapia Combinada , Femenino , Humanos , Hidroclorotiazida/uso terapéutico , Hipertensión/sangre , Irbesartán , Masculino , Persona de Mediana Edad , Quinapril

RESUMEN

Angiotensin II antagonists (AIIAs) were introduced to treat hypertension about 10 years ago. During this period they were evaluated not only in terms of efficacy and safety but also in several large studies with clinical outcomes. They are efficacious in all clinical forms of hypertension and are effective also in all ethnic groups. Cardiovascular and renal protection in proteinuric diabetic nephropathy beyond blood pressure reduction was proved in major clinical studies: Losartan Intervention For Endpoint reduction in hypertension study (LIFE), Reduction of Endpoint in Non-Insulin dependent Diabetes Mellitus with the AII Antagonist Losartan (RENAAL) and Irbesartan Type 2 Diabetic Nephropathy Trial (IDNT). Their blood pressure independent protective effect is also mentioned by the blockade of AT1 receptor. As a class AIIs have a tolerability profile similar to placebo.

Asunto(s)

Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Angiotensina II/antagonistas & inhibidores , Antihipertensivos/uso terapéutico , Nefropatías Diabéticas/prevención & control , Hipertensión/tratamiento farmacológico , Proteinuria/prevención & control , Compuestos de Bifenilo/uso terapéutico , Sistema Cardiovascular/efectos de los fármacos , Humanos , Irbesartán , Riñón/efectos de los fármacos , Losartán/uso terapéutico , Tetrazoles/uso terapéutico

RESUMEN

Angiotensin II antagonists (AIIAs) were introduced to treat hypertension about 10 years ago. During this period they were evaluated not only in terms of efficacy and safety but also in several large studies with clinical outcomes. They are efficacious in all clinical forms of hypertension and are effective also in all ethnic groups. Cardiovascular and renal protection in proteinuric diabetic nephropathy beyond blood pressure reduction was proved in major clinical studies: Losartan Intervention For Endpoint reduction in hypertension study (LIFE), Reduction of Endpoint in Non-Insulin dependent Diabetes Mellitus with the AII Antagonist Losartan (RENAAL) and Irbesartan Type 2 Diabetic Nephropathy Trial (IDNT). Their blood pressure independent protective effect is also mentioned by the blockade of AT1 receptor. As a class AIIs have a tolerability profile similar to placebo.

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Os antagonistas da angiotensina II (AAIIs) foram introduzidos para o tratamento da hipertensão arterial há cerca de 10 anos. Durante esse período eles foram avaliados não apenas em termos de eficácia e segurança, mas também em vários estudos grandes com desfechos clínicos. Os AAIIs são eficazes em todas as formas clínicas de hipertensão e, também, em todos os grupos étnicos. Os principais estudos clínicos em pacientes diabéticos com nefropatia e proteinúia comprovaram, além da redução da pressão arterial, proteção cardiovascular e renal: "Losartan Intervention For Endpoint reduction in hypertension study" (LIFE), "Reduction of Endpoint in Non-Insulin dependent Diabetes Mellitus with the AII Antagonist Losartan" (RENAAL) e "Irbesartan Type 2 Diabetic Nephropathy Trial" (IDNT). O seu efeito protetor independente da pressão sanguínea também é mencionado pelo bloqueio do receptor AT1. Os AAIIs, como classe medicamentosa, apresentam um perfil de tolerabilidade semelhante ao placebo.

Asunto(s)

Humanos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Angiotensina II/antagonistas & inhibidores , Antihipertensivos/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Nefropatías Diabéticas/prevención & control , Hipertensión/tratamiento farmacológico , Proteinuria/prevención & control , Tetrazoles/uso terapéutico , Sistema Cardiovascular/efectos de los fármacos , Riñón/efectos de los fármacos , Losartán/uso terapéutico

RESUMEN

AIM: To evaluate the effects of combined treatment of an ACE inhibitor and an angiotensin II receptor antagonist on parameters related to the progression of renal disease in type 2 diabetic patients. METHODS: 20 hypertensive type 2 diabetic patients with non-nephrotic proteinuria (0.5 - 3.0 g/day) and estimated creatinine clearance > or = 40 ml/min/1.73m2 were randomly assigned to be treated with perindopril 8 mg/day (Per), irbesartan 300 mg/day (Irb) or a combination of both with the same doses (Per + Irb). Each treatment phase lasting 16 weeks was preceded by a four-week washout period. Diuretics, clonidine and hydralazine were used as supplementary drugs for blood pressure control. Patients were evaluated at baseline and at the end of each treatment phase. RESULTS: 15 (3M/12F) patients completed all the phases. Use of Per, Irb and Per + Irb led to a reduction in 24-hour mean blood pressure of 6 mmHg, 4 mmHg and 4 mmHg, respectively. Changes in glomerular filtration rate were not significant at any phase. Renal plasma flow was significantly more elevated with Irb than Per. Treatment with both Irb and Per + Irb induced similar plasma renin elevation, but treatment with Per did not, suggesting escape. Plasma aldosterone was reduced only by treatment with Per + Irb (-36%, p < 0.02). Reduction in proteinuria during Per + Irb (-33%) was not significantly different from Per (-34%) or Irb (-22%). Urinary transforming growth factor beta1 (TGF-beta1) excretion was significantly reduced with both Irb (-24%, p < 0.05) and Per + Irb (-36%, p < 0.05) but not with Per (-11%, p = 0.60). CONCLUSION: Only combined therapy with irbesartan plus perindopril concurrently reduces plasma aldosterone, proteinuria and urinary TGF-beta1.

Asunto(s)

Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Nefropatías Diabéticas/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Sistema Renina-Angiotensina/efectos de los fármacos , Adulto , Anciano , Aldosterona/sangre , Angiotensina II/sangre , Angiotensina II/efectos de los fármacos , Biomarcadores/sangre , Compuestos de Bifenilo/uso terapéutico , Estudios Cruzados , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/sangre , Nefropatías Diabéticas/complicaciones , Quimioterapia Combinada , Femenino , Humanos , Hipertensión/sangre , Hipertensión/complicaciones , Irbesartán , Masculino , Persona de Mediana Edad , Perindopril/uso terapéutico , Renina/sangre , Renina/efectos de los fármacos , Tetrazoles/uso terapéutico , Resultado del Tratamiento

RESUMEN

BACKGROUND: Previous studies in type 2 diabetes have demonstrated the renoprotective effect of AT(1)-receptor antagonist drugs, but data on type 1 diabetic (T1DM) children are scarce. The aim of this study was to evaluate the effectiveness of the AT(1)-receptor antagonist irbesartan in reducing creatinine clearance rate (CCR) in non-hypertensive T1DM children with renal hyperfunction. METHODS: In this randomized, double-blind, placebo-controlled trial we enrolled 20 T1DM children aged 6-16 years and randomly allocated them to receive either irbesartan (1 mg/kg body weight) or placebo daily for 12 weeks. Children were eligible to participate if they had renal hyperfunction, defined as a CCR >20 ml/min/1.73 m(2) body surface area. In addition, the participants could not have high blood pressure or renal failure and they could not be receiving diuretics or angiotensin-converting enzyme inhibitors. The primary endpoint of the trial was the change in CCR. RESULTS: There were no significant differences in age, duration of diabetes or body mass index between the two groups. No subject dropped out, withdrew consent or had side effects or adverse events attributable to irbesartan or the placebo. In the irbesartan group, CCR decreased from 155.0+/-6.6 to 86.2+/-7.4 ml/min (P<0.0001); CCR did not change significantly in the control group (154.1+/-13.1 to 172.0+/-15.5 ml/min; P = 0.86). Blood pressures at baseline and throughout the study were similar in both groups. CONCLUSIONS: Irbesartan significantly reduces CCR in non-hypertensive, non-controlled T1DM children; the clinical significance of this finding, however, remains to be established.

Asunto(s)

Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Creatinina/orina , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Nefropatías Diabéticas/prevención & control , Riñón/efectos de los fármacos , Tetrazoles/uso terapéutico , Adolescente , Niño , Diabetes Mellitus Tipo 1/fisiopatología , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/fisiopatología , Método Doble Ciego , Humanos , Irbesartán , Riñón/fisiopatología