Selective beta-1 receptor blockade with oral practolol in man. A dose-related phenomenon.

The purpose of this study was to test the hypothesis that oral administration of a low dose of practolol in man produces selective beta-1 receptor blockade, whereas oral administration of a high dose blocks both beta-1 and beta-2 receptors. Normal men were studied 2-4 h after a single oral dose of practolol (1.5 or 12 mg/kg) and after placebo. Effects on beta-1 receptors were studied by measuring heart rate responses to exercise. Effects on beta-2 receptors were tested by measuring forearm vascular responses to brachial arterial infusions of isoproterenol. Neither dose of practolol altered base-line heart rate, forearm vascular resistance, and arterial pressure, Both low and high doses significantly attenuated heart rate responses to exercise. Forearm vasodilator responses to isoproterenol were attenuated by the high dose, but not the low dose, of practolol. Serum concentrations of practolol 2 h after administration of the drug and at the time of the studies of forearm vascular responses averaged 0.5+/-0.1 (SE) and 5.9+/-1.0 mug/ml for low and high doses of practolol, respectively. The results indicate that the phenomenon of selective beta-1 receptor blockade in man is related to the dose and serum concentration of practolol selectively block beta-1 receptors; a high dose and serum concentrations block both beta-1 and beta-2 receptors.

Liquid-phase microextraction based on carrier mediated transport combined with liquid chromatography-mass spectrometry. New concept for the determination of polar drugs in a single drop of human plasma.

Recently, we demonstrated for the first time liquid-phase microextraction (LPME) of polar drugs based on carrier mediated transport. In this new extraction technique, selected analytes were extracted as ion-pairs from small volumes of biological samples, through a thin layer of a water immiscible organic solvent immobilised in the pores of a porous hollow fibre (liquid membrane), and into a microl volume of an acidic aqueous acceptor solution placed inside the lumen of the hollow fibre. In the current paper, this new extraction technique was combined with liquid chromatography-mass spectrometry (LC-MS) for the first time. Carrier mediated LPME was evaluated for several new model drugs (0.01

Effects of practolol on exercise tolerance and cardiac haemodynamics and metabolism in patients with coronary artery disease.

Sixteen male patients with typical angina pectoris secondary to coronary atherosclerosis performed two daily standardized exercise tests during two consecutive days. Three hours before each exercise they received placebo or 400 mg practolol administered orally in double-blind fashion in order to complete a cross-over design. Practolol significantly prolonged the exercise duration by 30.6% and delayed the appearance time of ischaemic electrocardiographic changes by 67.7%. Maximal heart rate, systolic pressure, and pressure-rate product were also reduced after medication. In order to investigate further the effects of this beta blocking agent, myocardial function and metabolism at rest and during supine exercise were assessed in 12 male patients with coronary artery disease before and after practolol 30 mg, iv. At rest, practolol produced a decrease in tension-time index (18%), cardiac index (17%), heart rate (10%), and stroke index (7%). A significant reduction was also observed in resting stroke work index (14%) and systolic and mean aortic pressure (6%). Left ventricular end-diastolic pressure remained unchanged. During supine exercise, only time-tension index (12%), heart rate (12%), and cardiac index (10%) were significantly reduced after the beta blocking agent. Practolol did not significantly change the arterial glucose, lactate, inorganic phosphate, potassium, calcium, magnesium, pH, PCO2, or PO2. The beta blocking agent did not modify the myocardial extraction of any of these substrates at rest or during exercise. In the dosage used in both studies, practolol significantly improved the exercise tolerance and reduced the ischaemic manifestations. The efficacy of practolol in angina pectoris may result mostly from its ability to decrease heart rate and systolic pressure during exercise.

Effects of furosemide on glomerular filtration rate and clearance of practolol, digoxin, cephaloridine, and gentamicin.

Furosemide was shown to decrease inulin clearance in 20 of 27 normal subjects. The depression in inulin clearance occurred in both water-loaded and non-water-loaded subjects. The renal clearance of practolol, but not digoxin, was reduced when furosemide was given. The average total plasma clearances of gentamicin and of cephaloridine over a 6-hr period were decreased after furosemide. The reduced clearances of the antibiotics were associated with higher plasma levels, the increase in antibiotic concentration being as much as 100% at 1 hr after an intravenous bolus injection.

Cardioselectivity of prenalterol and isoproterenol.

We examined the hemodynamic effects and kinetics of prenalterol, a new beta-adrenoceptor agonist, in 10 normal subjects. There is some doubt whether prenalterol is selective for beta 1 adrenoceptors in animals; therefore, we also compared its cardioselectivity with that of the nonselective agonist, isoproterenol, with respect to heart rate (HR) and blood pressure (BP) responses after inhibition of cardiovascular reflexes with atropine, clonidine, and phentolamine. After intravenous (2.5 mg) and oral (10 mg and 100 mg) dosing, t 1/2 beta was 2 to 3 hr. Oral bioavailability averaged 33% and was independent of dose. Oral prenalterol, 10 mg and 100 mg, increased resting HR, systolic BP, and cardiac index by up to 27% but had no significant effects during graded exercise. Prenalterol infusions were calculated to attain steady-state plasma concentrations of 10, 20, and 40 ng/ml. HR and BP effects of the levels (10.8, 23.6, and 47.4 ng/ml) were compared with those of 0.5, 1.5, and 2.5 micrograms isoproterenol. Before autonomic block, prenalterol increased HR by 10 bpm at the highest dose and mean arterial pressure (MAP) by 10 mm Hg. In contrast, HR rose and MAP fell after isoproterenol. After block, at the highest doses of prenalterol and isoproterenol, there was an average rise in HR of 42 and 27 bpm; BP was almost maintained after the former but fell by 33 mm Hg after the latter. Prenalterol is an inotropic drug that has the effects of a full cardioselective beta-adrenoceptor agonist. Its inotropic effects are evident at doses that have little effect on HR because of the modifying effect of cardiovascular reflexes. The hemodynamic effects are most obvious at rest when sympathetic tone is low.

The effects of practolol on the dysrhythmias complicating acute ischemic heart disease.

The cardioselective beta-adrenoceptor blocking agent practolol was used in the management of ventricular and supraventricular dysrhythmias associated with acute myocardial infarction in 134 patients, and in the management of these dysrhythmias in 19 atients with acute myocardial ischemia. Practolol was frequently effective in controlling ventricular dysrhythmias which occurred within the first 24 hours after the onset of symptoms of acute myocardial infarction. It was also effective in controlling the ventricular dysrhythmias which occurred after resuscitation from ventricular fibrillation. It was of particular value when therapeutic doses of lidocaine had been ineffective. Practolol was much less effective in controlling ventricular dysrhythmias which occurred more than 24 hours after acute infarction. Atrial fibrillation and atrial flutter were infrequently abolished by practolol in undigitalized patients after acute myocardial infarction. There was no correlation between the effectiveness of practolol and the blood concentration of the drug. One adverse effect of practolol was the occurence of sinus bradycardia with or without an increase in the frequency of ventricular ectopic beats. Bradycardia was sometimes accompanied by hypotension. Severe hypotension occasionally occurred in the absence of bradycardia.

Inotropic effect of prenalterol in amitriptyline poisoning.

A case of severe amitriptyline poisoning with grade IV coma, seizures, bradycardia and hypotension who did not respond to dopamine was successfully treated with prenalterol, a new cardioselective beta-agonist. The case is discussed with respect to plasma concentrations of dopamine, prenalterol and amitriptyline. Prenalterol, hydrocortisone and insulin may be useful as inotropic agents in tricyclic poisoning where dopamine fails to provide an adequate response.

A dose response study with oral prenalterol in patients with chronic congestive cardiac failure.

Prenalterol is an orally active cardioselective beta agonist, with a long half-life. Previous studies have confirmed its inotropic activity following intravenous infusion in patients with heart failure. It has little chronotropic activity and no significant arrhythmogenicity. We have studied the response to sustained-release oral prenalterol given over four weeks at doses of 20, 40, 100, and 200 mg daily in 10 patients with New York Heart Association class II and III heart failure due to ischemic heart disease. All were in sinus rhythm and already receiving diuretics and digoxin. The drug was well tolerated and without side effects. Nine patients showed a dose-related improvement in their exercise tolerance as measured on the treadmill, up to a dose of 100 mg daily, with a significant increase in estimated oxygen uptake. There was a dose-related reduction in maximum heart rate, systolic blood pressure, and rate-pressure product during exercise, which is suggestive of a reduction in myocardial oxygen consumption. We conclude that prenalterol improves exercise tolerance without any significant cardiovascular or other side effects, and produces a clinically relevant and sustained improvement in patients with chronic heart failure. M-mode echocardiographic measurements of left ventricular dimension and function at rest did not show any change during the study.

[Toxicologic analysis of some adrenergic-beta blockers in the diagnosis of intoxications]. / Analiza toksykologiczna wybranych beta-adrenolityków w diagnostyce zatruc.

The study aimed at finding effective techniques of qualitative and quantitative analysis of selected beta-adrenergic blockers, useful both for monitoring of therapy and for thanatological diagnosis of intoxications. The studies took advantage of gas chromatography (GLC) and high performance liquid chromatography (HPLC). For isolation of studied compounds from biological material, classical and solid phase extraction procedures (SPE) Extrelut-20 (Merck), Abselut Nexus (Varian), STRATA C--18 E (Phenomenex) were used. The program included the analysis of most frequently applied derivatives: Acebutolol, Atenolol, Bunitrolol, Bupranolol, Labetolol, Metipranolol, Metoprolol, Oxprenolol, Practolol, Propranolol.

Determination of prenalterol in plasma and in urine by gas-liquid chromatography.

A description is given of a gas-liquid chromatographic method for the quantitative determination of unchanged prenalterol in plasma and for the total (free and conjugated) prenalterol in urine. After addition of an adequate internal standard, prenalterol together with the internal standard, is extracted with diethyl ether and derivatized with heptafluorobutyric anhydride-pyridine to form a tri-heptafluorobutyric derivative. This derivative has favourable properties for its estimation by gas-liquid chromatography using electron-capture detection. A large percentage of prenalterol is excreted as sulfate conjugate in man. Thus a hydrolysis step is added to the urine assay. The sensitivity of the method is about 2ng/ml.

Curve-fitting in pharmacokinetics--a comparison between gamma- and biexponential fits.

Seven sets of plasma concentration-time data were fitted to both a conventional biexponential equation and a gamma equation. The values of clearance (CL) and mean residence time (MRT) were calculated from the fitted parameters and compared with the values calculated by the trapezoid rule. Both the biexponential and gamma equations provided adequate fits to the data. The values of CL and MRT calculated from the biexponential fits correlated very closely with the values calculated by the trapezoid rule, but there were large discrepancies between the values calculated from the gamma fits and the trapezoid rule. The biexponential model appears to be less sensitive to scatter in the data.

Assay of prenalterol in plasma and urine by gas chromatography-mass spectrometry.

A sensitive and selective method for the quantitative analysis of prenalterol in plasma and urine is described. Prenalterol and the internal standard, deuterated prenalterol, are extracted with diethyl ether at pH 9.9 under salting-out conditions. Derivatization is performed by means of pentafluoropropionic anhydride in toluene before separation in the gas chromatograph. Detection and quantification of the triacyl derivatives are done by mass spectrometry in the selected ion monitoring mode. The method allows determination of concentrations down to 5 nmol/l (1 ng/ml) in 1 ml of sample, with a relative standard deviation below 10%.

The effect of age on plasma levels of propranolol and practolol in man.

1. Plasma levels of propranolol and practolol were measured in groups of elderly and young subjects, after the oral administration of propranolol (40 mg) and practolol (200 mg) on separate occasions. 2. At all sampling times the mean plasma propranolol level in the group of elderly subjects was substantially greater than the corresponding level in the group of young subjects, there being a significant difference between the two, and a fourfold difference in the mean peak levels. 3. After practolol, there was no significant difference between the mean plasma concentrations of the drug in the two groups for the first 2 hours. Subsequently, the mean plasma levels in the group of elderly subjects were somewhat higher than the corresponding levels in the young group, the differences between the two reaching significance. 4. It is suggested that there is a need to substantially reduce the dose of propranolol given to elderly patients. With practolol, however, no reduction is necessary providing renal function is normal for the patient's age.

Quantitative determination of clenbuterol enantiomers in human plasma by high-performance liquid chromatography using the macrocyclic antibiotic chiral stationary phase teicoplanin.

We report a method for the high-performance liquid chromatographic (HPLC) chiral separation of racemic clenbuterol in human plasma. Human plasma was spiked with stock solutions of clenbuterol hydrochloride and practolol as the internal standard. Following a liquid-liquid extraction procedure with 10% (+/-)-2-butanol/isopropyl ether under alkaline conditions, the dried samples were reconstituted in methanol and chromatographed using a macrocyclic antibiotic chiral stationary phase (CSP) known as Chirobiotic T(trade mark) (teicoplanin). The mobile phase composition was methanol:acetonitrile (70:30, v/v), containing 0.3% (v/v) acetic acid and 0.2% (v/v) triethylamine. The resulting chromatogram achieved baseline separation for the clenbuterol enantiomers. Calibration curves (peak area ratio vs plasma concentration, n = 10) were constructed for the (-)-R-and (+)-S-clenbuterol enantiomers with a plasma concentration range of 0. 25-10 microM. The correlation coefficient (r) range was 0.99988-0. 99999 (mean = 0.99999). The lowest concentration measured was 0.25 microM. Inter- and intra-assay variation was determined for the lowest, medium and highest plasma concentration (0.25, 2 and 10 microM) by calculating the analytical recoveries with a range of 96-104%. The percentage recoveries for the clenbuterol enantiomers were 88.4-102% over the concentration range used. Detailed methodology is presented.