Solid-phase microextraction for assessment of plasma protein binding, a complement to rapid equilibrium dialysis.

Aim: Determination of plasma protein binding (PPB) is considered vital for better understanding of pharmacokinetic and pharmacodynamic activities of drugs due to the role of free concentration in pharmacological response. Methodology & results: Solid-phase microextraction (SPME) was investigated for measurement of PPB from biological matrices and compared with a gold standard approach (rapid equilibrium dialysis [RED]). Discussion & conclusion: SPME-derived values of PPB correlated well with literature values, and those determined by RED. Respectively, average protein binding across three concentrations by RED and SPME was 33.1 and 31.7% for metoprolol, 89.0 and 86.6% for propranolol and 99.2 and 99.0% for diclofenac. This study generates some evidence for SPME as an alternative platform for the determination of PPB.

Multi-dry-electrode plate sensor for non-invasive electrocardiogram and heart rate monitoring for the assessment of drug responses in freely behaving mice.

Monitoring of electrocardiogram (ECG) and heart rate (HR) is essential in a wide range of experiments. For conscious animal studies, telemetry is the preferred approach; however, it requires 1-3 weeks of recovery after surgical device-implantation. The present paper describes a novel multi-dry-electrode plate (MDEP) sensor system to monitor ECG/HR in freely behaving mice without the need for surgery for device/electrode implantation. The MDEP sensor is a rectangular plate with 15 gold-plated stripe pattern electrodes, on which a mouse can walk around freely, and detects ECG whenever ≥2 paws (footpads) come in contact with the electrodes. Here we show that the MDEP sensor detected distinct QRS complexes which, were fragmented due to locomotion and insufficient perspiration on the footpads. Nonetheless, the HR calculated from the QRS complexes were similar to the HR calculated from R-R intervals simultaneously recorded from lead-II ECG (difference = 0.0 ±â€¯0.16 ms) as part of the validation exercise. Also, the archetypal responses to isoproterenol and metoprolol injections were successfully detected as a significantly elevation (+151 ±â€¯15 bpm) and reduction (-77 ±â€¯6 bpm) in HR, respectively, compared to vehicle at 20-60 min postdose. Conversely, the P wave was rarely identifiable unless signal averaging was undertaken. These results indicate a potential utility for the MDEP-sensor system for cardiac pharmacological studies. In addition, signal averaging appeared to be effective for detection of ECG intervals such as PR and QT, although the QT cannot be measured in the mouse heart as there is no T wave.

Cost-effectiveness of nitrendipine and hydrochlorothiazide or metoprolol to treat hypertension in rural community health centers in China.

OBJECTIVES: The objective of this article is to compare blood pressure (BP)-lowing effects of nitrendipine and hydrochlorothiazide and nitrendipine and metoprolol, and estimate the economic effect of these therapies on hypertension. METHODS: Outpatients (N = 793) 18-70 years of age with stage 2 or severe hypertension (SBP ≥ 160 mmHg and/or DBP ≥ 100 mmHg) were recruited from four randomly selected rural community health centers in Beijing and Jilin. After drug wash out, they were randomly divided into nitrendipine and hydrochlorothiazide group or nitrendipine and metoprolol group. The costs of drug treatment for hypertension were calculated and general estimation, whereas effectiveness was measured as a reduction in SBP and DBP at the end of a 24-week study period. RESULTS: Overall, 623 patients were eligible for the study and after a 24-week follow-up, SBP and DBP were 131.2/82.2 mmHg for the nitrendipine and hydrochlorothiazide group and 131.4/82.9 mmHg for the nitrendipine and metoprolol group and these were not significantly different (P = 0.7974 SBP and P = 0.1166 DBP). Comparing with nitrendipine and metoprolol, the cost of nitrendipine and hydrochlorothiazide was less, and its effectiveness was similar. The cost/effect ratio (US$/mmHg) was 1.4 for SBP and 2.8 for DBP for the nitrendipine and hydrochlorothiazide group, and 1.9 and 3.8 for the nitrendipine and metoprolol group's SBP and DBP values, respectively. The incremental cost per patient for achieving target BP was 5.1. Adverse events were mild or moderate and there were no differences between treatment groups. CONCLUSION: Treating hypertension with nitrendipine and hydrochlorothiazide was cost-effective than nitrendipine and metoprolol, and these data will allow more reasonable and efficient allocation of limited resources in low-income countries.

Promising approach for the preclinical assessment of cardiac risks using left ventricular pressure-volume loop analyses in anesthetized monkeys.

INTRODUCTION: Load-independent cardiac parameters obtained from the ventricular pressure-volume relationship are recognized as gold standard indexes for evaluating cardiac inotropy. In this study, for better analyses of cardiac risks, load-independent pressure-volume loop parameters were assessed in addition to load-dependent inotropic, hemodynamic and electrocardiographic changes in isoflurane-anesthetized monkeys. METHODS: The animals were given milrinone (a PDE 3 inhibitor), metoprolol (a ß-blocker), or dl-sotalol (a ß+IKr blocker) intravenously over 10min at two dose levels including clinically relevant doses (n=5/drug). RESULTS: Milrinone and metoprolol produced positive and negative inotropy, respectively. These effects were detected as changes in the slope of the preload-recruitable stroke work, which is a load-independent inotropic parameter. However, dl-sotalol did not alter the slope of the preload-recruitable stroke work. That means dl-sotalol produced no inotropy, although it decreased load-dependent inotropic parameters, including maximal upstroke velocity of left ventricular pressure, attributable to decreased heart rate and blood pressure. Other typical pharmacological effects of the compounds tested were also detected. Both ß-blockers produced PR prolongation, decreased left ventricular end-systolic pressure, increased left ventricular end-diastolic pressure, and increased maximal descending velocity of left ventricular pressure and time constant for isovolumic relaxation. dl-Sotalol also prolonged heart-rate-corrected QT interval. Milrinone induced reflex tachycardia, PR shortening, and decreased left ventricular end-diastolic pressure. DISCUSSION: The overall assessment by not only load-dependent inotropic parameters but also load-independent parameters obtained from the ventricular pressure-volume loop analysis using monkeys can provide further appropriate information for the assessment of drug-induced cardiac risks.

[The benefits of carvedilol therapy in the treatment of patients with high cardiovascular risk]. / A carvedilolterápia elonyei magas cardiovascularis kockázatú betegek kezelése során.

Among the variety of cardiologic pharmacological therapy options, beta-blockers stand on a prominent position. There are several reasons for this. On one hand they have numerous indication rounds, even though professional guidelines have recently tended to de-emphasize them for treatments of hypertension without complication or comorbidity. However, in addition to hypertonic cases associated with cardiac complication, they play a fundamental role in treating heart failure and arrhythmia and the different clinical manifestations (stable angina pectoris, myocardial state) of ischemic heart disease. The decade long development of the pharmacological group made its hemodynamic effects ever more refined. On the other hand we must not neglect the fact that more and more features came to light that positively influence the outcome of cardiovascular diseases. Verification of these latter features in numerous multicentric studies showed how to achieve a beneficial effect on survivability, independent on even hemodynamic effects during beta-blocker therapy.

Assessment of the potential drug-drug interaction between carvedilol and clopidogrel mediated through intestinal P-glycoprotein.

The most widely prescribed oral antiplatelet agent, clopidogrel, shows high interindividual variability resulting in an increased risk of cardiovascular events in the patients with reduced platelet inhibition. The purpose of this study was to investigate the role of the P-glycoprotein (P-gp) efflux pump in limiting the intestinal permeability of clopidogrel and the effect of a ß-blocker, namely, carvedilol, on its intestinal transport. Effective permeabilities (Peff) of clopidogrel and carvedilol were investigated in the proximal jejunum and distal ileum of rats using an in situ intestinal perfusion model. Peff values of clopidogrel and carvedilol were found to be concentration dependent with decreased Peff values at the low perfusate concentrations. Coperfusion with the P-gp inhibitors verapamil (100 µM) and carvedilol (10 µM) significantly increased the Peff of clopidogrel in the jejunum (8.31±0.20 x 10-5 and 6.98±0.75 x 10-5 vs. 3.60±0.51 x 10-5, respectively) and ileum (9.08±2.19 x 10-5 and 8.35±1.58 x 10-5 vs. 3.85±0.15 x 10-5, respectively). However, at the highest concentration tested (30 µM), clopidogrel exhibited 3 and 1.4 times higher Peff than those of metoprolol, an FDA high permeability reference standard, in the jejunum and ileum, respectively. Overall, this study indicates that the efflux function appears not to have a significant impact on the in vivo intestinal absorption of clopidogrel due to the saturation of P-gp, suggesting no clinically relevant interaction between carvedilol and clopidogrel mediated through P-gp at intestinal level.

Functional and histological assessment of an experimental model of Takotsubo's cardiomyopathy.

BACKGROUND: Our objectives were to characterize functional and structural features of an experimental model of Takotsubo cardiomyopathy, and its response to beta-blockers. METHODS AND RESULTS: In protocol 1, a dose-finding study: 69 rats received various doses of isoproterenol (ISO) and echocardiographic and histologic parameters were measured on days 2 to 3 or day 8. There were no dose-dependent effects and, out of 69 ISO-treated rats, 40 (58.0%) survived and 29 (42.0%) died within 24 hours. Of survivors, 30 had apical akinesis averaging 12.1 ± 1.6% of the long axis LV circumference. Out of the 40 survivors, 32.5% showed apical akinesis ≥ 10%, 42.5% showed akinesis<10% and 25% showed no apical akinesis. The basal portion of the LV was always preserved. At 24 hours, histology and ultrastructure showed necrosis, vacuolization, lipid droplets, mononuclear cell infiltration, damaged mitochondria, and edema. On day 8, apical akinesis fully resolved but histologic abnormalities were still present. In protocol 2, rats were randomized to Control; ISO100 mg/kg; propranolol+ISO; and metoprolol+ISO groups. Pretreatment with propranolol and metoprolol improved survival to 90% and 100% respectively, compared with 60% in the ISO group, but did not reduce the incidence and extent of akinesis or the structural damage. CONCLUSION: TC can be mimicked in a rat model of ISO exposure that demonstrates apical akinesis on days 2 to 3 with full recovery of systolic regional wall motion abnormality despite the presence of persistent foci of necrosis and fibrosis on day 8. Pretreatment with beta-blockers improved survival but did not affect structural and functional alterations.

Simultaneous pharmacokinetics assessment of caffeine, warfarin, omeprazole, metoprolol, and midazolam intravenously or orally administered to Microminipigs.

Small minipigs (Microminipig, registered as a novel variety of pig in Japan) were developed for use in non-clinical pharmacological/toxicological studies for new drug development. To assess the pharmacokinetics of selective substrates of human cytochrome P450s in Microminipigs, caffeine (human P450 1A2), warfarin (P450 2C9), omeprazole (P450 2C19), metoprolol (P450 2D6), and midazolam (P450 3A) were administered in combination, intravenously (0.20 mg kg(-1))( )or orally (1.0 mg kg(-1)). Plasma samples obtained, up to 24 hr after dosing, from four male and four female Microminipigs were analyzed by liquid chromatography tandem mass spectrometry to estimate typical pharmacokinetic parameters for each analyte. Bioavailabilities were approximately 80% for caffeine and warfarin, but less than 10% for omeprazole, metoprolol, and midazolam. No significant differences were noted, for the five probes, in area under the plasma concentration-time curve and peak plasma concentration values obtained from male and female Microminipigs. Clearance of caffeine, warfarin, omeprazole or midazolam in vivo, mediated mainly by cytochrome P450s 1A, 2C or 3A in Microminipigs, was similar to data reported for human. However, metoprolol metabolism, mediated by P450 2D enzymes in Microminipigs, was faster than reported for in vivo human kinetic parameters and in vitro in a human liver microsomal system. The results of this study suggest that the Microminipig is a suitable animal model for use in biological experiments for comparisons of pharmacokinetics of drugs in humans. The five-probes in combination used in this study demonstrate the disposition of typical P450 drugs in Microminipigs in vivo, with the aim of use in non-clinical pharmacological/toxicological studies.

Safety and accuracy of multidetector row computed tomography for early assessment of residual stenosis of the infarct-related artery and the number of diseased vessels after acute myocardial infarction.

BACKGROUND: Recent studies reveal that contrast-enhanced multidetector row computed tomography (MDCT) is a promising technique for noninvasive visualization of coronary artery stenoses. We investigated the safety and accuracy of MDCT for early assessment of the severity of residual stenosis of the infarct-related artery (IRA) and the number of diseased vessels in patients after acute myocardial infarction (AMI). METHODS AND RESULTS: Of 146 AMI cases admitted, 72 fit with criteria and underwent 16-slice MDCT (4 +/- 2 days after AMI) with beta-blockers. There were no complications except 1 patient who had from complete atrioventricular block. Results were compared with conventional coronary angiography (CCA) within 3 days. In 55 (73.3%) of 72 patients, all arteries were assessable. In total, the number of assessable arteries was 253 (87.8%), and 35 (12.2%) vessels were nonassessable, mostly because of motion artifacts and extensive calcification. Overall, 84 of the 115 lesions (> or = 50% lumen reduction) were correctly detected by MDCT (sensitivity 73.0%). The accuracy in classifying patients with nonsignificant, single-, or multiple-vessel diseases was 79.1%. The accuracy for residual lesions with >50% stenosis of IRA was 87.5%. There was a good correlation regarding the severity of residual stenosis of the IRA (0%, 1%-49%, 50%-89%, 90%-99%, or occlusion) between MDCT and CCA (Spearman correlation 0.94, P < .001). Lesions with 90% to 99% or occlusion of the IRA were accurately detected or ruled out in 31 of 36 cases (86.1%). CONCLUSIONS: With appropriate protocol, MDCT is safe and accurate in assessing the severity of IRA and the number of diseased vessels during the first week after AMI. It has the potential to provide triage for early management of patients after AMI.

Quantitative assessment of regional peak myocardial acceleration during isovolumic contraction and relaxation times by tissue Doppler imaging.

OBJECTIVE: To examine regional wall acceleration and its relation to relaxation. STUDY DESIGN: 8 sheep were examined by tissue Doppler ultrasound imaging (VingMed Vivid FiVe) in apical four chamber views to evaluate the left ventricular wall divided into six segments and the mitral annulus in two segments. Peak myocardial acceleration during isovolumic periods (pIVA) derived from tissue Doppler echocardiography was analysed during isovolumic contraction (ICT) and relaxation times (IRT) in each segment. INTERVENTIONS: After scanning at baseline, haemodynamic status was changed by administration of blood, dobutamine, and metoprolol. Changes of pIVA during IRT and ICT were compared over the four haemodynamic conditions in parallel with their peak positive and negative dP/dt measured with a high frequency manometer tipped catheter. RESULTS: pIVA of the basal lateral segment during ICT correlated most strongly with peak positive dP/dt (r = 0.96, p < 0.0001) and there was good correlation between pIVA of the mitral valve annulus in the septum during IRT and peak negative dP/dt (r = 0.80, p < 0.0001). pIVA differed significantly between the four haemodynamic conditions during ICT in all segments (p < 0.05); pIVA during IRT did not differ significantly between the four conditions. CONCLUSIONS: pIVA of the basal lateral wall during ICT correlated most strongly with peak positive dP/dt, and pIVA of the septal mitral valve annulus during IRT correlated well with peak negative dP/dt.

Assessment of in vivo CYP2D6 activity: differential sensitivity of commonly used probes to urine pH.

Drug/metabolite ratios (MRs) are used as in vivo markers of enzyme activity. The ratios are potentially confounded by the renal clearance of the drug (urine-based MRs) or metabolite (plasma-based MRs). The authors have investigated the relative sensitivity of urinary MR of 3 in vivo probe substrates of CYP2D6 debrisoquine (DB), dextromethorphan (DM), and metoprolol (MP) to changes in urine pH. Three groups of healthy volunteers each comprising 12 individuals were given DB (10 mg), DM (25 mg), or MP (100 mg) on 3 occasions. In 1 study arm, urine was acidified by the oral intake of ammonium chloride; in another, it was alkalinized by intake of sodium bicarbonate; and in the third, urine pH was uncontrolled. Urinary MP/alpha-hydroxy-MP, DM/dextrorphan, and DB/4-hydroxy-DB ratios were calculated. The mean(geo) MR for DB was not significantly different in any of the study arms, whereas those for MP and DM were significantly different under acidified and alkalinized urine conditions compared to uncontrolled urine pH (P < .01) and were correlated with urine pH (P < .001). Without control of urine pH, in vivo estimates of CYP2D6 metabolic activity are likely to be less precise using DM or MP as probe substrates compared to DB. Although this is unlikely to cause any problem in distinguishing the large functional differences in CYP2D6 in poor metabolizer (PM) and extensive metabolizer (EM) phenotypes, this may contribute to difficulties in differentiating in vivo metabolic activity among allelic variants within the overall CYP2D6 EM phenotype using MP or DM. However, because DB is not available in many countries (eg, United States), alternative in vivo markers of CYP2D6 with low sensitivity to urine pH should be sought.

A convenient five-drug cocktail for the assessment of major drug metabolizing enzymes: a pilot study.

AIMS: To assess the feasibility of administering at the same time low doses of five probe drugs, metoprolol (25 mg), chlorzoxazone (250 mg), tolbutamide (250 mg), dapsone (100 mg) and caffeine (100 mg) to determine simultaneously the activities of CYP2D6, CYP2E1, CYP2C9, CYP3A4, CYP1A2, N-acetyltransferase-2 and xanthine oxidase. METHODS: Ten healthy young non-smoking males received the following drugs or combinations of drugs over a 5-week period: week 1) metoprolol; 2) tolbutamide; 3) caffeine, chlorzoxazone and dapsone; 4) caffeine, chlorzoxazone, dapsone and metoprolol; 5) caffeine, chlorzoxazone, dapsone, metoprolol and tolbutamide. The drugs were self-administered at bedtime and urine was collected for the following 8 h. RESULTS: Mean molar phenotypic ratios obtained after administering metoprolol (mean change of -11%) or tolbutamide (mean change of -0.3%) alone, were not significantly different from those obtained when other drugs were co-administered (P > 0.05). The mean within-subject coefficients of variation were 33%, 18%, 22%, 13%, 16%, 13% and 5% for CYP3A4, CYP2D6, CYP2C9, CYP2E1, CYP1A2, N-acetyltransferase 2 and xanthine oxidase metabolic ratios, respectively. No significant interactions (P > 0.5) were observed during the simultaneous administration of various combinations of the five probe drugs. CONCLUSIONS: We propose that this cocktail, composed of five widely available drugs, constitutes a promising means of simultaneously determining the activities of the major CYP enzymes in large populations.

Cerebral carbohydrate cost of physical exertion in humans.

Above a certain level of cerebral activation the brain increases its uptake of glucose more than that of O(2), i.e., the cerebral metabolic ratio of O(2)/(glucose + 12 lactate) decreases. This study quantified such surplus brain uptake of carbohydrate relative to O(2) in eight healthy males who performed exhaustive exercise. The arterial-venous differences over the brain for O(2), glucose, and lactate were integrated to calculate the surplus cerebral uptake of glucose equivalents. To evaluate whether the amount of glucose equivalents depends on the time to exhaustion, exercise was also performed with beta(1)-adrenergic blockade by metoprolol. Exhaustive exercise (24.8 +/- 6.1 min; mean +/- SE) decreased the cerebral metabolic ratio from a resting value of 5.6 +/- 0.2 to 3.0 +/- 0.4 (P < 0.05) and led to a surplus uptake of glucose equivalents of 9 +/- 2 mmol. beta(1)-blockade reduced the time to exhaustion (15.8 +/- 1.7 min; P < 0.05), whereas the cerebral metabolic ratio decreased to an equally low level (3.2 +/- 0.3) and the surplus uptake of glucose equivalents was not significantly different (7 +/- 1 mmol; P = 0.08). A time-dependent cerebral surplus uptake of carbohydrate was not substantiated and, consequently, exhaustive exercise involves a brain surplus carbohydrate uptake of a magnitude comparable with its glycogen content.

Effect of beta-blockade on low-dose dobutamine-induced changes in left ventricular function in healthy volunteers: assessment by gated SPET myocardial perfusion scintigraphy.

Viability studies are often performed in patients receiving beta-blocking agents. However, the intake of beta-blocking agents could influence the identification of viable myocardium when low-dose dobutamine is used to demonstrate inotropic reserve. The aim of this study was to quantify the effect of beta-blockade on global and regional left ventricular function in healthy volunteers using low-dose dobutamine gated single-photon emission tomographic (SPET) myocardial perfusion scintigraphy. Ten subjects were studied once "on" and once "off" beta-blocker therapy (metoprolol succinate, 100 mg day(-1)). On each occasion four consecutive gated SPET acquisitions (of 7 min duration) were recorded after injection of 925 MBq technetium-99m tetrofosmin on a triple-headed camera equipped with focussing (Cardiofocal) collimators. Acquisitions were made at rest (baseline 1 and 2) and 5 min after the beginning of the infusion of 5 and 10 microg kg(-1) min(-1) dobutamine. Wall thickening (WT) was quantified using a method based on circumferential profile analysis. Left ventricular ejection fraction (LVEF) was obtained using the Cedars-Sinai algorithm. Blood pressure (BP) and heart rate (HR) were recorded at the end of each acquisition. At baseline LVEF, WT and systolic BP values under beta-blockade were not significantly different from those obtained in the non-beta-blocked state. The mean HR and diastolic BP at baseline were lower under beta-blockade. Dobutamine administration (at 5 and 10 microg kg(-1) min(-1)) induced a significant increase in WT, LVEF and systolic BP in all subjects both on and off beta-blockade. The increases in WT, LVEF and systolic BP in the beta-blocked state were less pronounced but not significantly different. HR increased significantly at 10 microg kg(-1) min(-1) dobutamine without beta-blocker administration, while no increase in HR was observed in the beta-blocked state. Beta-blocker therapy in healthy subjects attenuates the inotropic and chronotropic myocardial response to low-dose dobutamine. At doses of 5 and 10 microg kg(-1) min(-1) dobutamine, however, significant increases in global and regional left ventricular function can still be measured using consecutive gated SPET myocardial perfusion scintigraphy acquisitions even under beta-blocker therapy.

Miocardiopatía hipertrófica potencialmente obstructiva y la utilidad del eco-estrés en su valoración funcional: relato de un caso / Hypertrophic potentially obstructive myocardiopathy and the utility of the echo-stress in its functional evaluation

Se propone el empleo del eco-estrés farmacológico o por ejercicio físico para la valoración funcional de la miocardiopatía hipertrófica en sus diferentes variedades (la septal asimétrica y medioventricular en especial, así como también en el control "de salud" del deportista en actividades isométricas y alta competición que desarrollan severas hipertrofias), ya sea para el estudio hemodinámico por Doppler y búsqueda de gradientes intraventriculares ausentes en el reposo, como así también para el análisis de la contractilidad sectorial en la detección de isquemia miocárdica. Hipótesis de trabajo ésta, que surgió del caso clínico presentado, de una paciente con cardiopatía hipertrófica obstructiva con leve gradiente en reposo, con angor de esfuerzo, estudios de perfusión radioisotópicos positivos y coronariografía sin lesiones significativas de vasos subepicárdicos, que en el apremio con dobutamina presentó un gradiente medio ventricular mayor de 120 mm Hg. Dado lo amigable de la técnica, su poca invasividad y bajo costo fue posible la semicuantificación seriada de los diferentes parámetros diagnósticos y reproducir en el laboratorio cardiológico su vida diaria sintomática. También nos permitió el testeo de la terapéutica indicada

The effects of antianginal drugs on energy expenditure during exercise in normal subjects.

The respiratory quotient (RQ = VCO2/VO2) provides important information (ie, the ratio of carbohydrate to fat utilization) concerning energy expenditure. We studied the effects of various antianginal drugs on energy expenditure during steady-state aerobic exercise in 9 healthy adult men. The drugs used were propranolol (a non-selective beta-blocker), metoprolol (a beta-1 selective blocker), amosulalol (an alpha- and beta-blocker), nicardipine (a calcium antagonist) and isosorbide dinitrate. Each drug was administered for 2 weeks, followed by a 2-week washout period. VO2, VCO2 and RQ were measured with an expired gas analyzer during treadmill exercise tests before and during the administration of each drug. Two protocols of constant-load exercise were performed: Protocol 1 lasted for 10 min at a speed of 5.5 km/h and a grade of 0%, (at a level of about 30% peak VO2), while Protocol 2 lasted for 10 min at a speed of 7 km/h and a grade of 0%, (at a level of about 40% peak VO2). RQ during exercise was significantly increased and VO2 was decreased after propranolol, metoprolol and amosulalol (P < 0.05). Neither nicardipine nor isosorbide dinitrate produced significant changes in these values. These data suggest that propranolol, metoprolol and amosulalol increase the efficiency of energy expenditure during ordinary physical activity by increasing the utilization of carbohydrate and by decreasing the utilization of fat.

Metoprolol: a pharmacoeconomic and quality-of-life evaluation of its use in hypertension, post-myocardial infarction and dilated cardiomyopathy.

Metoprolol is a beta 1-selective adrenoceptor antagonist that is widely used in several indications. A recent investigation has also highlighted a potential role for metoprolol in selected patients with idiopathic dilated cardiomyopathy. Pharmacoeconomic and quality-of-life data for metoprolol are limited to the areas of hypertension, post-myocardial infarction and idiopathic dilated cardiomyopathy. In these settings, metoprolol has shown beneficial effects on morbidity and mortality, or closely-related end-points. Controlled release formulations offer the potential to maximise the confirmed antihypertensive benefits of metoprolol by maintaining clinically effective plasma drug concentrations within a narrow range over a 24-hour interval between doses. Recent data support the use of controlled release metoprolol at the low dose of 50 mg/day. Metoprolol is at least as effective as many other antihypertensive drugs, although compared with thiazide diuretics at relatively high doses in the MAPHY (Metoprolol Atherosclerosis Prevention in Hypertensives) trial, metoprolol was associated with a more favourable effect on mortality. Pharmacoeconomic analysis, also based on the MAPHY trial, indicates that metoprolol is more cost effective than high dose thiazide diuretics in middle-aged men with mild to moderate hypertension. However, the advantage for beta-blockade in this trial is not supported by results of other studies, and the applicability of these data to current medical practice using lower thiazide doses is therefore questionable. Quality of life in patients with mild to moderate hypertension did not deteriorate in most investigations with metoprolol. Furthermore, quality of life was similar for controlled release metoprolol and atenolol. With conventional/matrix-based sustained release metoprolol, quality of life was less satisfactory than with lisinopril but was only marginally different from that with diltiazem (at lower than usual therapeutic doses). Nevertheless, these newer agents have no proven beneficial effect on mortality, and further studies are also warranted with controlled release metoprolol 50 mg/day. When administered post-myocardial infarction, conventional metoprolol was associated with significant improvements in quality of life and was cost saving over a 3-year period. Significant improvements in quality of life were also evident for metoprolol-treated patients with idiopathic dilated cardiomyopathy. In summary, available data support the continued extensive usage of metoprolol as treatment for hypertension and as therapy post-myocardial infarction. Pharmacoeconomic data supporting an advantage for metoprolol over high dose thiazides in hypertension needs further assessment in settings reflecting usual general practice approaches to managing patients with hypertension, while differences in quality of life between metoprolol and other antihypertensive agents appear to be marginal.(ABSTRACT TRUNCATED AT 400 WORDS)

High-dose intravenous beta 1-blockade in patients early after cardiac operations. Negative inotropism versus myocardial oxygen economy.

A high adrenergic strain during reperfusion after ischemia impedes functional recovery. Conversely, adrenergic blockade may be beneficial during reperfusion. Negative inotropic effects may outweigh the expected benefit, however. Against this background hemodynamic and metabolic effects of early postoperative infusion with the beta 1-selective agent metoprolol were studied in 22 patients after coronary operations. During basal postoperative conditions, intravenous metoprolol reduced cardiac index and stroke volume index compared with control patients, while other variables were unaffected. During the higher adrenergic level of a dopamine infusion (7 micrograms/kg per minute), the heart rate, rate pressure product, and myocardial oxygen uptake were attenuated in proportion to the plasma level of metoprolol. Intravenous beta 1-blockade did not affect the cardiac output or stroke volume responses to dopamine (the cardiac output was still, however, 19% lower than in control patients). A release of myocardial creatinine kinase isoenzyme myocardial band was observed during dopamine infusion, suggesting that myocardial ischemia was induced. The release was not influenced by metoprolol, but it correlated with heart rate (r = 0.60; p < 0.01). It is concluded that infusion of metoprolol early after coronary operations depresses myocardial contractility with some 19%, which was without clinical significance in straightforward patients; the increased myocardial metabolic demand during a period of increased adrenergic stress was attenuated by metoprolol. This may be of importance for myocardial recovery.

Assessment of the beta 2 adrenoceptor and Ca2+ channel-blocking activity of drugs with the rat portal vein.

The rat portal vein has spontaneous mechanical activity. The effects of beta-adrenoceptor agonists and antagonists and verapamil alone and together on this mechanical activity have been determined. Isoprenaline, but not dobutamine, attenuated the contractile activity. Three successive challenges to isoprenaline produced identical attenuation curves. The responses to isoprenaline were antagonized by propranolol, metoprolol, and ICI 118,551, and the pA2 values, derived by Schild analysis, were 9.12, 6.78, and 9.33, respectively. Thus, the rat portal vein contains predominantly beta 2-adrenoceptors. Verapamil attenuated the contractile activity of the rat portal vein, and this attenuation was not altered by the presence of propranolol at 10(-5) M. The potencies of isoprenaline and propranolol were not altered by the presence of a 30% attenuation of the contractile activity with verapamil at 10(-7) M. Thus, the rat portal vein may be used to determine the potencies of drugs as beta 2-adrenoceptor antagonists and as voltage dependent calcium channel blockers. In addition, the potency of drugs as beta 2-adrenoceptor antagonists on the rat portal vein may be determined in the presence of some voltage dependent calcium channel blockade.

Simultaneous assessment of membrane-stabilizing and beta-adrenoceptor blocking activity of drugs with the rat isolated left atria.

Three consecutive challenges of the rat isolated left atria with electrical stimulation and then electrical stimulation and isoprenaline were made. The responses to electrical stimulation decreased and the responses to isoprenaline increased with consecutive challenges such that the maximal combined response to electrical stimulation and isoprenaline remained constant. The sensitivity (pD2) to isoprenaline decreased with successive challenges. Thus, in studies of the effects of drugs on the responses to electrical stimulation and isoprenaline, it is necessary to perform parallel experiments with untreated atria to monitor changes in the responses unrelated to the addition of drug. Analysis of the effects of procaine, metoprolol, and propranolol on the responses to electrical stimulation and/or isoprenaline demonstrated distinct contractile manifestations of beta-adrenoceptor blocking and membrane stabilizing activity. The beta-adrenoceptor blocking activity of metroprolol at 10(-7) M and propranolol (3 X 10(-9)-10(-6) M) consisted of parallel rightward shifts of the concentration-response curves to isoprenaline alone. There were three components to the membrane-stabilizing action of drugs: first, there was a decrease in the responses to electrical stimulation alone, which was observed with procaine at greater than or equal to 10(-4) M and propranolol at greater than or equal to 3 X 10(-9) M, second, there was a small parallel rightward shift of concentration-response curve to isoprenaline alone with metoprolol at 10(-6) M and propranolol at 3 X 10(-6) M (that the inhibitory effects of metoprolol at 10(-6) M or propranolol at 3 X 10(-6) M are greater than can be explained by beta-adrenoceptor blockade only may be detected either by determining pA2 values from the formula pA2 = pAx + log(x - 1) or by Schild analysis); third, the highest concentrations of procaine (3 X 10(-4) M) and propranolol (10(-5) M) tested decreased the maximal combined response to electrical stimulation and isoprenaline.