Search

Aims: To assess whether nursing home (NH) residents with type 2 diabetes mellitus (T2D) preferentially received "T2D-friendly" (vs "T2D-unfriendly") β-blockers after acute myocardial infarction (AMI), and to evaluate the comparative effects of the two groups of β-blockers., Materials and Methods: This new-user retrospective cohort study of NH residents with AMI from May 2007 to March 2010 used national data from the Minimum Data Set and Medicare system. T2D-friendly β-blockers were those hypothesized to increase peripheral glucose uptake through vasodilation: carvedilol, nebivolol and labetalol. Primary outcomes were hospitalizations for hypoglycaemia and hyperglycaemia in the 90 days after AMI. Secondary outcomes were functional decline, death, all-cause re-hospitalization and fracture hospitalization. We compared outcomes using binomial and multinomial logistic regression models after propensity score matching., Results: Of 2855 NH residents with T2D, 29% initiated a T2D-friendly β-blocker vs 24% of 6098 without T2D (P < 0.001). For primary outcomes among residents with T2D, T2D-friendly vs T2D-unfriendly β-blockers were associated with a reduction in hospitalized hyperglycaemia (odds ratio [OR] 0.45, 95% confidence interval [CI] 0.21-0.97), but unassociated with hypoglycaemia (OR 2.05, 95% CI 0.82-5.10). For secondary outcomes, T2D-friendly β-blockers were associated with a greater rate of re-hospitalization (OR 1.26, 95% CI 1.01-1.57), but not death (OR 1.06, 95% CI 0.85-1.32), functional decline (OR 0.91, 95% CI 0.70-1.19), or fracture (OR 1.69, 95% CI 0.40-7.08)., Conclusions: In older NH residents with T2D, T2D-friendly β-blocker use was associated with a lower rate of hospitalization for hyperglycaemia, but a higher rate of all-cause re-hospitalization., (© 2018 John Wiley & Sons Ltd.)

Medications used to control hypertension in pregnancy also improve trophoblast and endothelial cellular interaction in vitro. Tumour necrosis factor-α (TNF-α) inhibits trophoblast and endothelial cellular interactions and simultaneously decreases endothelial nitric oxide synthase (eNOS) expression. This study investigated whether antihypertensive medications improved these cellular interactions by modulating eNOS and inducible nitric oxide synthase (iNOS) expression. Human uterine myometrial microvascular endothelial cells (UtMVECs) were pre-incubated with (or without) low dose TNF-α (0.5 ng/mL) or TNF-α plus soluble fms-like tyrosine kinase-1 (sFlt-1) (100 ng/mL). The endothelial cells were cultured on Matrigel. After endothelial cellular networks appeared, trophoblast derived HTR-8/SVneo cells were co-cultured in the presence of clinically relevant doses of methyldopa, labetalol, hydralazine or clonidine for 24 hours. Cells were retrieved from the Matrigel to extract mRNA and eNOS and iNOS expression were examined by quantitative PCR. Methyldopa, labetalol, hydralazine and clonidine reversed the inhibitory effect of TNF-α on eNOS mRNA expression. After pre-incubating endothelial cells with TNF-α and sFlt-1, all the medications except methyldopa lost their effect on eNOS mRNA expression. In the absence of TNF-α, antihypertensive medications did not change eNOS expression. The mRNA expression of iNOS was not affected by TNF-α or any medications. This study shows that selected antihypertensive medications used in the treatment of hypertension in pregnancy increase eNOS expression in vitro when induced by the inflammatory TNF-α. The anti-angiogenic molecule sFlt-1 may antagonise the potential benefit of these medications by interfering with the NOS pathway., (© 2016 John Wiley & Sons Australia, Ltd.)

1. Hypertension plays a critical role in the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD), but it has also been postulated that antihypertensive drugs that block the renin-angiotensin system (RAS) show class-specific renoprotective actions beyond their blood pressure (BP)-lowering effects. 2. Because this notion has recently been questioned, in the present study we compared the effects of a RAS-dependent antihypertensive therapy (a combination of trandolapril, an angiotensin-converting enzyme inhibitor (ACEI) and losartan, an angiotensin-II (AngII) receptor subtype 1A receptor antagonist) with a 'RAS-independent' antihypertensive therapy (a combination of labetalol, an alfa- and beta-adrenoreceptor antagonist with the diuretics, hydrochlorothiazide and furosemide) on the progression of CKD after 5/6 renal ablation (5/6 NX) in Ren-2 renin transgenic rats (TGR), a model of AngII-dependent hypertension. Normotensive transgene-negative Hannover Sprague-Dawley (HanSD) rats after 5/6 NX served as controls. 3. RAS-dependent and -independent antihypertensive therapies normalized BP and survival rate, and prevented the development of cardiac hypertrophy and glomerulosclerosis to the same degree in 5/6 NX HanSD rats and in 5/6 NX TGR. The present findings show that renoprotection, at least in rats after 5/6 NX, is predominantly BP-dependent. When equal lowering of BP was achieved, leading to normotension, cardio- and renoprotective effects were equivalent irrespective of the type of antihypertensive therapy. 4. These findings should be taken into consideration in attempts to develop new therapeutic approaches and strategies aimed to prevent the progression of CKD and to lower the incidence of ESRD., (© 2010 The Authors. Clinical and Experimental Pharmacology and Physiology © 2010 Blackwell Publishing Asia Pty Ltd.)

Objectives: In two separate trials, we studied the concomitant administration of atosiban with labetalol and betamethasone to determine any possibility of a clinically relevant pharmacokinetic interaction., Design: Study 1 was an open-label, single dose atosiban, multiple dose labetalol, interaction study. Study 2 was an open-label, randomised, three-period crossover pharmacokinetic study., Setting: The studies were carried out at the Clinical Pharmacology Unit of AAI Deutschland GmbH & Co KG, Neu-Ulm, Germany., Population: The study population consisted of healthy female volunteers., Methods: In Study 1, 14 healthy female volunteers participated. On study day 1, a 12-hour intravenous infusion of 114.75 mg atosiban was administered; on days 2-4, participants received labetalol orally (100 mg twice daily), and on study day 5 they received the combined treatment. In Study 2, a total of 18 healthy female volunteers received, on three separate occasions, a 12-hour intravenous infusion of 114.75 mg atosiban, a single intramuscular injection of 12 mg betamethasone or the two drugs in combination., Main Outcome Measure: For Study 1, the outcome parameter for atosiban was area under the plasma concentration-time curve (AUC); the study parameters for labetalol were AUC, maximum plasma concentration (C(max)) and time to C(max) (t(max)). In Study 2, AUC, C(max) and time to C(max) (t(max)) were assessed for atosiban and betamethasone., Results: Labetalol had no clinically relevant influence on the bioavailability (AUC) of atosiban. For labetalol, the co-administration with atosiban did not affect the extent of bioavailability, however, C(max) decreased by 36% and t(max) increased by 45 minutes. The C(min) was not affected by atosiban. The betamethasone and atosiban combination led to similar mean plasma concentration-time curves as the administration of each substance alone. Pharmacokinetic parameters (AUC, C(max), t(max)) did not differ markedly between treatments and all 90% CIs for ratios between treatments were fully within limits (80-125%). The co-administration of atosiban with labetalol or betamethasone resulted in similar tolerability to each substance alone., Conclusion: The co-administration of atosiban with betamethasone or labetalol had no clinically relevant influence on their bioavailability or tolerability.

Aims: Obesity can modify the pharmacokinetics of lipophilic drugs. As beta-adrenoceptor blockers (BB) are often prescribed for obese patients suffering from hypertension or coronary heart disease, this study compares the pharmacokinetics of lipophilic beta-adrenoceptor blockers in obese and control subjects., Methods: Nine obese (157 +/- 24% of ideal body weight (IBW) mean +/- s.d.) and nine non-obese healthy volunteers (98 +/- 10% IBW), aged 32 +/- 9 years, were included in the study. Subjects were randomly given a single i.v. infusion of one of the following racemic beta-adrenoceptor blockers, whose doses (expressed as base per kg of IBW) were: propranolol (0.108 mg), labetalol (0.99 mg) and nebivolol (0.073 mg). The plasma concentrations of unchanged drugs were measured by h.p.l.c. The ionisation constants and lipophilicity parameters of beta-adrenoceptor blockers were assessed., Results: The pharmacokinetic data for the three drugs were qualitatively similar. There was a trend towards a greater total distribution volume (Vss) in obese patients than in controls. However, Vss expressed per kg body weight was slightly smaller in obese patients. The relationship between Vss and lipophilicity of five beta-adrenoceptor was studied by combining the current results with those previously obtained with a moderately lipophilic drug (bisoprolol) and a hydrophilic one (sotalol). The Vss of the five drugs was positively and well-correlated (r2 = 0.90; P < 0.01) with their distribution coefficient at pH 7.4 (log D7.4), but not with their partition coefficients. The linear regression coefficients for lean and obese subjects were very similar., Conclusions: Lipophilic beta-adrenoceptor blockers seem to diffuse less into adipose than into lean tissues. All electrical forms of the drugs (i.e. cations, neutral forms, or zwitterions) present at physiological pH contribute to their tissue distribution, in both obese and lean subjects. Their tissue distribution in obese patients could be restricted by the sum of hydrophobic forces and hydrogen bonds they elicit with macromolecules in lean tissues.

1. The alpha- and beta-adrenoceptor antagonist activity of carvedilol, a beta-adrenoceptor antagonist with vasodilating properties, and labetalol were investigated in 10 healthy male subjects. They received infusions with serially increasing concentrations of isoprenaline and phenylephrine before and after single oral doses of carvedilol 6.25, 12.5 and 25 mg, labetalol 400 mg and placebo at weekly intervals in a double-blind randomised manner. An exercise step test was performed at the end of the infusions. 2. The dose of isoprenaline required to increase heart rate by 25 beats min-1 (I25) and the dose of phenylephrine required to increase systolic and diastolic blood pressure by 20 mm Hg (PS20 and PD20) were calculated using a quadratic fit to individual dose-response curves. Comparisons were made with placebo and P < 0.05 was considered significant. 3. The I25 was increased by carvedilol 25 mg and labetalol 400 mg (P < 0.05). The dose ratios at I25 were: carvedilol 6.25 mg 2.1 +/- 1.6, carvedilol 12.5 mg 3.1 +/- 1.9, carvedilol 25 mg 6.4 +/- 4.9 and labetalol 400 mg 8.8 +/- 4.4. 4. The PS20 was increased by labetalol 400 mg (P < 0.05). The dose ratios at PS20 were: carvedilol 6.25 mg 1.0 +/- 0.2; 12.5 mg, 1.2 +/- 0.2; 25 mg, 1.3 +/- 0.4 and labetalol 400 mg 2.2 +/- 0.8. 5. The PD20 was increased by labetalol 400 mg (P < 0.05). The dose ratios at PD20 were: carvedilol 6.25 mg 1.1 +/- 0.3; 12.5 mg, 1.3 +/- 0.3; carvedilol 25 mg 1.3 +/- 0.4 and labetalol 400 mg 2.1 +/- 0.8.(ABSTRACT TRUNCATED AT 250 WORDS)

1. The alpha-adrenoceptor antagonist, beta 1-adrenoceptor antagonist and beta 2-partial agonist activity of dilevalol, a beta-adrenoceptor antagonist with vasodilating properties and labetalol were investigated in two studies. 2. In the first study, six healthy male subjects received serially increasing concentrations phenylephrine after single oral doses of dilevalol 200 mg, labetalol 400 mg and placebo at weekly intervals in a randomised double-blind manner. An exercise step test was performed at the end of the infusions. 3. The doses of phenylephrine required to increase systolic and diastolic blood pressures by 20 mmHg (PS20 and PD20 respectively) were increased by labetalol 400 mg (P < 0.05) but unchanged by dilevalol 200 mg. The dose ratios for PS20 (means +/- s.d.) were: dilevalol 200 mg 1.1 +/- 0.1, labetalol 400 mg 2.2 +/- 0.1. There was no difference in the percentage reduction in exercise tachycardia between dilevalol and labetalol. 4. In the second study, 10 healthy male subjects received infusions with serially increasing concentrations of phenylephrine and angiotensin II before and after single oral doses of dilevalol 200, 400 and 800 mg, labetalol 200 mg and placebo at weekly intervals in a double-blind randomised manner. Finger tremor was measured (piezoelectric accelerometer) with each infusion. An exercise step test was performed at the end of the infusions. 5. The PS20 and PD20 of phenylephrine were increased by labetalol 200 mg and unchanged by dilevalol. The dose ratios for PS20 were: dilevalol 200 mg 1.1 +/- 0.2. dilevalol 400 mg 1.1 +/- 0.4, dilevalol 800 mg 1.4 +/- 0.4 and labetalol 200 mg 2.5 +/- 0.7. The dose ratios for PD20 were: dilevalol 200 mg 1.1 +/- 0.4, dilevalol 400 mg 0.9 +/- 0.3. dilevalol 800 mg 1.3 +/- 0.4 and labetalol 200 mg 2.3 +/- 0.9. 6. The PS20 and PD20 of angiotensin II were unchanged by any of the drugs. 7. Exercise heart rate was reduced by dilevalol 200 mg (130 +/- 13 beats min-1), 400 mg (123 +/- 12 beats min-1), 800 mg (125 +/- 9 beats min) and labetalol 200 mg (143 +/- 12 beats min-1) vs placebo (161 +/- 17 beats min-1). 8. Finger tremor was significantly increased by dilevalol 800 mg (13.17 +/- 10.51 vs 6.62 +/- 4.51 centivolts for placebo: P < 0.01). Neither phenylephrine nor angiotensin II had an effect on finger tremor. 9. In conclusion, dilevalol 200, 400 and 800 mg demonstrated beta 1-adrenoceptor antagonist activity with no evidence of alpha 1-adrenoceptor antagonist activity. Labetalol 200 and 400 mg showed both beta 1- and alpha 1-antagonist activity. Dilevalol 800 mg demonstrated significant partial beta 2-adrenoceptor agonist activity by increasing finger tremor.

The acute effects of thiopentone on plasma glucose concentration and regulation in humans have not been well described. We therefore examined the effect of a single dose (6 mg/kg) of thiopentone on plasma glucose, insulin, glucagon, adrenaline and noradrenaline in 16 healthy women undergoing elective abdominal surgery. To assess involvement of the neuroendocrine system in the response to thiopentone, half of the patients received labetalol prior to induction of anaesthesia. Thiopentone injection resulted in a 50% increase in plasma glucose levels (P < 0.001) in both labetalol-treated and non-treated patients 90 s following its administration. This was associated neither with significant increases in plasma glucagon, adrenaline and noradrenaline nor with a decline in plasma insulin. We conclude that acute hyperglycaemia following thiopentone is most likely the consequence of a non-adrenergically-mediated increase in hepatic glucose release.

1. Dilevalol (R,R-labetalol) is a non-selective beta-adrenoceptor antagonist with beta 2-adrenoceptor agonist activity. Its effects after 1 month's administration on heart rate, blood pressure and muscle blood flow were studied in a double-blind crossover comparison with nifedipine in 16 hypertensive patients. 2. Dilevalol and nifedipine were similarly effective in lowering systolic and diastolic blood pressure at rest, but dilevalol limited the rise in systolic blood pressure induced by exercise more than nifedipine (rise of 27 vs 53 mm Hg respectively, P < 0.01). 3. Dilevalol decreased resting heart rate compared with nifedipine (73 vs 92 beats min-1 respectively, P < 0.01). Dilevalol limited the exercise induced rise in heart rate more than nifedipine (36 vs 48 beats min-1 respectively, P < 0.01). 4. Muscle blood flow (measured by strain gauge plethysmography) was not affected by either dilevalol or nifedipine at rest. After exercise, dilevalol caused an increase in excess blood flow compared with placebo (10.8 vs 5.1 ml min-1 dl-1 respectively, P < 0.01). The difference between dilevalol and nifedipine did not reach statistical significance (10.8 vs 6.5 ml min-1 dl-1 respectively, P > 0.05). 5. On blood pressure and heart rate, dilevalol demonstrated beta-adrenoceptor blocker activity at rest and on exercise. On muscle blood flow, dilevalol appeared to have no effect at rest, but may have acted as a beta-adrenoceptor blocker rather than as a beta 2-adrenoceptor agonist during exercise.

The effect of labetalol on deliberate hypotension was studied in 24 adult patients undergoing middle-ear surgery. Hypotension was induced in Group I (12 patients) with isoflurane 3.0 vol% in inspiratory gas, and in Group II (12 patients) with labetalol 0.5 mg.kg-1 i.v., in addition to isoflurane. The induction time of hypotension was 4.9 +/- 1.0 (s.e.mean) min in Group I, and 1.8 +/- 0.2 min in Group II (P less than 0.01). The mean isoflurane concentration in inspiratory gas for the maintenance of hypotension was 1.4 +/- 0.2 vol% in Group I, and 0.7 +/- 0.1 vol% in Group II (P less than 0.01). There were no differences in urine flow rates (UF) between the groups during any phase, though UF decreased in Group I from the prehypotensive value 0.58 +/- 0.12 ml.min-1 to 0.07 +/- 0.02 ml.min-1 during hypotension (P less than 0.01) and increased to 1.28 +/- 0.17 ml.min-1 after anaesthesia (P less than 0.05). UF in Group II were 0.56 +/- 0.17, 0.25 +/- 0.10 and 0.56 +/- 0.06 ml.min-1, respectively. Creatinine clearances per 1.73 m2 body surface area (CCreat) in Group I were 78 +/- 14 ml.min-1, and in Group II 78 +/- 11 ml.min-1 before hypotension. During hypotension, CCreat were lower in Group I (8 +/- 1 ml.min-1) than in Group II (33 +/- 8 ml.min-1) (P less than 0.01). After anaesthesia, there was no difference in CCreat between the groups (Group I: 110 +/- 17 ml.min-1 and Group II: 120 +/- 17 ml.min-1).(ABSTRACT TRUNCATED AT 250 WORDS)

1. The effect of exercise testing and beta-blockade on plasma norepinephrine (PNE), and secretion of its metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), was assessed in 28 mild-to-moderate hypertensives before and after the administration of dilevalol, a new beta-blocker with beta 2-agonism. 2. This double blind, placebo-controlled study consisted of two successive submaximal exercise tests before and after the administration of a single oral dose of dilevalol (200 mg, 400 mg or 600 mg). Plasma norepinephrine levels were determined at rest, at 100 watts step of exercise and at maximal effort (Emax). 3. During the control test, mean PNE levels increased from 1.73 +/- 0.52 nmol/L (resting value) to 8.01 +/- 4.01 nmol/L at Emax (P less than 0.01) as MHPG levels increased from 11.18 +/- 1.33 nmol/L (rest) to 17.50 +/- 1.15 nmol/L (Emax, P less than 0.01). After dilevalol, PNE increased significantly as compared to controls (P less than 0.05), from 2.32 +/- 0.99 to 12.42 +/- 5.97 nmol/L (P less than 0.01). PNE and MHPG levels were correlated, both at rest and during exercise. PNE levels after beta-blockade were linearly related to the dose of beta-blocker administered. MHPG levels were unaltered by the administration of dilevalol, both before and after exercise. 4. The increase in MHPG that occurs during bicycle exercise is largely generated from an increase in central nervous system noradrenergic activity. While dilevalol increases the peripheral sympathetic nervous system, both at rest and during exercise (which is reflected by increases in PNE levels) the drug does not alter resting central nervous system noradrenergic activity nor amplify the increase in central noradrenergic activity that occurs during exercise.

1. A single oral dose of dilevalol (200 mg or 400 mg) or placebo was administered to 15 normal male volunteers in a double-blind, random order crossover study. 2. Dilevalol had no significant effect on supine blood pressures or heart rates, but caused a significant fall in systolic blood pressure 1 and 30 min following standing, and attenuated the rise in diastolic blood pressure and heart rate that accompanies standing. 3. Dilevalol caused a dose dependent increase in plasma noradrenaline levels from arterialized blood which was due to an increase in noradrenaline spillover with no change in clearance. 4. Dilevalol increased plasma levels of the noradrenaline metabolite 3,4-dihydroxyphenylethylene glycol (DHPG) (which is formed in sympathetic nerves following neuronal uptake of noradrenaline), indicating that the increase in noradrenaline spillover was not due to the blockade of neuronal uptake. 5. Acute dilevalol administration had no effect on total plasma cholesterol, HDL-cholesterol or LDL-cholesterol levels.

1. The oral kinetics of oxazepam after a single 15 mg oral dose was investigated in six healthy volunteers before and during concomitant administration of the beta-adrenoceptor antagonists propranolol (80 mg) and labetalol (200 mg) (racemates). 2. A possible pharmacodynamic interaction between oxazepam and the beta-adrenoceptor antagonists was examined using a simple reaction time test (SRT) and by measurement of postural sway. 3. The kinetics of oxazepam were not affected significantly by propranolol or labetalol, although oxazepam and labetalol share the glucuronidation pathway. 4. The SRT was increased by combination of both beta-adrenoceptor antagonists with oxazepam, with the greatest increase after the coadministration of oxazepam with propranolol. Administration of the beta-adrenoceptor antagonists alone had no significant effect. 5. Postural sway was affected significantly only by the combination of oxazepam and propranolol.

Several physiologic changes accompany the aging process and may alter the pharmacokinetics and pharmacodynamics of drugs given to elderly patients. The primary purpose of the present investigation was to compare the pharmacokinetics of labetalol in young and elderly hypertensive patients. Limited data regarding the pharmacodynamics of labetalol in each of these age groups were also evaluated. Ten young (age 32-48 yrs) and nine elderly (age 60-68 yrs) patients with essential hypertension were evaluated after the first and last doses of a 15-day regimen of labetalol. The young group received 200 mg orally at 9:00 P.M. and 9:00 A.M.; the elderly group received 200 mg once daily at 9:00 P.M. No significant differences in the mean (SD) apparent oral clearance of the drug existed between groups after the first [4.8 (1.9) and 4.3 (1.2) L/hr/kg] and final [4.4 (2.2) and 3.4 (1.0) L/hr/kg] doses of labetalol. No changes in any pharmacokinetic values for labetalol were detected as a function of age. Changes in standing blood pressure and heart rate after the first and last doses were generally similar between the young and elderly hypertensives. Labetalol was effective and well tolerated in both groups.

Dilevalol is a novel antihypertensive drug that combines nonselective beta blockade with selective beta 2-receptor agonist activity. Its antihypertensive effect is mediated through arterial vasodilation and a decrease in systemic vascular resistance. At rest, dilevalol has little effect on heart rate or cardiac output. The drug is rapidly and completely absorbed but undergoes significant first-pass hepatic extraction. Its elimination half-life of approximately 12 hours allows for once-daily administration. In controlled clinical trials, dilevalol was at least as effective as angiotensin-converting enzyme inhibitors and comparable to beta blockers in antihypertensive efficacy. Preliminary data indicate that dilevalol reverses left ventricular hypertrophy in some patients. It does not adversely affect renal function and may have a favorable effect on plasma lipids, especially high-density lipoprotein cholesterol. The agent is usually well tolerated and may prove to be a useful addition to our antihypertensive drugs.

1 The pharmacological effects of labetalol have been studied in normal healthy subjects. The results of these studies are reviewed. 2 In the evaluation of the beta-adrenoreceptor-blocking effects of labetalol various indices of beta-adrenoceptor blockade in man were used. Labetalol administered orally and intravenously competitively antagonized the effects of isoprenaline on heart rate and diastolic blood pressure. The beta-adrenoceptor blockade induced was regarded as 'non-selective'. In addition, labetalol produced dose-related inhibitory effects on exercise-induced increases in heart rate any systolic blood pressure and similar dose-related inhibitory effects on the tachycardia induced by valsalva's manoeuvre. Labetalol had only a modest inhibitory effect on the tachycardia induced by tilting since blood pressure was reduced on a dose-related basis. 3 Labetalol was a specific competitive antagonist of the alpha-adrenoceptor agonist effects of systemically administered phenylephrine and locally infused noradrenaline. In addition, oral and intravenous administration of labetalol reduced systolic and diastolic blood pressure in the supine, standing and sitting positions. 4 The onset and duration of the alpha- and beta-antagonist effects of oral labetalol did not seem to be dissociated in time and there was a close correlation between the change in plasma concentration and pharmacological effects. 5 In comparative studies with propranolol, similar beta-antagonist effects were observed but propranolol was 4-6 times more potent weight for weight. Precise comparison, however, was complicated by the combined alpha- and beta -effects of labetalol, especially as the predominant effect of labetalol in normotensive subjects was to reduce blood pressure; whereas the predominant effect of propranolol was to reduce heart rate. In addition propranolol had inhibitory effects on ventilatory function in normal subjects, whereas labetalol in equivalent beta-adrenoreceptor-blocking doses did not. 6 From the details of the studies reviewed it was concluded that in man labetalol possesses combined alpha- and beta-adrenoreceptor antagonist properties.

The cardiovascular effects of adimolol, a new, potent, long acting beta-adrenoceptor blocking drug were investigated in three studies. In the first study blood pressure and heart rate were measured in five male volunteers before and at 2, 4, 6, 8, 24, 32, 48, 72 and 96 h after single oral doses of adimolol. All doses of adimolol reduced supine, standing and exercise heart rates in a dose dependent manner. The maximum effect ranged from 18% following 25 mg to 29% following 600 mg and all doses showed an effect at 96 h (range 3.5-17.2%). In the second study the effects of adimolol, 25 and 400 mg, labetalol, 200 and 800 mg, propranolol 40 mg and placebo were compared on supine and standing heart rate and blood pressure and on exercise heart rate before and at 2, 4, 6 and 8 h after single oral doses. The exercise heart rate was significantly reduced at all times following adimolol 25 and 400 mg, labetalol 800 mg and propranolol 40 mg. At 2 h all the drugs significantly reduced standing systolic blood pressure. In the third study, 4 h after single oral doses of adimolol 400 mg, labetalol 400 mg and propranolol 40 mg six subjects received serial 4 min infusions of phenylephrine. The blood pressure was measured after each infusion. Labetalol 400 mg significantly shifted the blood pressure dose-response curve to the right. There was no difference between propranolol 40 mg and adimolol 400 mg. These studies show that adimolol is a potent, long acting beta-adrenoceptor blocking drug without evidence of alpha-adrenoceptor blockade in man.

1 The effect of labetalol has been assessed in an open clinical trial in 19 patients with sub-optimal control of blood pressure on other therapy, and in a placebo-controlled cross-over study. Most patients were taking a diuretic before the trial and they continued to do so during the trial. 2 In the open trial, labetalol successfully lowered blood pressure in most of the patients. Average daily dose was about 600 mg. The placebo-controlled trial confrimed the anti-hypertensive effect. 3 A clear postural hypotensive effect was seen. A few patients noted postural faintness as a side-effect, especially in a hot environment; but it was not troublesome. 4 There were few other side-effects. One patient experienced an increase in serum glumatic--oxalic transaminase (SGOT) and another an increasing anti-nuclear factor titre, but it is not yet certain that these were due to labetalol.

The effect of nitroglycerine, sodium nitroprusside, trimetaphan, pentolinium, labetalol and propranolol on the affinity of haemoglobin for oxygen was studied in vitro. Only pentolinium had a significant effect, increasing the binding of oxygen by haemoglobin. The significance of these results is discussed.

1 The effects of food on the pharmacokinetics of orally and intravenously administered labetalol were assessed in six healthy volunteers. 2 Food caused a 38% increase in the mean systemic bioavailability of labetalol: from 0.26 +/- 0.03 (mean +/- s.e. mean) to 0.36 +/- 0.05 (P less than 0.05). 3 Food caused 20% increases in the volume of distribution of labetalol: (from 567 +/- 63 to 685 +/- 76) and in plasma clearance (from 1923 +/- 417 to 2344 +/- 566 ml/min. These changes did not reach statistical significance. Food did not alter the plasma half-life of labetalol after oral or intravenous dosing. 4 Food appears to increase labetalol bioavailability by decreasing its first pass metabolism. It is suggested that this change results from transient alteration of hepatic blood flow. The drug should therefore be taken at a standard time in relation to meals to minimise intraindividual variation in bioavailability.

The effects of a single intravenous bolus of labetalol (0.5 mg/kg) on the cardiovascular, hyperglycaemic and adrenocortical responses to major colonic surgery were studied in five patients. Results were compared with five patients who received the same anaesthetic and had similar operations performed but who did not receive labetalol. It was observed that labetalol reduced the rises in heart rate and rate-pressure product that occur at the time of skin incision but that it did not reduce the rise in mean arterial pressure. The rises in blood glucose and plasma cortisol were significantly less in the labetalol group after 30 minutes of surgery (p less than 0.05).

1 The efficacy of labetalol in lowering blood pressure has been assessed in a group of 16 patients with severe hypertension whose blood pressure was inadequately controlled (supine diastolic blood pressure greater than 110 mmHg on two consecutive occasions) on existing therapy or in whom severe side-effects necessitated a change in therapy. 2 All patients had an original pretreatment supine diastolic blood pressure of greater than 120 mmHg and most had evidence of target organ damage. Patients were hospitalized for the purposes of changeover of therapy, labetalol being added to the existing regime which was reduced stepwise and eventually withdrawn. 3 Treatment with labetalol resulted in satisfactory blood pressure control in 10 of 16 patients in this study but high doses were required, the mean daily dose being 3,091 mg (range 1,200-8,000). 4 Treatment with discontinued in 6 patients on account of postural hypotension (3), failure to control supine diastolic blood pressure (2) and retention of urine (1). Long-term treatment was relatively free from side-effects. 5 From preliminary studies in animals it is suggested that an action within the central nervous system may contribute to the hypotensive effect of labetalol.

1 The effect of an intravenous bolus of labetalol (0.6--1.6 mg/kg body weight) on central and peripheral haemodynamics was studied in nine subjects with essential hypertension and in eleven subjects with chronic renal disease and hypertension. 2 The BP reduction amounting to 20/13 mmHg was entirely due to the lowering of the total peripheral vascular resistance. This also included the vascular resistance in the muscles. 3 This peripheral vasodilatation was not counteracted by a reflex increase of the cardiac output. 4 The reflex tachycardia and overshoot of BP in Valsalva's manoeuvre were largely abolished. 5 Central and peripheral venous BPs, vascular volume of the forearm and venous distensibility did not show any significant change after treatment with labetalol. 6 In spite of the lowering of the vascular resistance of the forearm by labetalol, forearm blood flow was not significantly affected due to the parallel decrease in the perfusion pressure. 7 Plasma renin activity fell after labetalol in all instances.

Medroxalol, a new drug which has been reported to possess both alpha- and beta-adrenoceptor antagonist properties, was compared with labetalol in single dose studies in normotensive males. Oral doses of 400 mg of each drug significantly reduced blood pressure, both supine and erect, without significant changes in heart rate. The chronotropic and diastolic depressor responses to isoprenaline were significantly antagonised by both drugs, for at least 6-8 h after drug administration. Medroxalol was associated with significantly greater beta-adrenoceptor antagonism than labetalol. There was no significant antagonism by either drug of the pressor response to noradrenaline. However, in a sub-group of subjects the responses to the selective alpha 1-adrenoceptor agonist, phenylephrine, were consistent with modest alpha 1-adrenoceptor antagonism. This was significant only for labetalol. The ratios of beta 1- to alpha 1-adrenoceptor antagonism as calculated from the relative shifts of the isoprenaline and phenylephrine dose-response curves, were 3 to 1 for labetalol and about 7 to 1 for medroxalol.

1 The anti-hypertensive effects of labetalol have been compared and contrasted with other groups of anti-hypertensive drugs in this review of the published literature. 2 The data show that the pharmacological and haemodynamic profile of labetalol in man is distinctly different from that of other specific anti-hypertensive agents; namely the properties of competitive alpha-and beta-adrenoceptor blockade leading to haemodynamic effects of reduced blood pressure and peripheral vascular resistance with little accompanying changes in resting heart rate or cardiac output. 3 The anti-hypertensive effects of labetalol are dose related. In fixed dose comparative studies equivalent anti-hypertensive effects to those of labetalol have been shown for individual drugs of the beta-adrenoceptor-blocking and diuretic groups. In dose titration studies, equivalent anti-hypertensive effects at given doses of labetalol have been demonstrated for drugs of the following types: beta-adrenoceptor blockers, beta-blockers plus diuretics, methyldopa, adrenergic neurone blockers and the combination of beta-blockers plus a peripheral vasodilator. 4 Comparing side-effect liabilities, it is clear that quantitatively labetalol produces no greater burden of side-effects than drugs of the beta-adrenoceptor-blocking group. Qualitative differences, however, do exist; in particular, symptomatic postural hypotension is dose related and is more likely to occur when excessive doses (greater than 2 g daily) are used.

1 Hypertension in West Indians and Africans is common and has an unacceptably high mortality in the younger patients. 2 Fifty-three patients received labetalol (a combined alpha- and beta-adrenoreceptor antagonist) as part of an open evaluation of its anti-hypertensive effect. Ten non-caucasian patients were included. 3 Significant reductions in systolic and diastolic pressures were obtained in the caucasian patients, the African and West Indian patients remaining refractory to therapy.

Intracranial pressure measurements and ventricular volume pressure response curves were made during induced hypotension with labetalol, a combined alpha- and beta-adrenoceptor antagonist, in dogs without (group I) and with (group II) intracranial hypertension. The administration of 600 mg labetalol resulted in a percentage decrease of mean systemic arterial blood pressure (MAP) of 27% (+/- 10%) in group I, and 32% (+/- 9%) in group II from control values without changes in intracranial pressure and the ventricular volume pressure response curve. Larger decreases in MAP were not possible, even with a dose 3 times that clinically recommended. Labetalol may be a safe hypotensive agent to supplement neurolept analgesia, but it is not the drug of choice to induce deliberate hypotension.

1 Fourteen patients whose lying diastolic blood pressure was persistently 110 mmHg or greater were given labetalol 0.5--1 mg/kg intravenously. 2 The maximum hypotensive effect developed between 20 and 40 min, and on average lasted 3 h. The lying systolic mean blood pressure fell by 30 mmHg and the lying diastolic blood pressure by 17 mmHg (P less than 0.001). 3 This acute hypotensive effect was associated with a significant reduction in the peripheral resistance (P less than 0.02). The hypotension was not associated with significant secondary changes in the stroke volume or pulse rate. 4 The above 14 patients plus 1 additional subject received labetalol orally at a daily dose ranging from 150-2400 mg. The mean lying systolic blood pressure fell by 22 mmHg (P less than0.01) and the mean lying diastolic blood pressure by 26 mmHg (P less than 0.001). The standing values were similar and postural hypotension at this dose did not develop. There was no significant change in the pulse rate. 5 Renal function was monitored by estimates of plasma creatinine and creatinine clearance. Some patients were followed for 2 yr and others for a few months. With the long-term patients, there was no significant reduction in either measurement although in a few patients a slight reduction in creatinine clearance was observed.

Sperm immobilizing activity of three class I antiarrhythmic drugs, quinidine, procainamide, mexiletine, one adrenoceptor blocking drug, labetalol and one calcium channel blocking drug, diltiazem was measured with a trans-membrane migration method. All these drugs immobilized human sperm. Local anaesthetic effect is the underlying mechanism for these drugs to inhibit sperm motility. Sperm immobilization could be a screening test for the local anaesthetic effect of antiarrhythmic drugs.

1 Labetalol at a dose of 800 to 1600 mg daily inhibited isoprenaline-induced tachycardia and phenylephrine-induced elevation in arterial pressure in hypertensive subjects. The beta-adrenoreceptor effect was four times more potent than the alpha-adrenoreceptor effect. 2 Isoprenaline-induced tachycardia was more effectively blocked than isoprenaline-induced inotropism, thereby raising the possibility of a subselective effect on cardiac beta-adrenoceptors. 3 Labetalol reduced blood pressure in hypertensive subjects with no change in cardiac output in the supine or upright position and with marked inhibition of the heart rate and blood pressure response to treadmill exercise. 4 Labetalol administered in single doses to patients with stable, treated congestive heart failure impaired blood pressure support during exercise. 5 The unique adrenoceptor and haemodynamic effects of labetalol make it a potentially attractive drug for management of hypertension and other cardiovascular disorders.

The pharmacokinetics of medroxalol are described in normal subjects and compared with those of labetalol. Both drugs were administered in doses of 400 mg orally and 1 mg/kg intravenously. The data for both drugs was most appropriately described by a two compartment model. For oral medroxalol the clinical pharmacokinetic parameters were a terminal elimination half-life (t 1/2,Z) of 15.6 h, a peak level of 450 ng/ml and a time to peak of 2-3 h. Following intravenous medroxalol the bioavailability was calculated as 64%, the plasma clearance was 948 ml/min and the t 1/2,Z was 7.3 h. The t 1/2,Z following intravenous administration was significantly shorter than that following oral administration. The significant differences between medroxalol and labetalol were in time to peak, respectively 2.3 and 1.1 h; oral t 1/2,Z, 15.6 and 5.5 h; clearance 948 and 1560 ml/min; and bioavailability, 64 and 20%. Despite the pharmacokinetic differences a similar plasma concentration-hypotensive effect relationship was described for each drug.

1 The acute anti-hypertensive effect of intravenously administered labetalol, a combined alpha- and beta-adrenoreceptor antagonist, has been assessed in a pilot study involving 17 hypertensive patients. 2 In 11 patients with mild to moderately severe hypertension, there was a decrease in mean arterial pressure (24 mmHg) after a single intravenous dose of 50 mg labetalol. The peak response occurred approximately 4 min after administration of the drug. 3 In six patients with severe hypertension, there was a reduction in mean arterial pressure of 19 mmHg, but this was achieved after a further 50-mg dose administered 30 min after the initial injection. 4 In neither group was there any clinically significant decrease in heart rate, and drug-related side-effects were insignificant. 5 Labetalol reduced the blood pressure when administered intravenously and thus merits further investigation as a treatment for acute hypertensive crises.

1 The interaction of phentolamine with the beta-adrenoreceptor-blocking drug, oxprenolol, was studied in a controlled trial. 2 The combination was generally well tolerated. 3 Oxprenolol alone produced modest but significant reductions in supine, standing and post-exercise blood pressures. Small reductions were observed only with sustained phentolamine administration. 4 The combined effect of the two drugs seemed to be addictive only at the lower level of oxyprenolol dosage. 5 Labetalol produced significantly greater reductions in supine and standing blood pressure than combined oxprenolol-phentolamine. At a daily dose of 400 mg, postural hypotension was not observed, although transient symptoms were frequent.

1 The haemodynamic effects of labetalol have been studied in 11 hypertensive patients after 1 month of oral administration at a fixed dose of 800 mg/d. 2 Heart rate blood pressure and cardiac output were measured at rest and at two levels of exercise. 3 Labetalol significantly reduced heart rate and blood pressure at rest and after exercise but cardiac output remained unchanged. 4 The results suggest that labetalol is an effective anti-hypertensive agent acting by competitive adrenoreceptor blockade.

1. Acute hormonal and renal effects of dilevalol (200 mg), a non-selective beta-blocking drug with vasodilator properties, were compared with placebo in six normal men on constant sodium intake. 2. Control and treatment blood pressures were lower with dilevalol than placebo, although the pattern of blood pressure fall was similar in both. 3. Plasma active renin and aldosterone concentrations were lower on dilevalol than placebo after 4 h of recumbency (P less than 0.05). 4. Total plasma renin, renin substrate, cortisol and atrial natriuretic peptide concentrations were similar on dilevalol and placebo. 5. There were no differences in glomerular filtration rate and no deleterious biochemical or haematological changes on dilevalol or placebo.

1 After acute intravenous administration labetalol reduced mean values for BP, total peripheral resistance, heart rate and cardiac output. All changes were more pronounced during bicycle exercise. 2 After a mean duration of 20 months' treatment with oral labetalol the haemodynamic findings were broadly similar except for a more marked reduction in the total peripheral resistance and cardiac output had returned to pretreatment level due to an increased stroke volume which had counter balanced the reduction in heart rate. These changes occurred at rest, in the erect position and during exercise but the reductions in BP and peripheral resistance were most marked during exercise. 3 Left ventricular filling pressures and stroke volume/filling pressure ratios were not significantly altered after intravenous labetalol compared with pretreatment values. 4 Systolic BP x heart rate product was lowered particularly during exercise after both intravenous and oral labetalol. 5 After long-term oral labetalol, the most striking haemodynamic change was in the elevated resting stroke volume supine and standing.

1 Seven women with hypertension of pregnancy were given the combined alpha- and beta-adrenoceptor blocking drug labetalol (50 mg i.v.) in their last trimester. Acute effects were studied for 3 h after administration. 2 Systolic and diastolic blood pressures were significantly reduced from 143 +/- 4 (s.e. mean) to 127 +/- 5 mmHg and from 101 +/- 2 to 88 +/- 2 mmHg, respectively. Maternal heart rate fell significantly from 77 +/- 5 to 68 +/- 3 beats/min. The changes remained during the 3 h of observation. Foetal heart rate was not affected. No side-effects were encountered. 3 Plasma noradrenaline increased significantly from 1.54 +/- 0.16 to a peak value of 2.37 +/- 0.41 nmol/l suggesting sympathetic activation following labetalol. Plasma adrenaline levels were essentially unchanged. Plasma glucose, insulin and C-peptide showed only minor changes. No major effects on lipid metabolism were seen except a significant fall of nonesterified fatty acids at 60 min. Plasma cyclic AMP increased significantly throughout the observation period, perhaps indicating beta-adrenoceptor agonist activity of labetalol. 4 The effectiveness of labetalol as an acute hypertensive agent together with apparent absence of metabolic disturbances and other side-effects makes it an interesting drug for the treatment of hypertension during pregnancy.

1 The effects of oral propranolol (80 mg), labetalol (400 mg) and placebo on blood pressure, pulse rate and FEV1 at rest and after inhaled histamine, have been compared in six healthy male volunteers. 2 At 90 and 120 min after ingestion propranolol reduced the pulse rate and labetalol reduced the blood pressure, thus confirming absorption of each drug. 3 At 120 min propranolol reduced resting FEV1 and enhanced the fall in FEV1 after histamine, whereas the alterations in FEV1 after labetalol did not differ from placebo. 4 These findings suggest that labetalol is less likely than propranolol to cause bronchoconstriction in asthmatic patients.

1 Labetalol, a new hypotensive drug combining alpha- and beta-adrenoreceptor antagonist properties, has been compared with propranolol in the treatment of severe hypertension (blood pressure 190/115-249/139 mmHg) in a double-blind trial lasting 14 weeks. Additional diuretic therapy was given to both groups of patients. 2 Both drugs caused an effective reduction in blood pressure, bbut labetalol caused a greater fall in pressure in the standing position and after exercise. Two groups of nine patients have each completed the trial so far. Group average pressures for the last 3 weeks of treatment were: for labetalol 137/87 supine, 121/84 standing, and 117/78 mmHg after exercise; and for propranolol, 138/87 supine, 132/93 standing, and 133/94 mmHg after exercise. 3 Group average heart rates were lower in all three positions for those patients treated with propranolol compared with labetalol. 4 The average final dose ratio for labetalol: propranolol was 1.44:1 (w/w). 5 Labetalol initially induced a number of side-effects, predominantly related to alpha-adrenoreceptor blockade, which disappeared by the end of the trial. 6 Labetalol, in conjunction with diuretic therapy, was at least as effective as propranolol in lowering blood pressure in patients with severe hypertension.

The effects of single oral doses of indoramin (mean dose 58 mg), abetalol (mean dose 150 mg), alinidine 80 mg and placebo on arterial pressure and heart rate in the supine and standing positions were studied in six normal volunteers. Doses were chosen to give equivalent reductions of arterial pressure in the standing position. Observations were made before and at 2 and 4 h after drug administration. Plasma noradrenaline (NA) was measured at each time interval in the supine position, and after 4 min of standing. Plasma renin activity (PRA) was measured at each time interval after 30 min in the standing position. In the supine position, alinidine produced a significant reduction of systolic arterial pressure from 124.0 +/- 3.0 mm Hg to 104.3 +/- 4.1 mm Hg at 2 h (P less than 0.01) and to 101.7 +/- 2.2 mm Hg at 4 h (P less than 0.01). Diastolic pressure was reduced from 74.7 +/- 2.6 mm Hg to 57.0 +/- 4.6 mm Hg at 4 h (P less than 0.01). Arterial pressure was unchanged after indoramin or labetalol administration. In the supine position, heart rate was unchanged after indoramin, and small reductions were observed after labetalol and alinidine. Indoramin produced a significant increase in plasma NA. A small increase of plasma NA was observed after labetalol, and a small decrease after alinidine. In the standing position, the three active drugs reduced systolic arterial pressure to a similar extent (indoramin, -26.7 mm Hg at 4 h after drug administration; labetalol, -21.3 mm Hg at 2 h; alinidine, -21.7 mm Hg at 4 h).(ABSTRACT TRUNCATED AT 250 WORDS)

1 The effects of three day courses of propranolol 40 mg three times daily, atenolol 100 mg twice daily and labetalol 100 mg three times daily on antipyrine kinetics were examined in 13 normal subjects. 2 The mean antipyrine clearance initially was 41.3 +/- 12.4 ml/min (mean +/- s.d.) and fell to 35.0 +/- 12.1 ml/min following propranolol (P less than 0.025), 34.5 +/- 9.5 ml/min following atenolol (P less than 0.01), and 35.2 +/- 8.6 ml/min following labetalol (P less than 0.05). 3 The prolongation in antipyrine half-life was significant only following atenolol. Propranolol only caused a significant reduction in the volume of distribution of antipyrine. 4 These adrenoceptor antagonists appear to decrease antipyrine clearance in normal subjects. The reduction in antipyrine clearance was similar with all three drugs and appeared to be independent of the differing lipid solubilities and pharmacological profiles of the adrenoceptor antagonists examined.

1 The haemodynamic effects of labetalol 50 mg intravenously were studied in 13 hypertensive patients at rest in the supine and upright positions and during exercise using percutaneous right heart and brachial artery catheterization. 2 Labetalol induced immediate significant reductions in systolic and diastolic blood pressures in all conditions. 3 Heart rate, stroke volume and cardiac output were not significantly altered in the supine position at rest but were significantly reduced in the upright position. In addition systemic vascular resistance was significantly reduced. 4 During exercise, heart-rate, cardiac output and vascular resistance were significantly reduced; stroke volume was increased. Left ventriclac filling pressures were unchanged both at rest and during exercise. 5 It was concluded that these changes resulted from blockade to both alpha- and beta-adrenoreceptor.

1 Fourteen hypertensive patients were studied by intra-arterial BP monitoring to quantify the effects of standardized physiological stresses: Valsalva manoeuvre, isometric, treadmill and bicycle exercise, and 60 degree tilting before and after labetalol treatment. 2 The dose of labetalol ranged from 100--600 mg three times daily and the response was judged on outpatient clinic recordings. 3 The drug produced a sustained reduction of BP and heart rate responses during dynamic exercise and the Valsalva manoeuvre, but the degree of change from the lowered baseline were not changed by labetalol. The fall in BP on cessation of exercise was decreased rather than increased. 4 The response to controlled isometric muscle contraction was affected in a similar fashion. 5 Tilting produced a fall in BP after treatment, and this was most marked in those patients on the highest doses. However, compensatory increases in diastolic BP were observed.