Antihypertensive effect of atenolol alone or combined with chlorthalidone in patients with essential hypertension

1 The effect of atenolol, a cardioselective β-adrenoceptor acting drug, was studied alone or combined with chlorthalidone on blood pressure, heart rate, systolic time intervals, limb blood flow and limb vascular resistance. Plasma renin activity and plasma atenolol levels were also measured in the study.

2 Supine blood pressure was reduced in group A (11 patients) from 169.4 ± 5.06/111.2 ± 2.63 mmHg to 136.9 ± 2.55/90.9 ± 1.19 mmHg (P < 0.001) during the administration of atenolol alone. Concomitantly supine heart rate was decreased from 83.9 ± 4.10 beats/min to 59.7 ± 1.67 beats/min (P < 0.01) — 4th week. After the administration of atenolol over 8 weeks, supine blood pressure was 138.6 ± 1.21/94.4 ± 2.12 mmHg and supine heart rate was 59.5 ± 2.05 beats/min.

3 Supine blood pressure was reduced in group B (27 patients) from 183.6 ± 4.58/118.7 ± 2.01 mmHg (mean ± s.e. mean of systolic and diastolic blood pressure) to 171.3 ± 4.08/108.9 ± 2.26 mmHg (P < 0.01) during the administration of atenolol alone. Concomitantly supine heart rate was decreased from 84.0 ± 1.89 to 68.7 ± 1.94 (P < 0.001) beats/min. When atenolol was combined with chlorthalidone, supine blood pressure was reduced from 171.3 ± 4.08/108.9 ± 2.26 mmHg to 143.5 ± 3.68/94.8 ± 2.63 mmHg (P < 0.001). Heart rate did not alter significantly with the addition of chlorthalidone.

4 After the administration of atenolol alone in 12 patients of group B, there was a decrease of mean blood pressure from 131.8 ± 2.88 (mean ± s.e. mean) mmHg to 119.0 ± 4.05 mmHg (P < 0.001); of heart rate from 76.4 ± 3.58 beats/min to 57.0 ± 2.55 beats/min (P < 0.001); of calf blood flow from 9.23 ± 1.39 ml 100 g^-1 min^-1 to 5.05 ± 0.89 ml 100 g^-1 min^-1 (P < 0.001); and an increase of calf vascular resistance from 16.54 ± 1.90 (mmHg min^-1 100 g^-1)/ml to 28.53 ± 3.40 (mmHg min^-1 100 g^-1)/ml (P < 0.005). Atenolol did not alter significantly pre-ejection period index (P < 0.1). In atenolol-treated patients upon addition of chlorthalidone, there was a further decrease of mean blood pressure from 119.0 ± 4.05 mmHg to 105.9 ± 4.12 mmHg (P < 0.001). There were no further significant alterations of heart rate, pre-ejection period index, calf blood flow, and calf vascular resistance (P> 0.01).

5 Atenolol decreased plasma renin activity from 4.69 ± 0.87 to 2.85 ± 0.68 ng ml^-1 h^-1 (P < 0.05), and chlorthalidone increased it from 2.85 ± 0.68 to 3.81 ± 0.98 ng ml^-1 h^-1 (P < 0.05). Plasma renin activity on atenolol plus chlorthalidone was not significantly different from that on placebo (P> 0.1).

6 There was a 7.8 fold-interindividual variability in the relationship between plasma atenolol concentrations and the atenolol dose upon administration of a single oral dose of 100 mg.

     

Studies on the clinical pharmacology of prazosin: I: cardiovascular, catecholamine and endocrine changes following a single dose

1 Cardiovascular, catecholamine and neuroendocrine changes were studied following administration of prazosin to ten normal subjects. In response to a fall in standing blood pressure from 87±5 (s.d.) mmHg to 49±20 (P < 0.01) heart rate (measured by continuous ECG monitoring) rose from 81±11 to 118±20 (P < 0.01). Five of the ten subjects sustained their tachycardia on standing and developed at most mild symptoms. In the other five, tachycardia suddenly gave way to bradycardia and they became syncopal.

2 In the supine position, when blood pressure was not significantly different from control, plasma noradrenaline concentration (nmol/l) was 2±0.5 compared with a control value of 1.2±0.3 (P < 0.01). In response to standing hypotension plasma noradrenaline was 4.2±2.7 compared with a standing control value of 1.9±0.4 (P < 0.02).

3 Four hours after taking prazosin five of the subjects stood for 30 min and blood was drawn for plasma renin activity (PRA). Blood pressure at this time was 15 mmHg below control (P < 0.02). PRA (ng ml^-1 h^-1) was 6.4±2.3 compared with time matched placebo control of 1.4±0.8 (P < 0.01).

4 At the same time as the PRA sampling, plasma cortisol was 15.6±2.6 μg/100 ml during hypotension and 8.2±3.9 following placebo (P < 0.01). Growth hormone was 1.4±0.3 ng/ml during hypotension and 1.0±0.2 following placebo (P < 0.01). Prolactin did not rise significantly during hypotension induced by prazosin.

5 Isoprenaline infusion produced the same change in heart rate during the time of maximum prazosin action as when given alone.

6 It is concluded that these observations are not in keeping with earlier reports that prazosin lowers blood pressure without producing a reflex increase in heart rate or renin release. Nor are these findings in keeping with current theories of the mechanism of action of prazosin which variously suggest that noradrenaline concentration should not increase, or that the heart is incapable of responding to an adrenergic stimulus in the presence of prazosin.

     

Cardiovascular effects of alinidine and propranolol alone and in combination with hydralazine in normal man

1 The effect of single oral doses of alinidine 80 mg, propranolol 40 mg, hydralazine 50 mg, alinidine 80 mg combined with hydralazine 50 mg, propranolol 40 mg combined with hydralazine 50 mg, and placebo on arterial pressure and heart rate was studied in five normal volunteers in the supine and standing positions and during exercise. Observations were made before and at 1, 2, 3, 4 and 6 h after drug administration.

2 Alinidine 80 mg and propranolol 40 mg significantly reduced heart rate in the supine position, and on exercise. The reductions in supine heart rate produced by alinidine and propranolol were not significantly different, but the maximum effect of alinidine on exercise heart rate was observed later than that of propranolol. Propranolol reduced heart rate in the standing position at all time intervals after drug administration, but alinidine reduced standing heart rate only at 6 h (P < 0.01 when compared to placebo).

3 Hydralazine 50 mg increased supine heart rate by 8-10 beats min^-1 when compared to the pre-treatment value. These increases were significant (P < 0.05) when compared to the pre-treatment value, but not when compared to placebo. Hydralazine increased standing heart rate from 71.4 ± 6.5 to 90.0 ± 7.0 beats min^-1 (P < 0.05 when compared to placebo), but had no effect on exercise heart rate. The small increase in supine heart rate following hydralazine therapy was reduced by alinidine and propranolol, but only propranolol reduced the significant increase in standing heart rate produced by hydralazine.

4 Hydralazine reduced diastolic arterial pressure in the supine position at 2 and 4 h after drug administration (P < 0.05 when compared to placebo), but had no effect on systolic or diastolic arterial pressure in the standing position or on exercise.

5 Propranolol produced small reductions in systolic arterial pressure in the standing position, which were not significant when compared to placebo; diastolic pressure was unchanged. Propranolol reduced systolic pressure during exercise at 2, 4 and 6 h after drug administration (P < 0.05 when compared to placebo); diastolic pressure was unchanged. The effects of hydralazine and propranolol combined on arterial pressure in the standing position were similar to those observed after propranolol alone, but combined therapy produced a greater reduction in exercise systolic pressure, although these differences were not significant.

6 Alinidine reduced systolic arterial pressure in the supine position at 3, 4 and 6 h after drug administration (P < 0.01) and diastolic pressure at 2 and 4 h (P < 0.05 when compared to placebo). Alinidine reduced systolic arterial pressure in the standing position at 3, 4 and 6 h after drug administration (P < 0.05) and diastolic pressure at 2 h (P < 0.01) and 6 h (P < 0.05 when compared to placebo). During exercise, alinidine produced a small reduction in systolic arterial pressure which was not significant, and a reduction in diastolic pressure at 1 h (P < 0.05 when compared to placebo). The effects of hydralazine and alinidine combined on arterial pressure were similar to those observed after alinidine alone.

7 Hydralazine and alinidine combined produced a greater fall in systolic arterial pressure in the standing position than the changes observed after hydralazine alone; these differences were significant (P < 0.05) at 2, 3, 4 and 6 h after drug administration. However, the increase in heart rate after combined therapy was less than that observed after hydralazine alone, but these differences were not significant. This would suggest that alinidine may reduce the tachycardia produced by hydralazine.

8 Combined therapy with hydralazine and alinidine was associated with a high incidence of side effects. Alinidine alone produced dry mouth and tiredness in some subjects and syncope in one.

9 A linidine reduced heart rate and arterial pressure in normal man, and may therefore have a role in the treatment of hypertension, when used alone or in combination with vasodilator therapy.

     

Cardiovascular effects of indoramin in man--a dose ranging study

1 The effect of single and repeated oral doses of indoramin 25 mg, 50 mg, 100 mg and placebo on arterial pressure and heart rate supine, standing and following immersion of the hand in ice was studied in five normal volunteers.

2 Each study period lasted 4 days. Observations were made before and at 2 and 4 after drug administration on days 1 and 4. On days 2 and 3, the drugs were administered daily, but no observations were made.

3 Indoramin did not change arterial pressure or heart rate in the supine position.

4 Indoramin did not reduce the cold pressor response.

5 Indoramin 25 mg produced small reductions in arterial pressure in the standing position, with no change in heart rate.

6 Indoramin 50 mg reduced systolic arterial pressure in the standing position on day 1 from 106.4 ± 2.6 mm Hg (mean ± s.e. mean) to 88.4 ± 7.4 mm Hg at 2 h (P < 0.05 when compared to placebo) and to 96.8 ± 2.2 mm Hg at 4 h (P < 0.05); diastolic pressure was reduced from 76.4 ± 4.1 mm Hg to 57.2 ± 6.4 mm Hg at 2 h (P < 0.01) and to 64.4 ± 4.3 mm Hg at 4 h (P < 0.05). The reductions in arterial pressure were accompanied by an increase in heart rate from 94.0 ± 4.5 beats min^-1 to 102.0 ± 7.0 beats min^-1 at 2 h, and to 104.6 ± 8.1 beats min^-1 at 4 h (P < 0.05 when compared to placebo, but not when compared to the pre-treatment value). Similar changes were observed on day 4 after 50 mg indoramin, but the maximum reduction in arterial pressure was observed at 2 h on day 1, and 4 h on day 4.

7 Indoramin 100 mg reduced systolic arterial pressure in the standing position on day 1 from 114.0 ± 2.6 mm Hg to 99.2 ± 5.8 mm Hg at 2 h, and to 88.0 ± 5.9 mm Hg at 4 h (P < 0.01); diastolic pressure was reduced from 80.4 ± 3.4 mm Hg to 64.4 ± 3.2 mm Hg at 2 h (P < 0.05), and to 64.0 ± 4.5 mm Hg at 4 h (P < 0.05). The reduction in arterial pressure was accompanied by a small increase in heart rate from 102.2 ± 8.3 beats min^-1 to 107.2 ± 12.7 beats min^-1 at 2 h (P < 0.05 when compared to placebo, but not when compared to the pre-treatment value); no change in heart rate was observed at 4 h. The changes in arterial pressure and heart rate observed on day 4 after 100 mg indoramin were less than those observed on day 1, but these differences were not significant.

8 Indoramin reduces arterial pressure in normal man, but it is not possible to describe a dose-response relationship for the reduction. The reduction is accompanied by only a small increase in heart rate, possibly due to a direct bradycardic action of indoramin on the heart.

     

The effects of combined treatment with β1-selective receptor antagonists and lipid-lowering drugs on fat metabolism and measures of fatigue during moderate intensity exercise: a placebo-controlled study in healthy subjects

Aims We examined the effects of different combinations of β₁-selective adrenoceptor blockers and lipid-lowering drugs, on fat metabolism and fatigue during moderate intensity exercise in 14 healthy young volunteers. Methods The study was a randomized crossover design, each subject completing 5, 90 min walks at 50% of predetermined maximal oxygen uptake (VO₂ max), one following each 3 day treatment period with either: atenolol 100 mg and bezafibrate 400 mg, atenolol 100 mg and fluvastatin 40 mg, metoprolol CR 100 mg and bezafibrate 400 mg, metoprolol CR 100 mg and fluvastatin 40 mg, or placebo. Results Plasma free fatty acid (FFA) concentration during exercise was significantly reduced on all treatments, in comparison with placebo, P=0.0001. Following 90 min of exercise FFA levels were as follows: placebo 573 μmol l⁻¹ (105–1041), metoprolol CR+fluvastatin 277 μmol l⁻¹ (0–647), metoprolol CR+bezafibrate 182 μmol l⁻¹ (0–396), atenolol+fluvastatin 211 μmol l⁻¹ (0–511), and atenolol+bezafibrate 123 μmol l⁻¹ (0–352). Total fat oxidation during exercise was also reduced on all treatments in comparison with placebo: 38.1% (2–74), compared with 29.1% (0–61) on metoprolol CR+fluvastatin, P=0.02, 26.2% (2–51) on metoprolol CR+bezafibrate, P=0.002, 25.5% (3–48) on atenolol+fluvastatin, P=0.009, and 22.8% (0–47) on atenolol+bezafibrate treatment, P=0.0002. Plasma ammonia concentration was elevated on all treatments during exercise in comparison with placebo. After 90 min of exercise, plasma ammonia levels were as follows: placebo 37 μmol l⁻¹ (0–84), metoprolol CR+fluvastatin 56 μmol l⁻¹ (2–110), metoprolol CR+bezafibrate 79 μmol l⁻¹ (0–167), atenolol+fluvastatin 90 μmol l⁻¹ (10–170), and atenolol+bezafibrate 100 μmol l⁻¹ 26–174). In comparison with placebo, metoprolol CR+fluvastatin had the least adverse impact on measures of perceived exertion and the ‘feeling scale’ during exercise. Metoprolol CR+bezafibrate, atenolol+fluvastatin, and atenolol+bezafibrate treatments had greater adverse effects, particularly on perceived ‘cardiorespiratory effort’ and ‘feeling scale’ scores. Conclusions In healthy volunteers, combinations of β₁-selective blockers and lipid-lowering drugs were associated with significant reductions in fat metabolism, increased plasma ammonia levels, and raised the perception of effort during exercise, in comparison with placebo. Metoprolol CR+fluvastatin had the least effect, combinations metoprolol CR+bezafibrate and atenolol+fluvastatin had intermediate effects, and atenolol+bezafibrate had the most adverse effect.     

Effects of amlodipine on renal haemodynamics in mild to moderate hypertensive patients

Summary In this study the efficacy and safety of short-term amlodipine administration on renal haemodynamics were evaluated in mild to moderate hypertensive subjects. Our final goal was to evaluate whether the reduced blood pressure induced by treatment was associated with maintenance of renal function.After a run-in period with placebo, 30 hypertensive patients without cardiac or renal diseases were randomly allocated to a double-blind 4 weeks controlled study with amlodipine 10 mg once a day (15 patients) or placebo (15 patients).Renal haemodynamic measurements included effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) by radionuclide study using ¹³¹I-hippuran and ^99mTc, with methods described by Schlegel and Gates, respectively. In addition, effective renal blood flow [ERBF=ERPF/(1-Ht)], filtration fraction (FF=GFR/ERPF) ERPF) and renal vascular resistance (RVR=MBP×80/ERBF) were calculated. Plasma renin activity (PRA), serum aldosterone (ALD) and urinary excretion of sodium (NaU) were evaluated.At the end of amlodipine administration a significant decrease (P<0.001) in SBP, DBP and MBP from baseline values was observed. A significant decrease (P<0.01) in RVR and significant increases (P<0.05) in ERPF, ERBF and in NaU were also found, without relevant changes in GFR, FF, PRA and ALD.No significant variation in clinical and renal measurements was observed in the placebo group.No relevant side effects were observed in either group. In conclusion, amlodipine was effective in lowering blood pressure in mild to moderate hypertension and exerted favourable effects on renal haemodynamics and function.     

The haemoglobin-oxygen dissociation curve: In vivo and in vitro effects of five β-adrenoceptor antagonists and lignocaine

1 The effects of several β-adrenoceptor antagonists and lignocaine on blood oxyhaemoglobin dissociation curves have been studied in healthy non-smoking subjects.

2 The P_O2 at 50% saturation (P₅₀) did not significantly change after oral propranolol 80 mg (single dose, and following 2 weeks' administration of 80 mg twice daily), or following separate intravenous injection of propranolol (0.2 mg/kg), practolol (1 mg/kg), atenolol (0.2 mg/kg) and SL 75212 (0.15 and 0.6 mg/kg).

3 Increases in P₅₀ were found after the addition of propranolol 100 and 500 μg/ml, and lignocaine 5 μg/ml to whole blood, but incubation with propranolol at 1000 ng/ml or less, or sotalol 5 and 500 μg/ml and 5 mg/ml resulted in no significant change in P₅₀.

4 These results suggest that to increase P₅₀ with propranolol requires plasma propranolol concentrations far in excess of concentrations normally achieved, and that the therapeutic effect of propranolol in patients with ischaemic heart disease cannot be attributed to an increase in P₅₀.

     

Prazosin protein binding in health and disease

1 Experiments have been performed using equilibrium dialysis to determine the binding of [¹⁴C]-prazosin to albumin, to α₁-acid glycoprotein and to the plasma proteins of normal subjects and of patients with cirrhosis, chronic renal failure or chronic heart failure.

2 The influence of propranolol on prazosin binding has been studied. In addition, red blood cell to plasma partitioning of prazosin has been quantified.

3 The dissociation constant for prazosin binding to albumin was 3 × 10^-5 M and to α₁-acid glycoprotein was 1.9 × 10^-6 M.

4 In fourteen normal subjects the free fraction of prazosin was 0.051 ± 0.007.

5 In seven patients with cirrhosis free fraction of prazosin was 0.064 ± 0.017 (P < 0.05 compared to normal). In nine patients with chronic renal failure the free fraction was 0.077 ± 0.033 (P < 0.05) and in eight congestive heart failure patients the value was 0.064 ± 0.027 (P > 0.05).

6 The range of prazosin free fraction was substantially greater in the patients than in normal subjects. In cirrhotic patients free fraction of prazosin correlated significantly (r = -0.92) with albumin concentration.

7 Propranolol did not influence prazosin protein binding. In blood 20% of prazosin is associated with red cells.

8 The considerably greater range of prazosin free fraction in the patients suggests that caution should be used when prescribing the drug for subjects with these conditions. Both albumin and the acute phase reactant α₁-acid glycoprotein bind prazosin in vitro.

     

Inhibition of vascular epoprostenol (prostacyclin, PGI2) production in vitro by plasma from healthy subjects and patients with severe renal impairment

1 The production of 6-oxo-prostaglandin F_1α (6-oxo-PGF_1α) and epoprostenol (prostacyclin, PGI₂) by fresh rat aortic rings were measured by radioimmunoassay (RIA). The effect of citrated platelet poor plasma (PPP) from subjects with renal failure (U-PPP) and healthy age/sex matched controls (C-PPP) on 6-oxo-PGF_1α production were compared.

2 No difference was detected between either 6-oxo-PGF_1α or PGI₂ concentration when rings were incubated with U-PPP or C-PPP for 4, 8 and 30 min for 6-oxo-PGF_1α (P > 0.05, n = 8); and 30 min for PGI₂ (P > 0.05, n = 8).

3 Consistently more 6-oxo-PGF_1α was produced in PPP that had been heated at 100°C for 5 min (H-PPP) than in C-PPP: mean 6-oxo-PGF_1α was increased by factors of 1.45, 1.61, 1.57 and 1.57 at 4, 8, 30 and 60 min respectively (P < 0.005 at each time, n = 8).

4 Similar amounts of 6-oxo-PGF_1α were produced by aortic rings incubated in H-PPP and in Tris buffer (50 mM, pH 7.5), P > 0.05 at all times (n = 8).

5 The half-life of PGI₂ in U-PPP was similar to that in C-PPP; 7.8 ± 0.6 min and 10.2 ± 1.9 min (mean ± s.e. mean) respectively (P > 0.05).

6 In separate experiments a comparison was made of 6-oxo-PGF_1α production by aortic rings incubated in C-PPP, H-PPP and H-PPP to which albumin had been added to restore its original concentration. It was confirmed that more 6-oxo-PGF_1α was produced in H-PPP than in C-PPP (P < 0.05, n = 4). This increment was abolished in the H-PPP to which albumin had been added.

7 It was concluded that the heat-labile inhibitor of vascular PGI₂ synthesis in human plasma is albumin.

8 The failure to demonstrate a stimulator of PGI₂ synthesis in fresh aortic rings by U-PPP does not support the hypothesis that the bleeding diathesis of renal failure is due to an excess of a PGI₂ stimulating factor in plasma.

     

Elevated plasma noradrenaline in response to β-adrenoceptor stimulation in man

1 Dose-dependent increments of plasma noradrenaline were observed during graded infusions of (±)isoprenaline (3.5-35 ng kg^-1 min^-1 i.v.) in seven normal subjects and in ten subjects with borderline hypertension. At the highest dose of isoprenaline, noradrenaline rose by 166 ± 16 pg/ml in normals and by 169 ± 34 pg/ml in hypertensives (mean ± s.e. mean).

2 In the subjects with borderline hypertension isoprenaline infusions were repeated after 7 days of treatment with (±)propranolol (320 mg/day, divided into 4 doses) and subsequently after 7 days of treatment with (±)atenolol (100 mg/day) 2-3 h after the morning dose of β-adrenoceptor blocker. The dose-response curve for plasma noradrenaline was shifted to higher doses of isoprenaline by a factor of 4 by atenolol and the heart rate response was similarly shifted. The heart rate response was shifted by a factor of 16 by propranolol, but plasma noradrenaline did not change after isoprenaline under propranolol treatment, even when isoprenaline was given at doses high enough to induce increments of heart rate similar to those without β-adrenoceptor blocker treatment.

3 In the subjects with borderline hypertension mean and diastolic intra-arterial pressures fell at the highest dose of isoprenaline by 9 ± 2 and 13 ± 2 mm Hg respectively. These effects were antagonized by propranolol and not by atenolol.

4 The observed rise in plasma noradrenaline after isoprenaline might have been caused by baro-reflex-stimulation of central sympathetic outflow. The isoprenaline-induced decrease in mean arterial pressure, however, was small. Moreover pulse pressure rose and this tends to suppress rather than stimulate baroreflex-mediated sympathetic activity. Activation of presynaptic β-adrenoceptors, allegedly of the β₂-subtype, is known to facilitate noradrenaline release upon nerve stimulation of isolated tissues. Our results lend support to the hypothesis that such a facilitatory mechanism is also operative in intact man.

     

Modified renal function in pregnancy: impact on emtricitabine pharmacokinetics

Aims

The aims were to describe emtricitabine (FTC) pharmacokinetics in a large population of pregnant women during the different trimesters of pregnancy, and to explain FTC pharmacokinetic variability during pregnancy.

Methods

FTC plasma concentrations were measured in 103 non-pregnant and 83 pregnant women, including women in the different trimesters of pregnancy and on the day of delivery. A total of 457 plasma concentrations were available for analysis. A population pharmacokinetic model was developed with Monolix 4.1.3.

Results

FTC pharmacokinetics was best described by a two compartment model. The effect of creatinine clearance on apparent elimination clearance (CL/F) was significant. CL/F in pregnant women was significantly higher compared with non-pregnant women (geometric mean 24.1 vs 20.5 l h⁻¹, P < 0.001), reflecting a modified renal function. FTC daily exposures (AUC) during pregnancy were lower than AUC in non-pregnant women, regardless of the trimester of pregnancy. FTC AUC geometric means were 8.38 mg l⁻¹h in the second trimester of pregnancy, 8.16 mg l⁻¹h in the third trimester of pregnancy, 8.30 mg l⁻¹h on the day of delivery and 9.77 mg l⁻¹h in non-pregnant women. FTC concentrations 24 h after administration were lower in pregnant women compared with non-pregnant women (0.054 vs. 0.079 mg l⁻¹, P < 0.001) but still above the inhibitory concentration 50%.

Conclusions

FTC CL/F was increased by 18% during pregnancy, reflecting a modified renal function with 50% increase in estimated glomerular filtration rate. However, the impact of this modified renal function on FTC pharmacokinetics was not sufficiently large to consider dose adjustments during pregnancy.     

Systemic and renal effects of an ETA receptor subtype-specific antagonist in healthy subjects

1. Endothelins (ETs) might play a pathophysiological role in a variety of vascular diseases. The aim of the present study was to characterize the effects of BQ-123, a specific ET_A receptor antagonist on systemic and renal haemodynamics in healthy subjects. This was done at baseline and during infusion of exogenous ET-1.
2. The study was performed in a balanced, randomized, placebo-controlled, double blind 4 way cross-over design in 10 healthy male subjects. Subjects received co-infusions of ET-1 (2.5 ng kg⁻¹ min⁻¹ for 120 min) or placebo and BQ-123 (15 μg min⁻¹ for 60 min and subsequently 60 μg min⁻¹ for 60 min) or placebo. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were assessed by the para-aminohippurate (PAH) and the inulin plasma clearance method, respectively.
3. BQ-123 alone had no renal or systemic haemodynamic effect. ET-1 significantly reduced RPF (−24%, P<0.001) and GFR (−12%, P=0.034). These effects were abolished by co-infusion of either dose of BQ-123 (RPF: P=0.0012; GFR: P=0.020).
4. BQ-123 reversed the renal haemodynamic effects induced by exogenous ET-1 in vivo. This indicates that vasoconstriction in the kidney provoked by ET-1 is predominantly mediated by the ET_A receptor subtype.

     

Absorption and antidysryhthmic activity of oral disopyramide phosphate after acute myocardial infarction

1 In a prophylactic, double-blind, randomized placebo-controlled trial of oral disopyramide phosphate, initiated within 12 h of suspected acute myocardial infarction (MI), antidysrhythmic effect was evaluated. The loading dose was 150, 200, or 300 mg followed 6 h later by 100, 150, or 200 mg every 6 h for patients assessed to weigh <55, 55-85, or >85 kg, respectively. After each loading dose and a maintenance dose on one of days 4-7, 2 and 6 h venous blood samples were obtained for determination of plasma disopyramide and mono-N-dealkylated disopyramide (MND) concentrations (expressed herein as levels), by a technique incorporating fluorescence photometry and thin layer chromatography. Of 121 patients entering the trial, 101 had confirmed acute MI and of these, 12 on active drug were recalled during convalescence and restudied after a loading dose.

2 In acute MI patients on disopyramide phosphate, an important degree of antidysrhythmic effect was observed (on active drug and placebo, 19% v 37%, respectively (P = 0.047), received lignocaine for `warning arrhythmias'), even though in the first 6 h post-loading dose, disopyramide and MND levels were low and variable.

3 Disopyramide levels 2 h post-loading dose were lower in acute MI than in non-MI patients (P = 0.004), and similarly in the limited within patient study corresponding levels after acute MI were lower than during convalescence (P = 0.013). At 6 h post-loading dose, the levels had increased in acute MI patients but decreased in non-MI patients, this change being significantly different (P = 0.048). A similar significant difference existed in the limited within patient data available during acute MI and convalescence (P = 0.002).

4 Acute MI patients on active drug developing `warning arrhythmias' had lower post-loading dose, 2 and 6 h levels than in those without `warning arrhythmias' (P = 0.012 and P = 0.0002, respectively).

5 One patient who developed renal insufficiency developed excessive disopyramide levels.

6 On any given dose, there was no significant correlation between disopyramide level and body weight.

7 In acute MI patients given oral disopyramide phosphate (a) there was marked interindividual variation in the ensuing drug and metabolite levels, (b) absorption of disopyramide into the circulation was delayed, (c) prophylactic antidysrhythmic activity was present at levels of about 1.5 mg/l which is about half the minimal level recommended hitherto, (d) disopyramide accumulated in renal insufficiency, (e) elaborate dosage adjustments based on body weight are not useful.

     

A comparison in vitro of the vasoconstrictor responses of the mesenteric arterial vasculature from the chicken and the duckling to nervous stimulation and to noradrenaline

1 The vasoconstrictor responses of isolated mesenteric arterial vasculature of 2 to 5 week old domestic chickens (Gallus domesticus) and domestic ducklings (Anas platyrhynchos) to periarterial nerve stimulation and to intra- and extra-vascular noradrenaline were compared.

2 The tissues were perfused at a constant flow rate (2 ml/min) and the change in perfusion pressure produced by the various stimuli was used as a measure of the vasoconstrictor response. In a further study a constant pressure (50 mmHg)-variable flow system was used to corroborate the findings with the constant flow system.

3 The mean pressure response produced by nervous stimulation in the duckling mesentery (137 ± 62 mmHg) was approximately 3 times greater than that produced in the chicken mesentery (46 ± 29 mmHg; P < 0.001). Cocaine hydrochloride (1 × 10^-5 M) potentiated the responses in the duckling but not in the chicken.

4 The mean maximum pressure response evoked by intravascular noradrenaline in the duckling (170 ± 27 mmHg) was significantly greater than that in the chicken (92 ± 32 mmHg; P < 0.001). Cocaine produced a similar degree of potentiation in the 2 species.

5 The mean maximum pressure response evoked by extravascular noradrenaline in the chicken (70 ± 23 mmHg) was significantly greater than that in the duckling (36 ± 25 mmHg; P < 0.001) which was the converse of the effect for intravascular noradrenaline. Cocaine produced a much greater potentiation of the responses to extravascular noradrenaline in the duckling than in the chicken.

6 The results from the constant pressure study were similar to the corresponding findings in the constant flow studies. Nervous stimulation arrested flow in the duckling mesentery but not in the chicken. The maximum reduction in flow rate produced by intravascular noradrenaline was significantly greater in the duckling than in the chicken (P < 0.001).

7 Quantitative histological studies were performed on transverse sections of arteries prepared with haematoxylin and eosin staining and histochemical fluorescence from 4 chickens and 4 ducklings. The mean wall thickness:lumen diameter ratios of the primary and secondary branches of the duckling mesenteric arterial vasculature were 1.8 and 4.3 times greater than those of the chicken respectively (P < 0.05 and P < 0.001). The mean density of noradrenergic innervation of the main artery and its primary branches in the duckling was 1.7 and 2.4 times greater than that of the chicken respectively (P < 0.05 and P < 0.01).

8 The functional differences demonstrated in this study can be explained, at least partially, on the basis of the structural differences observed. During diving in the duck, intense peripheral vasoconstriction is believed to conserve the limited oxygen stores for those tissues most sensitive to oxygen lack. The structural and functional findings in the present study reveal that the duckling mesenteric arterial vasculature is well adapted to produce powerful vasoconstriction and hence play its rôle in oxygen conservation during diving.

     

A radionuclide method for the simultaneous study of the effects of drugs on central and peripheral haemodynamics

1 The central and peripheral cardiovascular effects of hydralazine and glyceryl trinitrate (GTN) have been contrasted using radionuclide techniques.

2 Following intravenous injection of technetium-99m labelled human serum albumin, radionuclide ventriculography was performed by the equilibrium blood pool method using a mobile gamma camera. Simultaneous measurements of `peripheral venous volume' were made using a collimated scintillation probe positioned above the patient's calf.

3 Ten patients with angina pectoris were studied at rest, after sublingual administration of 0.5 mg GTN and after intravenous administration of 10 mg hydralazine.

4 GTN caused a mean reduction in the end diastolic volume of the left ventricle of 14.6% ± 4.5% (P < 0.005) but ejection fraction increased by 0.034 ± 0.007 (P < 0.005) so that stroke volume was only reduced by 4.9% ± 5.0% (NS). There was a mean increase in heart rate of 10.8 ± 2.3 beats/min (P < 0.001) but no significant change in cardiac output. The calculated systemic vascular resistance fell by 10.0% ± 5.4% (P < 0.05). Associated with these changes there was a mean increase of 9.6% ± 1.5% (P < 0.05) in the counts from the calf.

5 Hydralazine caused a significant reduction in blood pressure and increase in heart rate. End-diastolic volume was reduced by 6.0% ± 2.7% but there was a mean increase in ejection fraction of 0.058 ± 0.010 (P < 0.001) so that in this instance stroke volume increased by 9.0% ± 3.7% (P < 0.05) and cardiac output increased by 16.4% ± 4.4% (P < 0.005). The calculated systemic vascular resistance fell by 18.9% ± 3.8% (P < 0.001). Despite these haemodynamic changes there was no significant change in counts from the calf.

6 The results confirm that GTN has a predominant venodilator effect while hydralazine acts largely on the arterial bed. These relatively simple radionuclide methods will allow a more detailed assessment of the cardiovascular effects of drugs.

     

Influence of intrinsic sympathomimetic activity of β-adrenoceptor blockers on the heart rate and blood pressure responses to graded exercise

1 The relationship between plasma concentration and effect on heart rate and blood pressure at rest and at three levels of exercise were examined for four β-adrenoceptor blocking drugs having differing pharmacological properties.

2 Four doses of each drug were administered, the highest doses producing maximum effects of the work-heart rate and work-blood pressure relationships.

3 Pindolol and oxprenolol, which have intrinsic sympathomimetic activity (ISA) differed from timolol and metoprolol (which do not) in having a smaller effect on resting heart rate at each dose.

4 During exercise the four drugs had similar maximum effects on slope of the work-heart rate relationship suggesting similar suppression of reflex enhancement of sympathetic activity during exercise by each drug. The higher heart rate after drugs with ISA at rest was therefore still present at each level of exercise, e.g. maximum reduction of heart rate at 0.5 maximum work capacity was 20.5, 20.8. 24 and 28% for pindolol, oxprenolol, metoprolol and timolol respectively (P < 0.01 for difference between drugs with and without ISA).

5 The relationship between plasma concentration and reduction of heart rate at 0.5 maximum work capacity was qualitatively similar for each drug and was adequately described by a sigmoidal relationship wtih half-maximal effects at 4.4, 22, 35 and 5 ng/ml for pindolol, oxprenolol, metoprolol and timolol respectively whilst maximal effects occurred at approximately 30, 150, 100 and 30 ng/ml.

6 The results suggest that differences with exercise heart rate due to ISA are mainly due to effects on resting heart rate. The dose-response relationship of β-adrenoceptor blockers reaches a plateau at higher doses, irrespective of whether or not they possess ISA.

     

Pharmacokinetics of cyclophosphamide and alkylating activity in man after intravenous and oral administration

1 Plasma cyclophosphamide levels were estimated by gas-chromatography in seven patients following intravenous and oral cyclophosphamide administration. Plasma alkylating activity was determined by the nitrobenzyl pyridine (NBP) reaction.

2 The plasma T_½ after intravenous administration ranged from 5.97 to 12.37 h but after oral administration was shorter, 1.32-6.8 h. The mean total body clearance was 66.6 ml kg^-1 h^-1 after intravenous dosing and 93.1 ml kg^-1 h^-1 following oral dosing. V_dβ was 0.71 (0.10 s.d.) 1 kg^-1 suggesting that cyclophosphamide is distributed largely in body water.

3 The mean hepatic extraction ratio was 0.25, indicating a modest first pass metabolism. The metabolic clearance was 3.72 1 kg^-1 and the intrinsic hepatic clearance 5.17 1 kg^-1.

4 The mean renal clearance was 4.8 ml kg^-1 h^-1 with 6.5% of the administered dose excreted unchanged in the urine suggesting tubular reabsorption of cyclophosphamide.

5 The mean T_½ of plasma alkylating activity was 8.82 h, there being no significant difference following oral and intravenous administration. On average, 3.5 times the alkylating activity was produced by an oral dose of cyclophosphamide as compared to an intravenous dose. It is possible that this may reflect production of a different pattern of alkylating metabolites following cyclophosphamide administration by different routes. The clinical significance of these observations is unknown.

     

NeuroD1 A45T and PAX4 R121W polymorphisms are associated with plasma glucose level of repaglinide monotherapy in Chinese patients with type 2 diabetes

AIMS

We aimed to determine whether NeuroD1/BETA2 and PAX4 polymorphisms were associated with the therapeutic efficacy of repaglinide in Chinese type 2 diabetes mellitus (T2DM) patients.

METHODS

Three hundred and sixty-eight T2DM patients and 132 healthy control subjects were genotyped by restriction fragment length polymorphism. Forty-three patients with various genotypes were randomly selected to undergo 8 weeks of repaglinide treatment (3 mg day⁻¹). Fasting plasma glucose, postprandial plasma glucose, glycated haemoglobin, fasting and postprandial serum insulin (FINS, PINS), homeostasis model assessment for insulin resistance, serum triglyceride, total cholesterol, low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol were determined before and after repaglinide treatment.

RESULTS

The allelic frequency of NeuroD1/BETA2 T45 was higher in T2DM patients than in the control subjects [13.45 vs. 6.82%, P < 0.01, odds ratios = 2.342 (1.365, 4.019), P= 0.002]. Type 2 diabetes mellitus patients with the mutated allele of NeuroD1/BETA2 A45T polymorphism showed higher FINS (13.46 ± 12.57 vs. 10.04 ± 7.09 mU l⁻¹, P < 0.05) (11.67, 14.83 vs. 8.38, 11.37) and PINS (52.11 ± 40.93 vs. 68.66 ± 43.87 mU l⁻¹, P < 0.05) (44.89, 58.35 vs. 55.35, 88.87) than individuals with the T allele. The PAX4 R121W R allele carriers had higher PINS (52.11 ± 40.93 vs. 68.66 ± 43.87 mU l⁻¹, P < 0.05) (44.89, 58.35 vs. 55.35, 88.87) than subjects with the W allele. After repaglinide treatment, patients with the T allele of NeuroD1/BETA2 A45T polymorphisms had attenuated efficacy on fasting plasma glucose (−2.79 ± 2.14 vs.−0.99 ± 1.80 mmol l⁻¹, P < 0.01) (−3.53, −1.84 vs.−1.99, −0.13) and postprandial plasma glucose (−6.71 ± 5.90 vs.−2.54 ± 3.39 mmol l⁻¹, P < 0.01) (−9.28, −4.62 vs.−4.34, −0.84). Patients with the RR genotype of PAX4 R121W showed better efficacy with respect to the level of postprandial plasma glucose than R/W genotypes (−6.53 ± 6.52 vs.−2.95 ± 1.17 mmol l⁻¹, P < 0.05) (−8.20, −4.89 vs.−3.92, −1.20).

CONCLUSIONS

The NeuroD1/BETA2 and PAX4 polymorphisms were substantially associated with plasma glucose level after repaglinide monotherapy.     

The effect of omeprazole on the pharmacokinetics of metronidazole and hydroxymetronidazole in human plasma, saliva and gastric juice

Aims To evaluate the effect of omeprazole on the pharmacokinetics of metronidazole and hydroxymetronidazole in plasma, gastric juice and saliva following intravenous infusion or oral dosing of metronidazole. Methods Eight volunteers received single doses of metronidazole (400 mg) intravenously and orally, whilst taking placebo or omeprazole (40 mg, twice daily for 5 days) in a randomized 4-way crossover study. Metronidazole and hydroxymetronidazole concentrations in plasma, saliva and gastric juice samples were determined by h.p.l.c. Pharmacokinetic parameters for metronidazole and hydroxymetronidazole were calculated, and the significance of the mean differences in parameters between omeprazole and placebo co-administration was assessed using a two-tailed, paired t-test. Results There were no significant differences (P<0.05) in any of the plasma or saliva pharmacokinetic parameter values for metronidazole between volunteers receiving omeprazole or placebo when metronidazole was administered either as an intravenous infusion or orally. Following intravenous administration of metronidazole to the placebo group and omeprazole treated group respectively, the gastric transfer of metronidazole was significantly reduced from 15.5±10.4% to 2.6±1.0% of the dose (P=0.007; 95% CI of difference 4.8 to 21.0) with concomitant changes in the metronidazole AUC (from 77.5±18.0 μmol l⁻¹ h to 352.6±182.1 μmol l⁻¹ h; P=0.0003; 95% CI of difference 127.6 to 422.7), C_max (from 61.4±26.5 μmol l⁻¹ to 271.8±104.3 μmol l⁻¹; P=0.0001; 95% CI of difference 118.6 to 302.1). Similarly, the gastric juice AUC of hydroxymetronidazole was significantly reduced from 3.2±1.9 μmol l⁻¹ h to 1.5±0.8 μmol l⁻¹ h of the dose (P=0.0043; 95% CI of difference 0.4 to 3.0) with a concomitant change in C_max (from 5.0±2.5 μmol l⁻¹ to 3.0±1.2 μmol l⁻¹; P=0.0007; 95% CI of difference 0.7 to 3.4). Conclusions Omeprazole had little effect on the plasma and salivary pharmacokinetics of metronidazole (or its hydroxymetabolite) after intravenous or oral administration, but it did have a substantial effect on the pharmacokinetics of metronidazole and hydroxymetronidazole in gastric juice.     

Effect of urinary pH and nicotine excretion rate on plasma nicotine during cigarette smoking and chewing nicotine gum

1 Plasma nicotine levels produced by chewing nicotine gum were compared with those obtained by cigarette smoking under conditions of controlled urinary pH.

2 Although absorption was slower, plasma levels comparable to cigarette smoking were built up on 4 mg (but not 2 mg) nicotine gum.

3 Urinary excretion of nicotine was influenced markedly by pH and the rate of urine flow.

4 Plasma nicotine was higher under alkaline compared to acidic conditions (P < 0.001) but the rate of urinary nicotine excretion appeared to have little effect on the plasma level.