Hemodynamic effects of flestolol, a titratable short-acting intravenous beta-adrenergic receptor blocker

The hemodynamic effects of flestolol were evaluated in 30 patients undergoing routine cardiac catheterization. Hemodynamic measurements were obtained during baseline (prior to flestolol), at steady state during IV flestolol infusion (1, 5, and 10 micrograms/kg/min) and at 20 to 30 minutes after discontinuation (postinfusion). Flestolol-induced hemodynamic changes were similar to those induced by other beta blockers without intrinsic sympathomimetic activity. Significant dose-dependent reduction in heart rate, rate pressure product, and increase in peripheral vascular resistance were seen. Flestolol produced clinically insignificant decrease in myocardial contractility as shown by slight decrease in LVdp/dt, CI, and LVEF. Hemodynamic data from patients with paced heart rate, further confirms a direct mild cardiac depressant effect of flestolol, a finding common to other beta blockers. Consistent with the short elimination half-life of flestolol (t1/2 = 6.5 minutes), most of the hemodynamic changes rapidly returned to preinfusion level within 20 to 30 minutes following its discontinuation. Thus flestolol, with its unique pharmacokinetic profile and titrability, may be beneficial in the treatment of critically ill patients.     

Effects of flestolol, an ultra-short acting beta-adrenoceptor antagonist, on hemodynamic changes produced by treadmill exercise or isoprenaline stimulation in conscious dogs.

The beta-blocking activity of flestolol was established during increasing isoprenaline infusions and during graded physical exercise in conscious, chronically instrumented dogs. After a control cycle, flestolol was infused at three doses (1, 2.67, and 10 micrograms/kg/min). Flestolol has an extremely short half-life, demonstrated by an 83% loss of effect within 25 min. Thus, flestolol allows easy titration of the effect, which might be a valuable property for its use in the treatment of critically ill patients. Due to the difference between pure beta-adrenergic stimulation and the much more complex regulation of circulation during exercise, the hemodynamic response to flestolol elicited marked differences between both set ups. Flestolol shifted the dose-response curves of isoprenaline-induced changes in heart rate, positive left ventricular dp/dtmax, and diastolic arterial pressure dose dependently to the right, while its main effect during exercise was a decrease in positive left ventricular dP/dtmax. Thus, testing of beta-adrenoceptor blockers using isoprenaline-induced tachycardia leads to an overestimation of potency and therefore is not appropriate to predict the clinical efficacy of these drugs to prevent stress- or exercise-induced increases in heart rate and hence myocardial oxygen-demand.     

Antiarrhythmic activity of flestolol, a novel ultra-short-acting beta-adrenoceptor antagonist, in the dog

The antiarrhythmic activity of flestolol, an ultra-short acting beta-adrenergic blocker lacking appreciable local anesthetic activity, was examined in several different canine ventricular arrhythmia models. Flestolol, at steady state infusions of 1-1,000 micrograms/kg per min, was generally ineffective in reversing either ouabain-induced or delayed ischemia-induced (24 h Harris dog) ventricular tachycardia. However, flestolol (1, 10 and 100 micrograms/kg per min) produced a dose-dependent decrease in l-norepinephrine (5 micrograms/kg i.v.)-induced ventricular tachycardia in the 5-6 day old Harris dog; the effect of 100 micrograms/kg per min flestolol, 94% suppression of norepinephrine-induced ventricular tachycardia, was completely reversed 60 min after termination of flestolol infusion. In pentobarbital-anesthetized open-chest dogs with pretreatment heart rates greater than or equal to 145 beats/min, flestolol (10 micrograms/kg per min) reduced the incidence of ventricular fibrillation resulting from abrupt coronary artery occlusion compared to placebo-treated controls (15% or 2/13 vs. 70% or 7/10, respectively). These results demonstrate that flestolol has an antiarrhythmic profile consistent with its lack of local anesthetic activity and its ultra-short duration of beta-blockade.     

Pharmacokinetics and pharmacodynamics of nifedipine in patients at steady state

The pharmacokinetics and associated pharmacodynamics of nifedipine were studied at steady state in 12 patients with angina pectoris who were receiving nifedipine 10-40 mg tid. After dosing, serum nifedipine concentrations rose rapidly and decayed in a log-linear fashion. The mean (+/- SEM) maximum serum concentration (Cmax) after dose normalization, and the time to Cmax (tmax) were 115 +/- 7 ng/mL and 0.72 +/- 0.13 hr, respectively. The mean area under the plasma concentration-time curve per 10-mg dose was 304 +/- 34 hr-ng/mL. The average elimination rate constant was 0.205 +/- 0.016 hr, and the harmonic mean elimination half-life was 3.4 hr (range, 2.5-4.9 hr). Heart rate increased (5-6 beats/min, P less than .05) from baseline for up to one hour after dose, while mean diastolic blood pressure decreased (6-15 mm Hg, P less than .05) for up to four hours. Cardiac output was increased (1.1-2.8 L/min, P less than .05), and calculated total systemic resistance (3.8-6.3 mm Hg/L/min, P less than .05) was decreased for the entire dosing interval after nifedipine dosing. Hysteresis plots for heart rate and mean diastolic blood pressure showed a time lag between changes in serum nifedipine concentrations and heart rate, but not between serum nifedipine concentrations and blood pressure. Changes in cardiac output did not correlate with serum nifedipine concentrations. The steady-state kinetic and dynamic parameter values in patients with angina pectoris in this study were similar to those found in healthy volunteers or hypertensive patients after acute nifedipine administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Haemodynamic action of B-type natriuretic peptide substantially outlasts its plasma half-life in conscious dogs

1. The objective of the present study was to determine the plasma half-life of B-type natriuretic peptide (BNP) in conscious dogs after intravenous administration and to compare this with its haemodynamic effects. In six chronically instrumented dogs, plasma BNP concentrations were measured under basal conditions, during a constant infusion of canine BNP-32 (10 pmol/kg per min; 25 min) to steady state and at nominated time points up to 75 min after stopping the infusion. Concomitant, continuous measurements of mean arterial blood pressure (MAP), heart rate (HR), central venous pressure (CVP) and mesenteric blood flow (MBF) were obtained. 2. Baseline plasma BNP levels were 15.0 +/- 2.3 fmol/mL and rose approximately 10-fold to 159 +/- 23 fmol/mL after 20-25 min BNP infusion. When the infusion was turned off, plasma BNP levels declined in a biphasic manner, with an initial half-life of 1.57 +/- 0.14 min and a terminal half-life of 301 +/- 85 min. The metabolic clearance rate of BNP was 2.29 +/- 0.34 L/min. 3. The infusion of BNP reduced MAP (approximately 10%), CVP (approximately 65%) and MBF (approximately 25%), whereas haematocrit (approximately 4%) and mesenteric vascular resistance (MVR) increased (approximately 40%; all P < 0.05). Plasma BNP levels returned to baseline by 20 min after BNP infusion had been stopped, whereas none of the haemodynamic variables returned to normal by this time. Mean arterial pressure returned to resting levels within 10-15 min after plasma BNP returned to normal. However, CVP, haematocrit and MBF remained substantially below baseline values for more than 20 min after circulating BNP levels had returned to pre-infusion levels. Of these, only mesenteric vascular changes were returned to baseline within 60 min of plasma BNP levels normalizing. 4. These results demonstrate that the removal of BNP from the canine circulation is rapid, similar to observations made regarding the metabolism of circulating atrial natriuretic peptide in dogs. The half-life of BNP in dogs was shorter than that in rats, sheep or humans. However, the haemodynamic actions of BNP substantially outlasted its plasma half-life. Whether this disparity in plasma level and haemodynamic activity of BNP reflects long-lasting activation of second messenger systems or slow recovery from the hydraulic changes at the capillary level, reflected in the haematocrit and CVP, remains to be answered.     

A comparison of tablets with oral suspension formulation of dipyridamole in thallium myocardial imaging.

Dipyridamole stress thallium imaging has been widely employed to diagnose and assess the extent of coronary heart disease in patients who cannot exercise. When oral dipyridamole administration was used, a wide range of results for sensitivity, specificity, hemodynamic response and side effect profile has been reported. The authors hypothesized that the formulation used for oral administration of dipyridamole plays a major factor in this variability, and that the pulverized form of dipyridamole will achieve faster and more consistent response than the standard tablet form. The authors studied 13 consecutive patients who underwent thallium scintigraphy. Eight patients received dipyridamole pulverized and dissolved in a glycol/aqueous base diluent (group A), and five patients received the standard form of dipyridamole (group B). In group A, mean peak systolic blood pressure decreased from 142 +/- 31 (mean +/- standard deviation) to 109 +/- 30 (P = .05), and mean diastolic blood pressure decreased from 76 +/- 14 to 51 +/- 5. The mean heart rate changed from 78 +/- 26 to 80 +/- 10. In group B, baseline systolic blood pressure was 165 +/- 12 and decreased to 156 +/- 7 at 45 minutes and to 155 +/- 14 at 90 minutes. Heart rate increased from baseline of 69 +/- 9 to 75 +/- 8 at 45 minutes and to 76 +/- 11 at 90 minutes. At 45 minutes, the systolic blood pressure of the 8 group A patients dropped by 33 +/- 19 mm Hg, whereas group B's changed by 9 +/- 6 mm Hg (P less than .005).(ABSTRACT TRUNCATED AT 250 WORDS)     

The pharmacokinetics of alfentanil in gynecologic surgical patients

The pharmacokinetics and serum protein binding of alfentanil during continuous intravenous infusion were determined in 11 women who were either healthy (American Society of Anesthesiologists [ASA] physical status 1) or had mild systemic disease (ASA physical status 2). Anesthesia was induced with intravenous thiopental 2 mg/kg and alfentanil 50 micrograms/kg and maintained with constant intravenous alfentanil infusions of 1-3 micrograms/kg/min until approximately ten minutes before the end of surgery. Venous blood samples were obtained after the bolus of alfentanil was administered and at various times during and after the alfentanil infusion. Serum alfentanil concentrations were measured by gas-liquid chromatography. There was considerable interpatient variability in alfentanil pharmacokinetics and serum protein binding. The mean +/- SD alfentanil serum clearance, volume of distribution at steady state (Vss), and elimination half-life were 5.2 +/- 2.0 mL/min/kg, 0.47 +/- 0.1 L/kg, and 97 +/- 52 minutes, respectively. The mean fraction of alfentanil unbound in serum (fu) was 0.18 +/- 0.08. There was a time-dependent decrease in alfentanil serum clearance that correlated with increasing duration of surgery. This decrease in clearance resulted in a prolonged alfentanil half-life. These results indicate there is considerable interpatient variability in the pharmacokinetic parameters and serum protein binding of alfentanil in these patients and suggest that the infusion rate of alfentanil during maintenance anesthesia should be adjusted for individual patient response. Infusion rates may need to be tapered during prolonged operations.     

Pharmacokinetics and pharmacodynamic effects of aqueous diltiazem in healthy humans

Aqueous diltiazem was given to ten healthy male volunteers in a single oral dose of 2.5 mg/kg body weight. Serum diltiazem levels were measured at various intervals up to 24 hours after administration of the drug as were blood pressure, heart rate, and PR interval. The pharmacokinetics followed a one-compartment model in six and two-compartment model in four subjects. The mean distribution half-life in the latter four subjects was 15.8 +/- 3.7 minutes (range, 10.4-18.8 min). In the ten subjects, the peak serum diltiazem level was attained in 20 to 45 minutes (mean, 32.5 +/- 9.5 min) and ranged from 136 to 701 ng/mL (mean, 332 +/- 180 ng/mL). The elimination half-life ranged from 2.8 to 4.8 hours (mean, 3.8 +/- 0.6 hr). The area under the concentration-time curve varied from 508 to 2,245 ng-hr/mL, indicating differing bioavailability. Slight but significant blood pressure reduction was seen only at one to three hours. Changes in heart rate were not significant at any measurement. Transient facial flushing, beginning at ten to 20 minutes after administration, was noted in nine subjects, reflecting the vasodilatory effect of the drug. Significant prolongation (greater than 10%) of PR intervals began at ten minutes in three, at 20 minutes in six, and at 30 minutes in one participant, and progressed to second-degree Wenckebach atrioventricular (AV) block in six subjects 20 to 60 minutes after administration and third-degree AV block in one person 45 minutes after dosing. These AV blocks resolved by the third hour without treatment, and PR prolongation resolved by the fifth to seventh hours.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of postoperative intravenous indomethacin in children

The disposition of indomethacin was studied in children aged one to four years. Indomethacin 0.35 mg/kg was administered as an intravenous infusion during 15 min. Venous blood samples were collected until 24 hr after infusion. Serum indomethacin was determined with gas chromatography. Using a non-linear regression analysis, the individual data were fitted by a two-compartment open mammillary model with central elimination. Calculated pharmacokinetic parameters were (mean +/- SD); alpha half-life 25.2 +/- 11.3 min; beta half-life 366 +/- 295 min; steady-state volume of distribution 0.74 +/- 0.75 l/kg; volume during elimination phase 1.53 +/- 1.27 l/kg; total body clearance 3.2 +/- 1.7 ml/min./kg. Accordingly, with respect to the pharmacokinetics of indomethacin, children seem to mature early, not later than at the age of one year.     

The effect of beta blockers on cardiac neural discharge associated with coronary occlusion in the cat

The effect of timolol on postganglionic cardiac sympathetic neural discharge, blood pressure, heart rate, and rhythm changes associated with acute coronary occlusion of the left anterior descending artery was examined and compared with the effects of the beta blockers practolol and metoprolol. Timolol (5 mg/kg, IV) was infused 15 minutes prior to coronary occlusion in cats anesthetized with alpha-chloralose. Control heart rate fell from 129 +/- 10 to 106 +/- 2 one minute prior to coronary occlusion and remained at 106 +/- 2 beats/minute in the minute prior to arrhythmia. Control blood pressure fell from 126 +/- 20 to 91 +/- 19 and stabilized at 99 +/- 19 mm Hg one minute prior to coronary occlusion. Mean time to arrhythmia and death was 4.7 +/- 2.3 and 68.0 +/- 51.0 minutes (P greater than .05 vs no drug), respectively. Three cats died and two were sacrificed six hours after coronary occlusion. Blood pressure fell to 86 +/- 20 mm Hg two minutes after coronary occlusion, rose to 95 +/- 23 mm Hg at ten minutes, and remained there for ten minutes. Timolol did not alter postganglionic cardiac sympathetic neural discharge prior to coronary occlusion. Two minutes after coronary occlusion, mean postganglionic cardiac sympathetic neural discharge was 128 +/- 27 and increased to 139 +/- 36 impulses/second (% control) 4 minutes after coronary occlusion. A similar trend was found for the data recorded in 15 nerves (eight cats) in which coronary occlusion was initiated without timolol. The data suggest that a difference exists among beta blockers because prior to coronary occlusion, the cardioselective drugs metoprolol (1, 5, and 10 mg/kg, IV) and practolol (8 mg/kg, IV) depressed postganglionic cardiac sympathetic neural discharge whereas noncardioselective timolol did not. Because all three beta blockers increased the times to arrhythmia and death (although the increase was significant only after metoprolol and practolol), the acute protective mechanism does not appear to be due primarily to a depression of spontaneous sympathetic neural discharge.     

Pharmacokinetics of flestolol in man: preliminary data.

The steady state pharmacokinetics of flestolol, a short acting beta-adrenoceptor blocking agent, were studied in six healthy subjects following intravenous infusion of six different doses; 18, 24, 35, 50, 75 and 100 micrograms kg-1 min-1, for 60 min. Steady state blood levels increased linearly with dose for all six subjects. The overall mean half-life was 6.5 min. The total body clearance averaged 208 ml min-1 kg-1 indicating significant extrahepatic metabolism of the drug. There were no significant changes in the half-lives or the total body clearances after the six doses, suggesting that the kinetics of flestolol are linear over the dose range studied.     

Enzyme replacement in Fabry disease: pharmacokinetics and pharmacodynamics of agalsidase alpha in children and adolescents

This multicenter, open-label study evaluated pharmacokinetics, pharmacodynamics, and safety of agalsidase alpha in pediatric compared with adult patients with Fabry disease. The pharmacokinetic parameters of pediatric patients (19 boys, 5 girls, 6-18 years old; mean age, 11.8 years) were compared to those of adult male and female patients who participated in other clinical studies. All patients received agalsidase alpha at a dose of 0.2 mg/kg infused over 40 minutes every other week. Agalsidase alpha exhibited a biphasic serum elimination profile with a maximum serum concentration at the end of the 40-minute infusion; <1% of the maximum concentration was detected 8 hours after dosing. In children, serum clearance was 2.0 to 9.4 mL/min/kg and tended to decrease with increasing age. The average clearance in children, 3.7 +/- 1.5 mL/min/kg (mean +/- SD), was significantly greater than that measured in 33 adults (2.3 +/- 0.7 mL/min/kg, P < .0001). Mean terminal elimination half-life of agalsidase alpha was prolonged in week 25 compared with baseline (150 vs 66 minutes) in 8 of 19 male children. The magnitude of the reduction of plasma globotriaosylceremide was similar in all age groups and was independent of area under the curve and other pharmacokinetic parameters. Except for clearance in younger patients, agalsidase alpha appears to have comparable pharmacokinetic and pharmacodynamic profiles in pediatric and adult Fabry patients of both genders.     

Beta-adrenoreceptor antagonist potency and pharmacodynamics of ASL-8123, the primary acid metabolite of esmolol

The beta-adrenoreceptor antagonist properties of ASL-8123, the primary metabolite of esmolol, were determined in vitro and in vivo. ASL-8123 demonstrated weak competitive beta-adrenoreceptor blocking activity in isolated guinea pig right atria with a pA2 of 3.73 +/- 0.07; no agonist-like activity was observed in this tissue at concentrations of ASL-8123 from 3 X 10(-5) to 1 X 10(-2) M. In anesthetized dogs, ASL-8123 was infused at increasing dosages from 0.2-25.6 mg/kg/min, each dose rate maintained for 20 min. The compound produced a slight decrease in heart rate of 15-22 beats/min at cumulative doses of 508-1,020 mg/kg and decreased diastolic blood pressure by 14-47 mm Hg at cumulative doses of 252-1,020 mg/kg. ASL-8123 dose-dependently inhibited the heart rate and diastolic blood pressure responses to isoproterenol (0.5 micrograms/kg i.v.). Blood levels of ASL-8123 were linearly correlated with inhibition of the heart rate response to isoproterenol (r = 0.95-0.99 for each dog, n = 6). The blood level of ASL-8123 that produced a 50% inhibition of isoproterenol-induced tachycardia averaged 293 +/- 65 micrograms/ml. Recovery from beta-adrenoreceptor blockade after terminating the infusion of ASL-8123 occurred slowly, decreasing from 81% at the end of the infusion to 55% 60 min later, and was paralleled by a slow decrease in blood levels of ASL-8123. Thus, ASL-8123 is a weak beta-adrenoreceptor antagonist which is approximately 1,600-1,900 times less potent than its parent, esmolol.     

Hemodynamic effects of a single moderate dose of alcohol in elderly subjects

The effects of 0.5 g ethanol/kg body weight and of an iso-volumic control drink were compared in eight normotensive subjects aged 70-96 years. Blood alcohol concentration reached a mean (+/- SEM) maximum of 44.4 +/- 5.0 mg/dl at 50 minutes after the start of drinking. Compared to control, alcohol increased mean sitting and standing heart rates by 3.4 +/- 1.3 (p = .08) and 5.4 +/- 1.9 (p less than .05) beats/minute, respectively; mean venous haematocrit rose by 3.9 +/- 1.3% (p less than .05). There were no significant changes in sitting or standing systolic or diastolic blood pressures after alcohol compared to the control drink. A single moderate dose of alcohol has only minor haemodynamic effects in normotensive elderly subjects. The rise in heart rate after alcohol may be a reflex response that helps to maintain blood pressure in the face of reduced circulating plasma volume due to alcohol-induced diuresis.     

Esmolol-digoxin drug interaction

An open-label baseline-controlled study was conducted in 11 healthy male subjects to study the possible interaction between the cardioselective, short-acting beta blocker esmolol and digoxin when administered concurrently under steady-state conditions. Steady-state concentration, elimination half-life, and the total body clearance of esmolol were not changed significantly (P greater than .05) by digoxin. Digoxin peak concentration and the time to reach the peak concentration were not affected by esmolol. However, the digoxin AUC during the six-hour esmolol infusion increased from 2.60 +/- 0.59 to 2.88 +/- 0.75 ng.hr/mL (P less than .05). There were no clinically significant changes in the heart rate and blood pressure during this drug interaction study. The PR intervals were similar between digoxin monotherapy and esmolol plus digoxin combined treatment. Although digoxin did not influence the kinetics of esmolol, the small increase seen in digoxin serum concentration during the combination therapy warrants that caution be exercised during concurrent administration of esmolol and digoxin to patients.     

Pharmacokinetics and pharmacodynamics of famotidine in infants

The pharmacokinetics and pharmacodynamics of intravenous famotidine were evaluated in 10 infants ranging from 5 to 19 days of age who had a therapeutic indication for the prophylactic treatment of stress ulceration. After a 0.5-mg/kg infusion of famotidine, timed serum (n = 6), urine (24-hour collection), and repeated measurements of gastric pH were obtained. The mean +/- standard deviation maximum plasma concentration (Cmax) was 640.66 +/- 250.66 ng/mL, the elimination half-life (t1/2 beta) was 10.51 +/- 5.43 hours, and the apparent volume of distribution at steady state (Vdss) was 0.82 +/- 0.29 L/kg. Plasma clearance (Cl) and renal clearance (ClR) were 0.132 +/- 0.061 L/hr/kg and 0.093 +/- 0.056 L/hr/kg, respectively. No significant correlations were found between t1/2 beta, Vdss, Cl, and ClR and age. Six of the nine infants who had intragastric pH monitoring maintained a gastric pH > 4 until the final 24-hour sampling point. In this study, the t1/2 beta of famotidine was prolonged and the Vdss, Cl, ClR were reduced compared with corresponding parameters in previously reported studies of children older than one year of age and adults.     

Cardiovascular effects in man of intravenous prizidilol hydrochloride (SK&F 92657); a new antihypertensive agent.

1 Cardiovascular responses to intravenous prizidilol hydrochloride (SK&F 92657) 0.86 mg/kg were studied in eight supine resting healthy volunteers. Five subjects were slow and the remaining three were fast acetylators of sulphamethazine. Compared with pre-infusion values, mean resting systolic and diastolic blood pressures were significantly reduced, while mean resting pulse rate was significantly increased at 30 min after the start of the twenty minute infusion. 2 During the 6 h study period the lowest mean +/- s.e. mean systolic blood pressure (108.8 +/- 1.7) was recorded 30 min after the start of the infusion. This represented a mean reduction of 5.2 mmHg. Reductions in mean diastolic blood pressure were greater and of longer duration, the lowest mean value (44.8 +/- 2.0 mmHg) being recorded 3.5 h after the start of the infusion and representing a reduction of 18.5 mmHg from the pre-dosing value. At 6 h after the start of the infusion mean diastolic blood pressure was still significantly reduced (by 15.3 mmHg). 3 The maximum mean +/- s.e. mean resting pulse rate (79.3 +/- 4.4 beats/min) occurred 3 h after the start of the infusion, an increase of 23.0 beats/min over the pre-infusion value. At the end of the study the pulse rate was still significantly raised (by 17.7 beats/min). 4 The left ventricular ejection fraction, evaluated in five subjects, 45 min after the start of the infusion, was not altered by prizidilol hydrochloride, but the left ventricular area decreased significantly. 5 Intravenous prizidilol hydrochloride decreases resting blood pressure and left ventricular area, increases pulse rate and has virtually no effect on left ventricular ejection fraction.     

Controlled beta-receptor blockade with flestolol: a novel ultrashort-acting beta-blocker

The pharmacological properties of an ultrashort-acting beta-receptor blocking agent, flestolol, were evaluated in rabbits. Infusion of graded doses (1-100 micrograms/kg/min, i.v.) into conscious rabbits produced dose-dependent bradycardia without any significant effect on mean arterial pressure. A desired level of heart rate could be obtained by either increasing or decreasing the dose infused. Such titration could be done by changing the dose of flestolol at 20-min intervals. Infusion of 31 micrograms/kg/min of flestolol into reserpinized, conscious rabbits had no effect on mean arterial pressure or heart rate but produced significant inhibition of isoproterenol-induced hypotension and tachycardia. This dose had no effect on the chronotropic and vascular effects of norepinephrine (NE), angiotensin II, adenosine, or acetylcholine. In these rabbits, flestolol was greater than 10-fold as active as esmolol, another ultrashort-acting beta-blocking agent, in inhibiting the responses to isoproterenol. In rabbits under pentobarbital anesthesia, infusion of flestolol (3.1, 10, and 31 micrograms/kg/min) produced dose-dependent beta-receptor blockade. On termination of a 70-min infusion, recovery of the responses to isoproterenol occurred within 30 min. In a separate series of experiments, the effects of infusion of flestolol (10 micrograms/kg/min) into the portal vein were compared with the effects of infusion of the same dose of flestolol into the femoral vein of anesthetized rabbits. Infusion into the femoral vein produced bradycardia and inhibited the hypotensive as well as cardioaccelerator effects of isoproterenol. Infusion into the portal vein was devoid of either effect, suggesting extensive inactivation by the liver.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal and adrenal function following acute administration of urapidil in hypertensive patients with normal and impaired renal function

The effects of i.v. injection of urapidil (Ebrantil) (25 mg) on arterial blood pressure, renal function and renin-aldosterone system were studied in a group of patients with hypertension and normal renal function, in patients with hypertension and chronic renal failure and in normotensive controls. The pharmacokinetics of urapidil were evaluated simultaneously by measuring blood levels of the compound and its main metabolite. In the controls and in patients with hypertension, systolic and diastolic blood pressure were lowered few minutes after injection. Minimal blood pressure values were reached after 15-20 min. Hypotensive action was more pronounced in hypertensive patients as compared to controls. In contrast, increment in heart rate was greater in the controls. Despite the fall in blood pressure, renal plasma flow and glomerular filtration rate remained unchanged. Following the injection of urapidil, plasma renin activity increased with no change in plasma aldosterone levels. Plasma half-life of urapidil averaged 1.96 +/- 0.17 h in controls, 3.31 +/- 0.75 h in patients with hypertension and normal renal function and 2.52 +/- 0.46 h in patients with hypertension and chronic renal failure. Urapidil effectively lowers arterial blood pressure in patients with normal and impaired renal function with no deterioration in renal function.     

Pharmacokinetics of ceftriaxone in subjects with renal insufficiency

The pharmacokinetics of ceftriaxone was studied in 14 men and women volunteers with renal insufficiency. Subjects were grouped by renal function: those with end-stage renal disease (CLcr less than 15 mL/min/1.73 sq m) but not receiving dialysis, those with severe renal insufficiency (CLcr 16-30 mL/min/1.73 sq m), and those with moderate renal insufficiency (CLcr 31-60 mL/min/1.73 sq m). Ceftriaxone 1 g as the sodium salt was administered by i.v. infusion over 30 minutes, and blood and urine samples were collected before and up to 48 hours after drug administration. The pharmacokinetic data were described using a nonlinear least-squares computer program. For volunteers with a creatinine clearance of less than 15 mL/min/1.73 sq m, the mean half-life was 15.6 hours. For subjects with a creatinine clearance of 31-60 mL/min/1.73 sq m, the mean half-life was 11.9 hours. Plasma ceftriaxone concentrations measured at the conclusion of the infusion (mean peak concentration 122 +/- 53.1 micrograms/mL) or 24 hours after the infusion (mean concentration 20.2 +/- 6.14 micrograms/mL) were similar in each study group. A dose of ceftriaxone 1 g every 24 hours in patients with renal insufficiency is probably adequate for inhibiting most susceptible gram-positive and gram-negative microorganisms.