RESUMEN
BACKGROUND: Up to 40% of patients suffering from anxiety disorders do not benefit from currently available pharmacological treatments. Overactivity of the orexin-1 receptor (OX1R) has been implicated in anxiety- and panic-related states. AIM & METHODS: We investigated the pharmacokinetics and characterized the pharmacodynamic (PD) profile of the OX1R antagonist JNJ-61393215 using a battery of central nervous system assessments investigating relevant functional domains such as alertness, attention, (visuo)motor coordination, balance, subjective effects and resting-state electroencephalography in a single ascending dose placebo-controlled study in doses from 1 to 90 mg inclusive, assessing PD up to 10 h after dosing, safety and pharmacokinetic in 48 healthy male subjects. RESULTS: Average time to maximal plasma concentration (Tmax) ranged between 1.0 and 2.25 h; average half-life ranged from 13.6 to 24.6 h and average maximum plasma concentration ranged from 1.4 to 136.8 ng/mL in the 1 and 90 mg groups, respectively. JNJ-61393215 did not demonstrate any statistically significant or clinically meaningful effects on any PD endpoint at any dose investigated at Tmax nor over the total period up to 10 h post-dose and was well tolerated. The reported somnolence rate was 16.7% (which was attributable to the cohorts receiving 6 mg and higher doses) compared to 12.5% in placebo. CONCLUSION: This observation is in line with our knowledge about the OX1R in preclinical studies, where only inconsistent and non-dose-dependent changes in electroencephalography or other behavioural measures were observed under non-challenged conditions, potentially exemplifying the need for a challenged subject.
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Antagonistas de los Receptores de Orexina , Humanos , Masculino , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Semivida , Voluntarios Sanos , Antagonistas de los Receptores de Orexina/efectos adversos , Antagonistas de los Receptores de Orexina/farmacocinética , OrexinasRESUMEN
BACKGROUND AND PURPOSE: The neuropathological process starts years before the diagnosis of Parkinson's disease (PD). Assessment of prodromal features in healthy individuals may help to define those with high risk for future PD. Our aim was to evaluate the presence and progression of prodromal markers in individuals with low risk [healthy controls (HC), n = 14] and high risk for PD (HR-PD, n = 34) and early PD (n = 14) patients. METHODS: Several risk or prodromal markers were combined to define HR-PD. Other prodromal markers were followed in 6-month intervals for 2 years. As recommended by the Movement Disorder Society Task Force, likelihood ratios (LRs) of markers, motor scores and PD probability scores were calculated and compared. RESULTS: The baseline LR for non-motor prodromal markers was significantly higher in PD and HR-PD compared to HC. Within 2 years, changes in these LRs did not significantly differ between the groups. Motor worsening was significant only in the PD group (50% of the patients) against HR-PD (15%) and HC (7%). Change in the non-motor prodromal LR did not significantly correlate with motor worsening, but higher baseline non-motor LRs were associated with Unified Parkinson's Disease Rating Scale III values at 2 years of follow-up. CONCLUSIONS: Our study shows that the frequency of non-motor prodromal markers is higher in the HR-PD group but does not increase within 2 years. The progression of motor and non-motor markers seems to be independent, but higher baseline non-motor burden is associated with the motor status after 2 years. Moreover, our data argue for a high impact of motor markers in the risk estimation for future PD.
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Enfermedad de Parkinson/diagnóstico , Síntomas Prodrómicos , Anciano , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/fisiopatología , Riesgo , Evaluación de SíntomasRESUMEN
Alterations in rapid eye movement sleep (REM) have been suggested as valid translational efficacy markers: activation of the metabotropic glutamate receptor 2 (mGluR2) was shown to increase REM latency and to decrease REM duration. The present paper addresses the effects on vigilance states of the mGluR2 positive allosteric modulator (PAM) JNJ-40411813 at different circadian times in rats and after afternoon dosing in humans. Due to its dual mGluR2 PAM/serotonin 2A (5-HT2A) receptor antagonism in rodents, mGlu2R specificity of effects was studied in wild-type (WT) and mGluR2 (-/-) mice. 5-HT2A receptor occupancy was determined in humans using positron emission tomography (PET). Tolerance development was examined in rats after chronic dosing. EEG oscillations and network connectivity were assessed using multi-channel EEG. In rats, JNJ-40411813 increased deep sleep time and latency of REM onset but reduced REM time when administered 2 h after 'lights on' (CT2): this was sustained after chronic dosing. At CT5 similar effects were elicited, at CT10 only deep sleep was enhanced. Withdrawal resulted in baseline values, while re-administration reinstated drug effects. Parieto-occipital cortical slow theta and gamma oscillations were correlated with low locomotion. The specificity of functional response was confirmed in WT but not mGluR2 (-/-) mice. A double-blind, placebo-controlled polysomnographic study in healthy, elderly subjects showed that 500 mg of JNJ-40411813 consistently increased deep sleep time, but had no effect on REM parameters. This deep sleep effect was not explained by 5-HT2A receptor binding, as in the PET study even 700 mg only marginally displaced the tracer. JNJ-40411813 elicited comparable functional responses in rodents and men if circadian time of dosing was taken into account. These findings underscore the translational potential of sleep mechanisms in evaluating mGluR2 therapeutics when administered at the appropriate circadian time.
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Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/fisiología , Ritmo Circadiano/efectos de los fármacos , Piperidinas/administración & dosificación , Piperidinas/sangre , Piperidinas/farmacología , Piridonas/administración & dosificación , Piridonas/sangre , Piridonas/farmacología , Receptores de Glutamato Metabotrópico/fisiología , Sueño/efectos de los fármacos , Adulto , Regulación Alostérica , Animales , Ondas Encefálicas/efectos de los fármacos , Corteza Cerebral/diagnóstico por imagen , Electroencefalografía , Humanos , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Actividad Motora/efectos de los fármacos , Tomografía de Emisión de Positrones , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2A/metabolismo , Receptores de Glutamato Metabotrópico/genética , Antagonistas del Receptor de Serotonina 5-HT2/administración & dosificación , Sueño REM/efectos de los fármacos , Investigación Biomédica Traslacional , Adulto JovenRESUMEN
Acute studies suggested a therapeutic benefit for fundus-relaxing drugs in functional dyspepsia (FD) with visceral hypersensitivity (VH) to gastric distention or impaired accommodation (IA), but long-term studies are lacking. R-137696 is a serotonin-1A (5-HT(1A)) receptor agonist which relaxes the proximal stomach in man. Our aim was to investigate the influence of R-137696 on symptoms in FD with VH or IA. Randomized, double-blind, placebo-controlled, parallel group study of 4 weeks R-137696 2 mg t.i.d. in FD with VH or IA. Symptoms were assessed using the patient assessment of upper gastrointestinal symptom severity index (PAGI-SYM) total score and individual symptom subscales. Barostat studies were performed before and after 4 weeks of treatment. Fifty-three patients (33 VH and 20 IA), 18 men, mean age 40 +/- 13 years were recruited. Twenty-four received placebo and 29 received R-137696. In VH patients, both placebo and R-137696 improved total symptom scores, with a tendency for superiority of placebo (-1.12 vs-0.51, P = 0.07). Placebo was superior for the subscales of early satiety, bloating, fullness and discomfort (all P < 0.05). In IA, both placebo and R-137696 had no significant influence on total or individual symptom scores (-0.08 and -0.27). In VH, both placebo and R-137696 increased the discomfort volume, without a statistical difference between both arms (+120 and +164 mL). In IA, both placebo and R-137696 enhanced accommodation, without a statistical difference between both (+77 and +159 mL). Adverse events were similar for drug and placebo. A 4-week administration of the fundus-relaxing 5-HT(1A) agonist R-137696 failed to significantly improve symptoms, VH or gastric accommodation compared to placebo.
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Dispepsia/tratamiento farmacológico , Hipersensibilidad/tratamiento farmacológico , Agonistas del Receptor de Serotonina 5-HT1 , Agonistas de Receptores de Serotonina/uso terapéutico , Adulto , Citocromo P-450 CYP2D6/metabolismo , Interpretación Estadística de Datos , Dextrometorfano , Relación Dosis-Respuesta a Droga , Dispepsia/fisiopatología , Femenino , Vaciamiento Gástrico/efectos de los fármacos , Fundus Gástrico/fisiología , Motilidad Gastrointestinal/efectos de los fármacos , Humanos , Hipersensibilidad/fisiopatología , Masculino , Persona de Mediana Edad , Agonistas de Receptores de Serotonina/efectos adversos , Estómago/fisiopatologíaRESUMEN
As fundic dysaccommodation represents one of the pathophysiological mechanisms underlying functional dyspepsia, gastric relaxant agents may serve as a new treatment of this disorder. Previous studies have suggested the involvement of 5HT1 receptors in the control of gastric tone. Our aim was to study the effect of R137696, a novel 5HT1A agonist, on fundus sensorimotor function in healthy volunteers. The effect of single oral doses (1-2 mg) R137696 was evaluated in a double-blind, placebo-controlled manner on fasting fundic volume, visceral perception, distension-evoked symptoms and fundic compliance in 21 healthy male subjects. R137696 increased the proximal stomach volumes in a dose-dependent manner. Distention-evoked symptoms or distention and discomfort threshold were not altered by R137696. A logistic regression model, characterizing the relationships between the volume and the visual analogue scale score for dyspeptic symptoms (nausea, fullness, discomfort, pain and satiety) as a sigmoidal curve, revealed that R137696 had no effect on distension-induced discomfort, fullness, pain and satiety compared to placebo. R137696 relaxes the gastric fundus in fasting conditions but has no effect on distension-evoked dyspeptic symptoms in healthy volunteers.
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Músculo Liso/efectos de los fármacos , Agonistas de Receptores de Serotonina/farmacología , Estómago/efectos de los fármacos , Adulto , Adaptabilidad/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Humanos , Masculino , Manometría , Relajación Muscular/efectos de los fármacos , Dimensión del DolorRESUMEN
BACKGROUND: Ridogrel at low doses inhibits thromboxane synthase. Oral ridogrel, from 5 mg once daily to 150 mg twice daily, improves the endoscopic appearance of colonic mucosa and clinical manifestations in mild to moderate ulcerative colitis. AIM: One US trial and one international trial were conducted to determine the effect of ridogrel on mild to severe active ulcerative colitis. METHODS: Two 12-week, double-blind, randomized, parallel-group trials were conducted. A US trial compared 0.5 mg, 2.5 mg and 5 mg of ridogrel once daily with placebo. An international trial compared 0.5 mg of ridogrel once daily with 2.5 mg and 5.0 mg of ridogrel once daily and 800 mg of mesalazine (known as mesalamine in the USA) three times daily. The primary efficacy outcome measure was the rate of complete remission. RESULTS: In the US trial, complete remission was achieved in 20.8% of patients in the 0.5 mg ridogrel group, 17.9% in the 2.5 mg ridogrel group, 20.6% in the 5.0 mg ridogrel group and 13.6% in the placebo group. In the international trial, 14.4% of patients in the 0.5 mg ridogrel group, 19.6% in the 2.5 mg ridogrel group, 19.4% in the 5.0 mg ridogrel group and 16.4% in the mesalazine group experienced complete remission. In the international trial, rates of complete remission at the end-point were greater in the 2.5 mg and 5.0 mg ridogrel groups than in the 0.5 mg ridogrel group, but the differences were not statistically significant. In the US trial, rates of complete remission at the end-point were greater in the 2.5 mg and 5.0 mg ridogrel groups than in the placebo group, but the differences were not statistically significant. Approximately 30% of the patients in each group discontinued treatment before the 12-week end-point owing to a lack of therapeutic response. All doses of ridogrel were well tolerated and comparable with placebo or mesalazine in terms of safety. CONCLUSIONS: No significant differences in the primary efficacy outcome measure were found between either the 2.5 mg or the 5.0 mg dose of ridogrel and placebo in the US trial and between either the 2.5 mg or the 5.0 mg dose of ridogrel and the 0.5 mg dose of ridogrel, a surrogate dose for placebo, in the international trial. There was no clear indication in either trial of an effective dose of ridogrel in the treatment of ulcerative colitis.
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Colitis Ulcerosa/tratamiento farmacológico , Fármacos Gastrointestinales/efectos adversos , Fármacos Gastrointestinales/farmacología , Ácidos Pentanoicos/efectos adversos , Ácidos Pentanoicos/farmacología , Piridinas/efectos adversos , Piridinas/farmacología , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/farmacología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Masculino , Mesalamina/efectos adversos , Mesalamina/farmacología , Persona de Mediana Edad , Placebos , Resultado del TratamientoRESUMEN
Nebivolol was compared in a dose of 5 mg once daily with enalapril 10 mg once daily over 7 months in a double-blind randomised trial in essential hypertension. The two drugs had very similar sustained effects in lowering both systolic and diastolic pressures; neither had an orthostatic component. Both drugs were well-tolerated. No haematological, biochemical, or urinary abnormalities were seen.
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Antagonistas Adrenérgicos beta/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/uso terapéutico , Benzopiranos/uso terapéutico , Enalapril/uso terapéutico , Etanolaminas/uso terapéutico , Antagonistas Adrenérgicos beta/administración & dosificación , Adulto , Anciano , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Antihipertensivos/administración & dosificación , Benzopiranos/administración & dosificación , Presión Sanguínea/efectos de los fármacos , Peso Corporal , Método Doble Ciego , Electrocardiografía/efectos de los fármacos , Enalapril/administración & dosificación , Etanolaminas/administración & dosificación , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Hipertensión/tratamiento farmacológico , Hipotensión Ortostática/prevención & control , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Nebivolol , Satisfacción del Paciente , PlacebosRESUMEN
The effects of racemic nebivolol, 2.5, 5.0, and 10.0 mg; d-nebivolol, 2.5 mg; l-nebivolol, 2.5 mg; atenolol, 50 mg; and placebo, each given once daily for 7 days, on exercise-induced increases in heart rate and systolic blood pressure were compared in a seven-way double-blind randomized crossover trial in 14 healthy male volunteers. Observations on these variables were made 3 and 24 hours after dosing on the first and last days of therapy. Similar effects on both exercise-induced tachycardia and increases in systolic blood pressure were seen with nebivolol 5.0 mg and with d-nebivolol 2.5 mg; l-nebivolol 2.5 mg was no different from placebo. These data show that the beta-blocking effects of nebivolol reside in the d-isomer. A dose-related response was evident with racemic nebivolol in inhibiting exercise-induced tachycardia over the range of doses studied. Whereas the effects of atenolol on both exercise-induced tachycardia and increases in systolic blood pressure were fully evident on the first day of treatment, those of nebivolol, especially with regard to heart rate, and, to a lesser degree, systolic pressure, were greater on the final than on the first day. Nebivolol had a clearly superior trough-to-peak efficacy ratio than atenolol.
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Antagonistas Adrenérgicos beta/uso terapéutico , Atenolol/farmacología , Benzopiranos/farmacología , Presión Sanguínea/efectos de los fármacos , Etanolaminas/farmacología , Ejercicio Físico/fisiología , Frecuencia Cardíaca/efectos de los fármacos , Adulto , Estudios Cruzados , Método Doble Ciego , Humanos , Masculino , Nebivolol , PlacebosRESUMEN
A double-blind, randomised, parallel-group trial was conducted in patients with essential hypertension in British general practices, of nebivolol 5 mg, atenolol 50 mg, and placebo each given once daily. Both active drugs, in comparison with placebo, caused highly significant and similar reductions in systolic and diastolic pressures without orthostatic effect, and small significant falls in heart rate. Both active drugs were well tolerated, nebivolol marginally more so. Nebivolol, a long-acting, cardioselective, vasodilating beta-blocker which acts partly via the l-arginine/nitric oxide mechanism, appears potentially valuable for the treatment of hypertension.
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Antagonistas Adrenérgicos beta/uso terapéutico , Atenolol/uso terapéutico , Benzopiranos/uso terapéutico , Etanolaminas/uso terapéutico , Hipertensión/tratamiento farmacológico , Adolescente , Adulto , Anciano , Atenolol/efectos adversos , Benzopiranos/efectos adversos , Método Doble Ciego , Etanolaminas/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , NebivololRESUMEN
The efficacy and acceptability of 5 mg nebivolol once daily, a long-acting, vasodilating cardioselective beta blocker that additionally facilitates the L-arginine/nitric oxide system, was assessed in a double-blind, randomized trial in comparison with 20 mg nifedipine retard twice daily in patients with essential hypertension. At 2 weeks of treatment, nebivolol was significantly more effective. Thereafter, both drugs effectively and similarly lowered systolic and diastolic pressures without orthostatic effect. Nebivolol had a trough-to-peak antihypertensive effect ratio of 90%. Nifedipine gave the expected side effects of headache, flushing, and edema. Nebivolol was well tolerated. Nebivolol slightly but significantly lowered heart rate. Neither drug adversely affected plasma levels of lipids.
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Antagonistas Adrenérgicos beta/uso terapéutico , Antihipertensivos/uso terapéutico , Benzopiranos/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Etanolaminas/uso terapéutico , Hipertensión/tratamiento farmacológico , Nifedipino/uso terapéutico , Adulto , Anciano , Presión Sanguínea/efectos de los fármacos , Método Doble Ciego , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Nebivolol , Resultado del TratamientoRESUMEN
A double-blind placebo-controlled dose-response trial of nebivolol, a cardioselective beta-blocking drug which also induces endothelium-dependent dilatation via nitric oxide, has been performed. Nebivolol reduced blood pressure (BP) in a dose dependent way, and was shown to be effective given once daily, without appreciable differences between peak and trough drug levels. There was no postural component to the BP fall. There was no clear inferiority of efficacy in black patients. A single daily dose of 5 mg was appropriate, with no evident advantage at 10 mg. The drug was well tolerated, even at 10 mg daily. BP control was achieved largely in the absence of typical side effects of beta-blockade. The combination of properties of nebivolol renders it an attractive addition to the antihypertensive repertoire.
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Antihipertensivos/administración & dosificación , Benzopiranos/administración & dosificación , Etanolaminas/administración & dosificación , Hipertensión/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , NebivololRESUMEN
OBJECTIVES: The aims of the present study were to determine (1) the beta 1-blocking potency and (2) the beta 1-adrenoceptor selectivity of nebivolol in man after repeated dosing (7 days) compared with that after a single oral intake and with that after atenolol for 7 days. In addition, it was investigated whether (3) nebivolol has alpha 1-blocking properties which might at least in part explain the vasodilating property of the compound. METHODS: Twelve healthy subjects were randomized in an open, two-way cross-over study. beta 1-Blocking potency and beta 1-adrenoceptor selectivity of nebivolol 5 mg once daily (o.d.) were compared with those of atenolol at three doses (25, 50 and 100 mg) o.d. Measurements were performed after 1 and 7 days of drug intake. beta 1-Adrenoceptor potency was assessed by the percentage decrease in exercise-induced tachycardia (delta EIT) during beta-blockade. beta 1-Selectivity of nebivolol and atenolol were investigated using the heart rate response to isoprenaline at equipotent beta 1-blocking dosages of both drugs. alpha 1-Blockade of nebivolol was measured using the phenylephrine dose-response test. RESULTS: delta EIT after a single oral dose of nebivolol 5 mg (10%) was significantly smaller than after nebivolol 5 mg o.d. for 7 days (15%). After 1 week of treatment no difference was seen in delta EIT between nebivolol 5 mg o.d. and atenolol 25 mg o.d. (16%). At these dosages the suppression in isoprenaline-induced tachycardia by both drugs did not differ (CD20 ratio 1.7). In contrast to atenolol 25 mg, after 1 week of nebivolol 5 mg o.d., blood pressure decreased. This decrease averaged 10% and-like in a study with hypertensive patients-was similar with that after atenolol 100 mg o.d. None of the phenylephrine test parameters changed from pre-study values after nebivolol. CONCLUSIONS: beta 1-Blockade of nebivolol 5 mg is larger after repeated dosing than after a single oral intake. After once daily repeated dosing nebivolol 5 mg and atenolol 25 mg are equipotent in beta 1-antagonism. No difference in beta 1-selectivity is observed between the two drugs. Nebivolol has no additional alpha 1-blocking property, which may at least in part explain its vasodilating effect.
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Antagonistas Adrenérgicos beta/farmacología , Atenolol/farmacología , Benzopiranos/farmacología , Etanolaminas/farmacología , Adulto , Análisis de Varianza , Presión Sanguínea/efectos de los fármacos , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Ejercicio Físico , Prueba de Esfuerzo , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , NebivololRESUMEN
The aim of this double-blind, parallel group study was to compare the effects of nebivolol and atenolol on blood pressure (BP) and insulin sensitivity in hypertensive patients with type II, non-insulin dependent diabetes mellitus (NIDDM). After a 4-week run-in period on placebo, 30 patients (14 males and 16 females) aged 43 to 69 years, with stable NIDDM and mild to moderate hypertension (DBP > or =95 and <116 mm Hg) were randomised to receive either nebivolol 5 mg or atenolol 50 mg, both administered once daily for 6 months. At the end of the placebo and the active treatment periods, supine and standing BP was measured, 24-h urinary C-peptide, HbA1c, plasma glucose and lipid levels were evaluated and an euglycaemic hyperinsulinaemic clamp was performed to evaluate insulin sensitivity: glucose infusion rate during the last 60 min of clamp and total glucose requirements were evaluated. Nebivolol 5 mg once daily was of an equivalent efficacy as atenolol 50 mg once daily at reducing supine and standing systolic and diastolic BP values. Neither beta-blocker adversely affected carbohydrate metabolism in terms of insulin sensitivity, whole body glucose utilization, HbA1c and 24-h urinary C-peptide excretion. No significant changes in cholesterol (total, high density and low density lipoprotein) and triglycerides plasma levels were observed with both beta-blockers. These findings indicate that, in hypertensive patients with NIDDM, ie, in subjects who have established insulin resistance, treatment with nebivolol and atenolol neither further deteriorated insulin sensitivity nor adversely affected the lipid profile.
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Antagonistas Adrenérgicos beta/uso terapéutico , Antihipertensivos/uso terapéutico , Atenolol/uso terapéutico , Benzopiranos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Angiopatías Diabéticas/tratamiento farmacológico , Etanolaminas/uso terapéutico , Hipertensión/tratamiento farmacológico , Resistencia a la Insulina , Antagonistas Adrenérgicos beta/efectos adversos , Adulto , Anciano , Antihipertensivos/efectos adversos , Atenolol/efectos adversos , Benzopiranos/efectos adversos , Diabetes Mellitus Tipo 2 , Angiopatías Diabéticas/fisiopatología , Método Doble Ciego , Etanolaminas/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nebivolol , Método Simple CiegoRESUMEN
The efficacy and acceptability of nebivolol 5 mg and enalapril 10 mg, each given once daily, were compared in essential hypertension in a multicentre, randomised, double-blind trial over 3 months. For the index pre-declared variable, sitting diastolic pressure at trough drug level, nebivolol achieved greater falls in pressure (-12.3 vs -9.9 mmHg; P = 0.009) and a higher response rate (70% vs 55%; P = 0.002). The trough-to-peak sitting diastolic ratios also favoured nebivolol (84% vs 60%, P = 0.002). Nebivolol, but not enalapril, slightly but significantly lowered heart rate. Both drugs were well-tolerated, although enalapril was accompanied by a significantly higher incidence of coughing.
Asunto(s)
Antagonistas Adrenérgicos beta/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Benzopiranos/uso terapéutico , Enalapril/uso terapéutico , Etanolaminas/uso terapéutico , Hipertensión/tratamiento farmacológico , Adolescente , Adulto , Anciano , Benzopiranos/efectos adversos , Presión Sanguínea/efectos de los fármacos , Método Doble Ciego , Enalapril/efectos adversos , Etanolaminas/efectos adversos , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Lípidos/sangre , Masculino , Persona de Mediana Edad , Nebivolol , Cooperación del PacienteRESUMEN
BACKGROUND: Nebivolol is a highly cardioselective long-acting beta-blocker with vasodilating properties, which acts in part via the endothelial L-arginine/nitric oxide pathway. As an antihypertensive drug it is effective in once-daily dosage. Nebivolol has previously been shown to improve left ventricular function in patients with cardiac impairment. METHODS AND RESULTS: This paper reports a double-blind randomized trial comparing, in patients with heart failure, once-daily nebivolol 2.5 or 5.0 mg (initiated in all at 2.5 mg) with placebo on a constant background of digitalis plus diuretic. There was with nebivolol no overall deterioration of cardiac function or cardiac symptoms, and especially not of exercise capacity, in comparison with placebo. One patient on nebivolol 2.5 mg developed hypotension and pulmonary edema, and one patient on nebivolol 5 mg, bradycardia. All the remaining patients continued with unchanged diuretic and digitalis dosage. Nebivolol was accompanied by a trend toward clinical and functional improvement; rather better results were obtained with 2.5 than 5.0 mg. CONCLUSIONS: In view of increasing interest in beta-blockade in heart failure, nebivolol merits further study in this context. The capacity of nebivolol to enhance endothelial nitric oxide production appears potentially attractive.
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Antagonistas Adrenérgicos beta/uso terapéutico , Benzopiranos/uso terapéutico , Etanolaminas/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Vasodilatadores/uso terapéutico , Adulto , Anciano , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , NebivololRESUMEN
The aim of this study was to compare the effects on left ventricular function and exercise tolerance of a selective beta-antagonist (atenolol) with those of another selective beta 1-antagonist with vasodilator properties (nebivolol) in patients with ischemic left ventricular dysfunction but no overt congestive heart failure. Beta blockers are widely used in ischemic heart disease, but their effects on left ventricular mechanics and exercise tolerance are poorly defined in the subgroup of patients with significant systolic dysfunction but without clinical evidence of ischemia or congestive heart failure. Angiographic and symptom-limited exercise data were obtained at baseline and after an 8-10-week double-blind treatment with placebo (n = 10), 50 mg atenolol daily (n = 10), or 2.5 mg (n = 10) or 5 mg (n = 10) nebivolol daily. When compared to placebo, both atenolol and nebivolol reduced resting heart rate and improved left ventricular ejection fraction (from 33.9 to 39.2% with atenolol and from 36.5 to 40.8% with nebivolol, both P < .05) while lowering mean systolic wall stress. Only nebivolol, however, produced a parallel downward shift of the pressure-volume relationship during early diastolic filling and improved the early peak filling rate when compared to placebo (+ 10%, P < .05). When compared to baseline, maximal exercise duration increased by 7 and 13 seconds with placebo and atenolol, respectively (both NS vs baseline), and increased by 44 seconds with nebivolol (P = .0077 vs baseline). Both atenolol and nebivolol decreased maximal exercise heart rate; the reduction was more pronounced with atenolol. Prolonged beta 1-adrenoceptor blockade leads to a significant increase in left ventricular ejection fraction in patients with ischemic left ventricular dysfunction. The dissociation between the changes in resting left ventricular function and the changes in exercise duration suggests that in this clinical setting, the changes in systolic function may have less impact on functional capacity than an improvement in diastolic distensibility during the rapid filling phase.
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Antagonistas Adrenérgicos beta/uso terapéutico , Atenolol/uso terapéutico , Benzopiranos/uso terapéutico , Etanolaminas/uso terapéutico , Isquemia Miocárdica/tratamiento farmacológico , Disfunción Ventricular Izquierda/tratamiento farmacológico , Adulto , Anciano , Método Doble Ciego , Prueba de Esfuerzo , Tolerancia al Ejercicio/efectos de los fármacos , Femenino , Estudios de Seguimiento , Hemodinámica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Isquemia Miocárdica/complicaciones , Isquemia Miocárdica/fisiopatología , Nebivolol , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/fisiopatología , Función Ventricular Izquierda/efectos de los fármacos , Función Ventricular Izquierda/fisiologíaRESUMEN
Nebivolol, a beta 1 selective adrenergic receptor antagonist with additional properties, is a racemic mixture of (S,R,R,R)- and (R,S,S,S)-enantiomers. We investigated its effects on human forearm vasculature. Blood flow was measured using venous occlusion plethysmography during brachial artery infusion of drugs. Interaction between nebivolol and the L-arginine/nitric oxide pathway was investigated via comparison with carbachol (an endothelium-dependent agonist) and nitroprusside, and by coinfusion of a competitive inhibitor of nitric oxide synthase, NG-monomethyl L-arginine (LNMMA) +/- L-arginine. Nebivolol (354 micrograms/min) increased blood flow by 91 +/- 18% (mean +/- SEM, n = 8, P < .01) whereas an equimolar dose of atenolol had no significant effect. L-NMMA (1 mg/min) inhibited vasodilation to nebivolol (by 65 +/- 10%) and carbachol (by 49 +/- 8%) to a significantly greater extent than it reduced responses to nitroprusside. Inhibition of nebivolol response by L-NMMA was abolished by L-arginine (62 +/- 11% inhibition by L-NMMA, 15 +/- 17% inhibition by L-NMMA with L-arginine, 10 mg/min, n = 8). Vasodilation caused by the (S,R,R,R)- and (R,S,S,S)-enantiomers was similar. We conclude that nebivolol vasodilates human forearm vasculature via the L-arginine/nitric oxide pathway.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Arginina/fisiología , Benzopiranos/farmacología , Arteria Braquial/efectos de los fármacos , Etanolaminas/farmacología , Óxido Nítrico/fisiología , Vasodilatadores/farmacología , Antagonistas de Receptores Adrenérgicos beta 1 , Antagonistas Adrenérgicos beta/administración & dosificación , Antagonistas Adrenérgicos beta/química , Adulto , Arginina/análogos & derivados , Arginina/farmacología , Benzopiranos/administración & dosificación , Benzopiranos/química , Arteria Braquial/fisiología , Etanolaminas/administración & dosificación , Etanolaminas/química , Antebrazo/irrigación sanguínea , Humanos , Infusiones Intravenosas , Masculino , Nebivolol , Flujo Sanguíneo Regional/efectos de los fármacos , Estereoisomerismo , Vasodilatadores/administración & dosificación , Vasodilatadores/química , omega-N-MetilargininaRESUMEN
(D-L) Nebivolol is a new beta 1-selective adrenoceptor blocker which in normal individuals preserves rest and exercise hemodynamics. We assessed the effects of the enantiomers (L- and D-nebivolol) on left ventricular (LV) systolic and diastolic function and compared their effects with those of the racemic mixture. LV angiography (+Millar) was performed before and after intravenous (i.v.) infusion of either D- or L-nebivolol (1.25-2.5 mg, n = 22) in patients with ischemic heart disease and previous myocardial infarction. Neither L- nor D-nebivolol produced significant changes in heart rate (HR), peak (+) dP/dt, (dP/dt) DP40, cardiac index (CI) or ejection fraction (EF). Diastolic distensibility, evaluated from the shift of the pressure-volume data at the time of mitral valve opening, did not improve after D- or L-enantiomers administration. In contrast, both D-L-nebivolol 2.5 mg (n = 9) and atenolol 15 mg (n = 9) significantly reduced HR and peak (+) dP/dt, but in comparison to atenolol D-L nebivolol improved EF (+4% after D-L nebivolol vs. -4% after atenolol; p < 0.05 D-L nebivolol vs. atenolol) and maintained cardiac output CO, (+2% vs. -21%; p < 0.05 between groups). Moreover, unlike any of the other drugs in the study, the racemate shifted the diastolic pressure-volume data downward, suggesting improved LV distensibility. The beneficial effects of nebivolol on LV systolic and diastolic function appears to require the presence of both D- and L-enantiomers.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Atenolol/farmacología , Benzopiranos/farmacología , Etanolaminas/farmacología , Función Ventricular Izquierda/efectos de los fármacos , Antagonistas Adrenérgicos beta/efectos adversos , Adulto , Anciano , Angiografía , Atenolol/efectos adversos , Benzopiranos/efectos adversos , Presión Sanguínea/efectos de los fármacos , Cateterismo Cardíaco , Gasto Cardíaco/efectos de los fármacos , Etanolaminas/efectos adversos , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Contracción Miocárdica/efectos de los fármacos , Nebivolol , EstereoisomerismoRESUMEN
This prospective, double-blind study used invasive monitoring and echo-Doppler techniques to compare the hemodynamic effects of nebivolol, a new beta 1-selective beta-blocking agent with those of atenolol in patients recovering from coronary artery bypass grafting surgery. Five milligrams nebivolol and 50 mg atenolol equally decreased heart rate (HR) and blood pressure (BP) but, nebivolol, in contrast to atenolol, caused no decrease in stroke index (SI), cardiac index (CI), and right ventricular ejection fraction (RVEF). These differences appeared to be related in part to different peripheral effects of the two agents because nebivolol administration was associated with a reduction in systemic vascular resistance (SVR). After < or = 10 days of treatment, acceleration of aortic flow velocity increased and isovolumic relaxation time decreased with nebivolol but not with atenolol treatment. Both drugs were equally well tolerated. Therefore, nebivolol shares most of its effects with classical beta 1-blockers but is devoid of the potentially harmful effects on cardiac output (CO) and peripheral resistance.
Asunto(s)
Antagonistas Adrenérgicos beta/uso terapéutico , Función del Atrio Izquierdo/efectos de los fármacos , Benzopiranos/uso terapéutico , Puente de Arteria Coronaria/efectos adversos , Etanolaminas/uso terapéutico , Complicaciones Posoperatorias/prevención & control , Antagonistas de Receptores Adrenérgicos beta 1 , Antagonistas Adrenérgicos beta/efectos adversos , Anciano , Atenolol/efectos adversos , Atenolol/uso terapéutico , Benzopiranos/efectos adversos , Volumen Sanguíneo/efectos de los fármacos , Volumen Sanguíneo/fisiología , Método Doble Ciego , Ecocardiografía Doppler , Etanolaminas/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nebivolol , Complicaciones Posoperatorias/diagnóstico por imagen , Estudios Prospectivos , Volumen Sistólico/efectos de los fármacos , Taquicardia Supraventricular/prevención & control , Transductores de Presión , Resistencia Vascular/efectos de los fármacosRESUMEN
Nebivolol is a novel selective beta 1-adrenergic antagonist with an unusual haemodynamic profile. It improves left ventricular function in normals and in patients with a damaged left ventricle. We compared the cardiac effects of a 14-day treatment period with 10 mg o.d. of bisoprolol, 400 mg o.d. of celiprolol, 25 mg o.d. of carvedilol and 5 mg o.d. of nebivolol in a placebo-controlled crossover study in 7 volunteers with a mean age of 39 (range 30-53) years. Cardiac haemodynamics were assessed serially by means of systolic time intervals. The ratio of the preejection period to the left ventricular ejection time (PEP/LVET) was used as a indirect measure of left ventricular performance. The results show that the PEP/LVET is a very sensitive and reproducible index of left ventricular function. During treatment with placebo and bisoprolol no changes occurred; during treatment with celiprolol and carvedilol a significant but transient decrease of PEP/LVET occurred, and only during treatment with nebivolol a long-lasting and significant decrease of PEP/LVET occurred. With bisoprolol an increase of PEP and QS2c (total electromechanical systole) was observed, indicative of a negative inotropic effect. In conclusion, nebivolol, in contrast with both classical and vasodilating beta-blocking agents, substantially improves left ventricular function, possibly due to an improvement of diastolic function and left ventricular compliance, which may be of therapeutical value in the treatment of congestive heart failure.