bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiovascular effects of single oral doses of the new beta‐ adrenoceptor blocking agents betaxolol (SL 75212) in healthy volunteers.
Authors: Cadigan PJ , London DR , Pentecost BL , Bianchetti G , Gomeni R , Kilborn JR , Morselli PL
Published: July 2012

1 The effects of betaxolol (SL 75212), a new beta‐adrenoceptor blocking agent, on the cardiovascular response to exercise have been studied in six normal subjects after placebo and single oral doses of 5, 10, 20 and 40 mg given double‐blind in a randomized sequence. 2 All doses reduced exercise heart rate, with a significant reduction persisting to 23 h after doses of 20 mg and 40 mg. Systolic blood pressure on exercise was reduced after all doses, with a reduction continuing to 23 h after doses of 10 mg and above. 3 The mean elimination half‐life of SL 75212 was 17.5 +/‐ 3.9 h. The plasma clearance ranged from 0.15‐ 0.48 1 kg‐1 h‐1 and the volume of distribution from 5.8–13 1 kg‐1. 4 There was a significant correlation between the peak blood levels and change in exercise heart rate (r = 0.53, P less than 0.05) and between the area under the blood concentration curve and the effect of the exercise heart rate (r = 0.55, P less than 0.01).
Comparison of plasma and saliva levels of diazepam.
Authors: de Gier JJ , 't Hart BJ , Wilderink PF , Nelemans FA
Published: July 2012

1 Salivary, unbound and total plasma levels of diazepam have been compared in nineteen subjects. 2 Salivary diazepam levels were significantly higher (P < 0.001) than, but closely related to the corresponding unbound levels (r = 0.97) at 2.5‐3 h after administration of the drug. 3 The results presented suggest that saliva levels can be used to predict the corresponding plasma levels at a given time, but there is no 1:1 relation between the unbound diazepam concentration in plasma and the saliva level of the drug.
Studies on the mechanism and characteristics of action of a uricosuric diuretic, indacrinone (MK‐196).
Authors: Brooks BA , Blair EM , Finch R , Lant AF
Published: July 2012

1 The renal action of indacrinone (MK‐196), a phenoxyacetic acid derivative with diuretic and uricosuric properties, has been studied in fifteen male subjects. 2 Increasing single doses of up to 60 mg of oral indacrinone produced a linear increase in urinary volume and excretion of Na+ and Cl‐, whilst the responses of urinary K+, Ca2+, Mg2+ and uric acid excretion, rose to a plateau at the 40 mg dose. 3 Indacrinone evoked a rapid diuretic response which reached a maximum of 2‐4 h and was largely complete at 8‐12 h after administration. 4 During maximal hydration, indacrinone produced a substantial fall in fractional free water clearance (CH2O), from 8.89% to 5.83% of the filtered load of water, associated with an increase in osmolal clearance, from 1.38% to 5.78% of the filtered load of solute. The reduction in CH2O was of the same order as that produced by a dose of ethacrynic acid with comparable saluretic activity and significantly greater than that produced by an equi‐saluretic dose of hydrochlorothiazide. These findings imply an action of indacrinone upon solute transport in the diluting segments of the distal tubule. 5 At the time of maximal indacrinone‐induced saluresis, which amounted to an increase from 0.48% to 4.61% of the filtered load of NaCl, fractional urate clearance increased from 5.16% to 12.24% of the filtered load of uric acid. 6 Indacrinone is a long acting diuretic, sharing some properties in common with both loop diuretics and benzothiadiazines. The results are discussed in relation to structure‐activity amongst derivatives of phenoxyacetic acid.
Repeated investigations of cyclophosphamide disposition in myeloma patients receiving intermittent chemotherapy.
Authors: Edwards G , Calvert RT , Crowther D , Bramwell V , Scarffe H
Published: July 2012

1 The disposition of cyclophosphamide was investigated in a group of myeloma patients. 2 Marked changes in clearance and volume of distribution of cyclophosphamide occurred between investigations. 3 The observed changes in disposition did not correlate with biochemical estimates of renal and hepatic function or plasma protein status.
Comparison of guanfacine and clonidine as antihypertensive agents.
Authors: Jaattela A.
Published: July 2012

1. The antihypertensive effects and side‐effects of guanfacine and clonidine were compared in a single‐blind, cross‐over study. 2. The study consisted of two active treatment periods of 6 weeks each, which were both preceded by a 2 weeks placebo period. Thirty ambulatory, hypertensive patients (blood pressure WHO severity grades I‐II) were admitted to the study. The results are based on the 24 patients who completed the study. 3. The optimal daily dose of guanfacine was in over half of the patients 3‐4 mg, and of clonidine correspondingly 0.3‐ 0.45 mg. A similar and statistically significant decrease in blood pressure was achieved with both drugs. 4. The most common side‐effects with both drugs were tiredness and dryness of the mouth.
Guanfacine in essential hypertension: effect on blood pressure, plasma noradrenaline concentration and plasma renin activity.
Authors: Schoeppe W. , Brecht HM
Published: July 2012

1. The acute and chronic effects of guanfacine on blood pressure, plasma noradrenaline concentration and plasma renin activity were investigated in 23 patients (15 males, 8 females) with essential hypertension (WHO grade I‐II). 2. Guanfacine induced a decrease in plasma noradrenaline concentration and plasma renin activity concomitant with a fall in blood pressure and heart rate in both the acute and the chronic study. 3. The adrenergic response to upright posture, reflected by an increase in plasma noradrenaline concentration and plasma renin activity, was not abolished after chronic guanfacine therapy. 4. The decrease in blood pressure 15 min after intravenous administration of guanfacine was inversely correlated with the basal sympathetic activity before treatment and with the decrease in plasma noradrenaline. 5. After chronic treatment with guanfacine no significant correlation existed between blood pressure reduction and the concomitant changes in peripheral sympathetic and/or plasma renin activity. 6. Despite the lack of a close correlation it is suggested that the antihypertensive effect of guanfacine in patients with essential hypertension is at least partially mediated by an inhibition of the sympathetic nervous and plasma renin activity.
An ambulatory trial of guanfacine.
Authors: Mann S. , Millar Craig MW , Melville DI , Cashman PM , Raftery EB
Published: July 2012

1. The effects of acute and long‐term treatment with guanfacine on ambulatory BP were studied. 2. The first day of therapy with guanfacine 1 mg produced a small reduction in BP whereas chronic therapy with doses up to 6 mg given once daily produced a substantial smooth reduction throughout the whole 24 hours. 3. There were no noticeable symptoms or rebound effects on withdrawal of the drug; side‐effects, were, however, prominent during therapy. 4. The drug reduced BP during dynamic exercise but did little during isometric exercise; no postural hypotension was noted during tilting.
Comparison of once and twice daily administration of acebutolol in hypertension.
Authors: Watson RD , Stallard TJ , Littler WA
Published: July 2012

1 Thirteen hypertensive patients completed a double‐blind comparison of placebo, acebutolol 200 mg twice daily and acebutolol 400 mg once daily, administered for 4 weeks in random order. 2 Blood pressure and heart rate were significantly reduced by both acebutolol treatments. The mean reduction of resting pressure 12 h after 200 mg twice daily (12/7 mmHg) was similar to that 24 hr after 400 mg once daily (13/9 mmHg). 3 Compared to placebo, reductions in exercise heart rate and systolic pressure at 12 h after 200 mg twice daily and 24 h after 400 mg once daily were significant and similar. 4 Beta‐adrenoceptor antagonism was also assessed by inhibition of the heart rate response to sublingual glyceryl trinitrate taken in the standing position. Both acebutolol treatments reduced the response; the reduction after twice daily treatment (mean 25 beats/min) was significantly greater than after once daily treatment (mean 19 beats/min). 5 There was no difference in blood pressure control between acebutolol administered once and twice daily in a total daily dose of 400 mg.
Kinetic disposition and diuretic effect of frusemide in acute pulmonary oedema.
Authors: Perez J. , Sitar DS , Ogilvie RI
Published: July 2012

The kinetic disposition and diuretic effect of frusemide was assessed in 16 patients with acute pulmonary oedema utilizing a specific gas‐ liquid chromatographic assay for the drug. Serum frusemide concentrations decayed biexponentially with wide variation in both alpha half‐life (range 15‐79 min) and beta half‐life (range 127‐1190 min). The beta phase half‐life was inversely related to creatine clearance. The apparent volume of distribution varied greatly among the patients (range 0.085‐0.818 l/kg), and patients with an acute myocardial infarction had a larger peripheral kinetic compartment. Patients with acute myocardial infarction excreted less unchanged drug and had a lesser urinary excretion of sodium and volume compared to patients without infarction. The urinary excretion of sodium, chloride, calcium and volume was linearly related to the urinary excretion of unchanged frusemide.
The effect of age on the pharmacokinetics of metoprolol and its metabolites.
Authors: Quarterman CP , Kendall MJ , Jack DB
Published: July 2012

1 Plasma concentrations of metoprolol and a pharmacologically active metabolite, H119/66, have been measured in young and elderly volunteers after a single dose of 100 mg metoprolol tartrate and after repeated administrated over a period of 1 week. Whilst concentrations of metoprolol are similar in each group, concentrations of H119/66 are approximately twice as high in the elderly. 2 Concentrations of unchanged metoprolol and of the major, but pharmacologically inactive, metabolite, H117/04, together with the two active metabolites of metoprolol have been determined in urine. Only the excretion of metoprolol was diminished in the elderly. 3 Areas under the plasma concentration curve for metoprolol after repeated administration are greater than would be predicted from single dose data, and possible explanations for this are discussed. Concentrations of the pharmacologically active metabolite, H119/66, remain unaltered during chronic dosing of metoprolol. 4 This study has shown that the effect of age on the pharmacokinetics of metoprolol and its metabolites is less pronounced than that observed for other drugs.
Effect of naproxen on glucose metabolism and tolbutamide kinetics and dynamics in maturity onset diabetics.
Authors: Whiting B , Williams RL , Lorenzi M , Varady JC , Robins DS
Published: July 2012

1 The influence of the nonsteroidal anti‐inflammatory drug naproxen on glucose metabolism and on tolbutamide pharmacokinetics and pharmacodynamics has been studied in ten maturity‐onset diabetics. 2 Comparison of both plasma glucose decay curves and insulin responses during an intravenous glucose tolerance test before and after eight 12 hourly doses of naproxen revealed that naproxen had no significant influence on fasting glucose levels or on rates of glucose elimination. 3 When the subjects were given a combination of naproxen and tolbutamide for 3 days naproxen had no influence on tolbutamide absorption, protein binding, disposition or pharmacological effect. 4 Treatment with tolbutamide in maturity‐onset diabetics need not be modified if concurrent administration of naproxen is contemplated.
Inhibition of gastric acid secretion with a mast cell stabiliser, FPL− 52694.
Authors: Davies HA , Rhodes J , Thomas M
Published: July 2012

1 The effect on gastric acid secretion of a mast cell stabiliser FPL− 52694 was examined in nine healthy volunteers. 2 The compound which is moderately well absorbed after oral ingestion, was taken for 5 days prior to the measurement of acid secretion and was also given intravenously during part of the gastric test. A submaximal dose of pentagastrin (0.3 microgram/kg/h) was given by intravenous infusion for 2 h in a controlled test and then after administration of FPL‐52694. 3 There was a significant reduction (37%) in acid secretion during the second test which was probably due to the effect of the compound on mast cell degranulation in the gastric mucosa.
Sodium cromoglycate: spincaps or metered dose aerosol.
Authors: Robson RA , Taylor BJ , Taylor B
Published: July 2012

1 Sodium cromoglycate administered as a dry powder inhalation (20 mg/dose) via the Spinhaler was compared with a metered dose aerosol (2 mg/dose) in an eight week double dummy double blind crossover trial in 29 asthmatic children. 2 The powder formulation was associated with significantly less symptoms (night wheeze, night cough, day wheeze, day cough, activity) and bronchodilator intake; and significantly greater weight gain than aerosol therapy. There were no significant differences in morning or evening peak flow measurements on the two treatments. 3 The powder may be more effectively inhaled than the aerosol or the dose of the aerosol may not be large enough.
Systemic availability of oral verapamil and effect on PR interval in man.
Authors: Johnston A , Burgess CD , Hamer J
Published: July 2012

1 The plasma levels of verapamil and its major metabolite norverapamil were related to its effect as a Ca‐antagonist on atrio‐ventricular (AV) conduction, judged from prolongation of the PR interval in six normal volunteers. 2 Intravenous administration (0.1 mg kg‐1) was compared to oral administration (120 mg) in each subject. 3 Intravenous verapamil showed a mean distribution half‐life (alpha) of 8.5 min and elimination half‐life (beta) of 2.0 h. The volume of distribution was about 112.1. Oral dosage gave an elimination half‐life of 2.7 h, and a norverapamil half‐life which averaged 4.6 h. The bioavailability of the oral dose averaged 22% (17 to 29%). 4 After the oral dose the percentage change in PR interval in the five appropriate subjects correlated significantly with the log plasma verapamil level (r = 0.732), but not with the log plasma norverapamil level (r = 0.078); norverapamil could not be detected after the intravenous dose. One subject developed Wenckebach type second degree AV block after each dose.
The effect of diflunisal on hyaluronic acid production by ‘activated’ human synovial fibroblasts.
Authors: Yaron M , Yaron I
Published: July 2012

1 Cultured human synovial fibroblasts were ‘activated’ by leucocytes or poly (I) . poly (C) to overproduce hyaluronic acid. 2 Diflunisal in concentrations of 30, 15 and 10 microgram/ml completely abrogated the overproduction of hyaluronic acid induced by leucocytes. 3 Diflunisal (10 microgram/ml), indomethacin (2 microgram/ml) and aspirin (200 microgram/ml) partially inhibited the overproduction of hyaluronic acid induced by poly (I) . poly (C), although none of them decreased it to control non ‘activated’ levels. 4 Diflunisal 25 microgram/ml completely abrogated hyaluronic acid overproduction induced by poly (I) . poly (C). 5 This model could be an in vitro indicator for in vivo pharmacological levels of anti‐inflammatory drugs.
The effects of intravenous prenalterol on ventricular performance, as assessed by radionuclide ventriculography, in patients with ischaemic heart disease.
Authors: Muir AL , Hannan WJ , Dewhurst NG , Slessor IM
Published: July 2012

1 We have observed the effects of intravenous prenalterol (1 mg and 2 mg) on ventricular performance, assessed by radionuclide ventriculography, in nine patients with ischaemic heart disease with varying degrees of impairment of ventricular performance. In seven of these patients the effects of prenalterol were compared with those of isoprenaline infused at 1 microgram/min. 2 Prenalterol caused no significant increase in heart rate, but systolic blood pressure increased by 26% (P less than 0.002). In contrast, isoprenaline caused heart rate to increase by 22% (P less than 0.02) and diastolic blood pressure to fall by 9% (P less than 0.01). 3 Left ventricular ejection fraction (LVEF) increased with both drugs, but the increase was greater with isoprenaline, as was the fall in the ratio mean ejection time: left ventricular ejection time, which is an index of improved ventricular performance. 4 Because of the increased heart rate and stroke volume produced by isoprenaline, cardiac output increased 45% above control values (P less than 0.001), but the increase in cardiac output after prenalterol did not reach statistical significance. 5 In three patients with very poor ventricular function (LVEF less than 0.30) prenalterol had little effect on ejection fraction, and caused increased regional ventricular dyskinesia. 6 The increase in systolic blood pressure, and therefore cardiac afterload brought about by prenalterol may limit ventricular response. The response might be enhanced by the addition of vasodilator therapy.
The distribution of propranolol, pindolol and atenolol between human erythrocytes and plasma.
Authors: Taylor EA , Turner P
Published: July 2012

1 This study aimed (1) to measure the whole blood to plasma (WB:P) and red blood cell to plasma (RBC:P) concentration ratios of propranolol in healthy volunteers and two types of patients, and (2) to compare the concentration ratios of the lipophilic drug propranolol with moderately lipophilic pindolol and hydrophilic atenolol. 2 There was no significant difference between the WB:P and RBC:P ratios of propranolol concentration in healthy volunteers and neurological patients compared with hypertensive patients. The mean +/‐ s.d. WB:P ratios of propranolol concentration in the three groups were 0.74 +/‐ 0.03, 0.71 +/‐ 0.05, and 0.76 +/‐ 0.08 respectively. The mean RBC:P ratios were 0.39 +/‐ 0.08, 0.36 +/‐ 0.11, and 0.47 +/‐ 0.15 respectively. WB:P and RBC:P concentration ratios of propranolol were linearly correlated with the free fraction of drug in plasma. Propranolol was 90% bound in plasma. 3 The mean WB:P and RBC:P ratios of pindolol in seven volunteers were 0.69 +/‐ 0.08 and 0.37 +/‐ 0.14 respectively. Pindolol was 71.4 +/‐ 8.6% bound to plasma proteins. The concentration of pindolol in the RBC was linearly correlated with that unbound in plasma. 4 In four healthy volunteers, the mean WB:P concentration ratio of atenolol was 1.07 +/‐ 0.25 and the mean RBC:P ratio was 1.15 +/‐ 0.55. 5 The similarity of the RBC:free plasma drug concentration ratios for all three drugs suggests that the use of organic solvent partition coefficients for the prediction of in vivo distribution may be unreliable.
Observations on the clinical pharmacology and plasma concentrations of diacetolol, the major human metabolite of acebutolol.
Authors: Ohashi K , Warrington SJ , Kaye CM , Houghton GW , Dennis M , Templeton R , Turner P
Published: July 2012

1 The pharmacological effects and plasma levels of diacetolol, the major human metabolite of acebutolol, were measured in a double‐blind, balanced study in which five healthy men received single oral doses of diacetolol 100, 200, 400 and 800 mg, or placebo, at weekly intervals. 2 Resting and exercise heart rate (HR), forced expiratory volume in 1 second (FEV1), resting and exercise peak expiratory flow rate (PEFR), and plasma concentrations of diacetolol were determined at 0, 2, 4, 6, 8 and 24 h after each treatment. 3 Diacetolol caused a slight dose‐ related reduction in resting HR and a substantial dose‐related reduction in exercise HR. AT the same time it was found that diacetolol had no significant effects on FEV1 and resting and exercise PEFR. 4 Mean highest observed plasma concentrations (ng/ml) of diacetolol were 177 at a mean of 4.4 h after the 100 mg dose, 243 at 4.0 h after the 200 mg dose, 807 at 5.2 h after the 400 mg dose, and 1,306 at 4.4 h after the 800 mg dose. 5 Using the mean data, there was a strong correlation (r = 0.90) between % reduction in exercise HR and the logarithm of the plasma concentration of diacetolol. 6 Diacetolol exhibits marked cardiac beta‐adrenoceptor blocking activity in man which is still evident 24 h after the administration of the higher doses of the drug. No adverse effects on pulmonary function could be detected.
Pharmacokinetics of sustained release theophylline in low and high multidose regimens.
Authors: Koeter GH , Jonkman JH , de Vries K , Schoenmaker R , Greving JE , de Zeeuw RA
Published: July 2012

1 The in vitro characteristics (dissolution rate) of a sustained release theophylline preparation (Theo‐Dur were first measured in acid medium (pH = 1) for 2 h and after that in a phosphate buffer (pH = 6.8) for 6 h. 2 The tablets released more than 95% of the active ingredient within 5 h at a rate of approximately 11% of the dose per hour at pH = 1 and about 18% at pH = 6.8. 3 Dose dependency of the pharmacokinetics of theophylline was tested in seven healthy volunteers by giving them either 300 mg Theo‐Dur or 900 mg Theo‐Dur in two doses a day for 5 days in a cross over design. After the last tablet on day 6 the fall‐off curve was followed in order to calculate the pharmacokinetic parameters. 4 Theophylline (300 mg) resulted on day 6 in a mean serum concentration of 4.4 +/‐ 0.8 microgram ml‐1. The dose of 900 mg resulted in a proportional increase in the serum concentration. The result was 13.3 +/‐ 2.2 micrograms ml‐1. 5 The T1/2 (300 mg) was 9.3 +/‐ 1.4 h and the T1/2 (900 mg) was 8.5 +/‐ 2.0 h. These values do not significantly differ (0.10 less than P less than 0.20). 6 It was concluded that theophylline exhibits the rules of linear pharmacokinetics when serum concentrations are in the therapeutic range.
Determination of nomifensine plasma concentrations: a comparison of radioimmunoassay and gas chromatography.
Authors: McIntyre IM , Norman TR , Burrows GD , Maguire KP
Published: July 2012

1 A gas‐liquid chromatography (g.l.c.) method for measurement of the antidepressant nomifensine was developed and compared for precision, accuracy, sensitivity and convenience with radioimmunoassay (RIA). 2 No significant difference was found between the two techniques for unconjugated nomifensine (y = 1.07x = 2.7; r = 0.996) or total nomifensine (y = 1.;02x + 0.02; r = 0.999). 3 RIA proved more sensitive than g.l.c. (detection limit of RIA being 1 microgram/l and g.l.c. 5 micrograms/l). 4 RIA was found to be a more convenient technique (up to 50 samples per day with RIA, and 16 samples with g.l.c.).
The effects of propranolol and acebutolol on the overnight plasma levels of anterior pituitary and related hormones.
Authors: Lewis MJ , Groom GV , Barber R , Henderson AH
Published: July 2012

1 The effects of single evening doses of the beta‐adrenoceptor blocking agents propranolol (80 mg orally) and acebutolol (200 mg orally) on plasma levels throughout the night of prolactin, growth hormone, luteinising hormone, follicle stimulating hormone, cortisol and testosterone have been studied in seven healthy male volunteers. 2 Three way analysis of variance showed that acebutolol significantly reduced circulating levels of prolactin and follicle stimulating hormone, but did not alter the levels of the other hormones studied. 3 Propranolol significantly reduced follicle stimulating hormone and testosterone, and significantly increased circulating levels of cortisol, but caused no change in the other hormones studied. 4 Prolactin, luteinising hormone, testosterone and cortisol showed a significant variation with time indicating the existence of a diurnal rhythm in the pattern of their secretion. 5 There was a significant inter‐subject variability in all the hormones studied. 6 There was a significant between‐subject variation in response to both propranolol and acebutolol. 7 Different subjects showed significant variations with respect to time in prolactin, growth hormone and cortisol levels. 8 Neither propranolol nor acebutolol significantly altered the time course of secretion of any of the hormones studied. 9 Possible relationships of these beta‐adrenoceptor blocker‐induced changes in anterior pituitary and related hormones to the antihypertensive mechanism of acebutolol and propranolol are discussed.
Effectiveness of ibopamine in the management of ascitic liver cirrhosis‐a controlled study v placebo and frusemide.
Authors: Melloni GF , Minoja GM , Melloni R , Piatto E , Scarazzati E , Bauer R , Ghirardi P
Published: July 2012

1 Thirty in‐patients of both sexes suffering from ascitic liver cirrhosis were divided into three groups treated with (a) a placebo, (b) ibopamine (SB 7505, a new oral dopaminergic drug) and (c) frusemide, for 10 days. 2 Body weight decreased with both frusemide and ibopamine, diuresis and urinary excretion of Na+ and Cl‐ increased with both drugs; whereas urinary excretion of K+ increased only with frusemide. 3 An important difference between the frusemide and ibopamine treatment was encountered in creatinine clearance, which increased only with ibopamine, and in blood uric acid which increased only with frusemide. 4 The antidiuretic hormone (ADH) in the plasma of cirrhotic patients was lower than the sensitivity limit of the radioimmunoassay method, whereas in a group of healthy subjects it could be clearly measured. 5 The treatments did not affect systolic or diastolic blood pressure, heart rate, or a series of haematochemical parameters. 6 The increase in diuresis and creatinine clearance and the very good tolerability encountered with ibopamine highlight this new oral dopamine agonist as a useful drug in the management of liver cirrhosis.
A study of long acting propranolol in the early management of hyperthyroidism.
Authors: Jones GR , Lazarus JH , Wynford‐Thomas D
Published: July 2012

1 The effects of propranolol in its long acting formulation, 160 mg long acting (LA) propranolol, were assessed in a double‐blind, controlled study of 20 hyperthyroid patients. Further observations with the addition of carbimazole were also made. 2 LA propranolol effectively improved the clinical manifestations of hyperthyroidism. 3 Plasma concentrations of total T4 and rT3 were increased, but total T3 did not fall significantly during LA propranolol treatment. 4 LA propranolol with carbimazole produced a greater reduction in the clinical indices of hyperthyroidism than carbimazole alone. 5 Total serum T4 and rT3 concentrations remained elevated with LA propranolol and carbimazole compared to carbimazole alone. 6 Carbimazole therapy for 2 weeks did not alter the mean plasma propranolol concentration. 7 We concluded that LA propranolol is effective in hyperthyroidism and its effects are similar to those reported by other workers with conventional propranolol. The clinical and biochemical effects of LA propranolol continue during concomitant carbimazole therapy.
The effect of a single oral dose of prazosin on venous reflex response, blood pressure and pulse rate in normal volunteers.
Authors: Schapel GJ , Betts WH
Published: July 2012

1 A single 500 micrograms oral dose of prazosin was associated with significant suppression of sympathetically mediated venoconstriction, as measured by the venous reflex response in six healthy volunteers. 2 The impaired venous reflex response consistently preceded orthostatic hypotension and tachycardia, which were associated with faintness and other unpleasant symptoms. 3 The plasma prazosin concentration, which was measured by a sensitive, specific h.p.l.c. assay, varied appreciably both between and within individual subjects. 4 There was no precise relationship between the plasma prazosin concentration and the symptomatic haemodynamic effects observed. 5 It was concluded that reduced venous return to the heart, due to significant suppression of sympathetically mediated venoconstriction by small initial oral dosage of prazosin, contributes to the pathophysiology of the orthostatic hypotension and faintness, described as the ‘first‐dose phenomenon’.
The pharmacokinetics of cimetidine and its sulphoxide metabolite in patients with normal and impaired renal function.
Authors: Larsson R , Erlanson P , Bodemar G , Walan A , Bertler A , Fransson L , Norlander B
Published: July 2012

1 The pharmacokinetics of cimetidine and its sulphoxide metabolite was studied after a single intravenous dose of 200 mg cimetidine in nine patients with normal renal function and ten patients with severe renal failure on regular haemodialysis and during continuous oral cimetidine treatment in ten patients with normal renal function and 31 patients with different degrees of renal failure. 2 In normal renal function a mean of 47.3% of the single intravenous dose was excreted as unchanged drug and 12.8% as cimetidine sulphoxide. The mean plasma elimination half‐life (T1/2) of cimetidine was 2.0 h and of cimetidine sulphoxide 1.7 h. 3 In severe renal failure a mean of 2.2% of the single intravenous dose was excreted as unchanged drug and 0.5% as cimetidine sulphoxide. The mean plasma T1/2 of cimetidine was 3.9 h. The plasma concentrations of the sulphoxide metabolite increased successively with time after dosing and no elimination phase was observed still 9 h after dose. The mean non‐renal clearance of cimetidine was 210 ml/min and lower than in normal renal function, suggesting decreased metabolism of cimetidine in uraemia. 4 During continuous oral cimetidine treatment in patients with normal renal function and in patients g and no elimination phase was observed still 9 h after dose. The mean non‐renal clearance of cimetidine was 210 ml/min and lower than in normal renal function, suggesting decreased metabolism of cimetidine in uraemia. 4 During continuous oral cimetidine treatment in patients with normal renal function and in patients g and no elimination phase was observed still 9 h after dose. The mean non‐renal clearance of cimetidine was 210 ml/min and lower than in normal renal function, suggesting decreased metabolism of cimetidine in uraemia. 4 During continuous oral cimetidine treatment in patients with normal renal function and in patients with different degrees of renal failure given reduced doses of cimetidine the plasma concentrations of the sulphoxide metabolite were higher with decreasing renal function. The mean plasma T1/2 of cimetidine was 3.1 h in mild renal dysfunction (creatinine clearance 50‐ 75 ml/min) and 4.5 h in severe renal failure (creatinine clearance 5‐15 ml/min) and of cimetidine sulphoxide 5.3 and 14.4 h respectively. 5 Toxicity studies of cimetidine sulphoxide may be needed to assess if high plasma concentrations of the sulphoxide metabolite in severe renal failure are of clinical significance.
Performance studies with the H1‐histamine receptor antagonists, astemizole and terfenadine.
Authors: Nicholson AN , Stone BM
Published: July 2012

1 Effects of the antihistamines, terfenadine (60 mg) and astemizole (10 and 20 mg), on performance (visuo‐motor coordination, arithmetical ability and digit symbol substitution) and on mood were studied in six healthy adult females. The study was double‐blind, placebo controlled and included an antihistamine with known central effects (triprolidine 10 mg in sustained release form). 2 There were no changes in performance after terfenadine (60 mg) and astemizole (10 and 20 mg). Triprolidine (10 mg) caused a decrement in visuo‐motor coordination (P less than 0.01) 0.5 h after ingestion which lasted until 3.5 h (P less than 0.001). The subject assessed their performance as impaired from 1.5‐3.5 h (P less than 0.05) with triprolidine (10 mg), and their mood assessments were also altered. 3 Terfenadine (60 mg) and astemizole (10 and 20 mg) are likely to prove useful antihistamines for those involved in skilled activity.
Effects of the angiotensin converting enzyme inhibitor, captopril, in essential hypertension.
Authors: Campbell BC , Shepherd AN , Reid JL
Published: July 2012

1 The effects of the orally active angiotensin converting enzyme inhibitor, captopril, were examined in 15 patients with mild or moderate essential hypertension. 2 Following initial dosing with captopril 25 mg, there was a significant fall in supine and erect blood pressure in 2 h and lasting for 6 h. There was no significant alteration of heart rate. No reduction was seen in plasma noradrenaline concentration. Maximum inhibition of plasma converting enzyme activity occurred 60 min post‐dosing. 3 There was a strong positive correlation between blood pressure reduction and converting enzyme inhibition. The magnitude of the blood pressure reduction and converting enzyme inhibition following initial dosing was reflected in subsequent success with captopril monotherapy during a 12 week follow‐up period. 4 It was also found that patients who did not achieve adequate blood pressure control on captopril in doses of 50 mg three times daily or less still were not controlled on a dose of 150 mg three times daily without the addition of a diuretic. 5 The risks of renal and marrow toxicity from captopril may be reduced by administering only low doses with the addition, where necessary, of a thiazide diuretic.
The gut wall metabolism of ethinyloestradiol and its contribution to the pre‐systemic metabolism of ethinyloestradiol in humans.
Authors: Back DJ , Breckenridge AM , MacIver M , Orme M , Purba HS , Rowe PH , Taylor I
Published: July 2012

1 Five patients have been studied to determine the contribution of the gut wall to the pre‐systemic metabolism of ethinyloestradiol. All patients had a catheter inserted into their hepatic portal vein as part of their surgical management. 2 After an oral dose of 50 micrograms (65 microCi) ethinyloestradiol, blood samples were taken from the hepatic portal vein and from a peripheral vein at intervals for 1 h. 3 In each patient the concentration of conjugated ethinyloestradiol in the portal vein was considerably higher than in the peripheral vein. 4 Although a number of assumptions have been made, calculations showed that the gut wall appeared to be twice as effective as the liver in conjugating ethinyloestradiol on the first pass. 5 In two patients there was no evidence of major uptake or metabolism of ethinyloestradiol in the lung.
On the role of alpha 1‐acid glycoprotein in lignocaine accumulation following myocardial infarction.
Authors: Barchowsky A , Shand DG , Stargel WW , Wagner GS , Routledge PA
Published: July 2012

1 Blood plasma and free lignocaine concentrations have been measured 12 h after beginning a constant infusion of 2 mg/min and again at the end of the infusion (36‐72 h) in five patients with myocardial infarction (MI) and compared with five control patients who did not develop objective evidence of MI. 2 In MI patients, total plasma concentration rose significantly between 12 h and the end of infusion. Because of an increase in alpha 1 acid glycoprotein (AAG) plasma binding increased, so that free drug concentration did not change. The rise in whole blood concentration was less than that in plasma as a result of drug redistribution out of red cells due to enhanced binding. 3 In control patients, neither blood nor plasma concentrations changed with time and plasma binding remained constant. Free drug concentrations, however, rose slightly. 4 The concentrations of GX and MEGX remained unchanged in all patients, but the ratio of lignocaine/MEGX concentrations fell in controls but rose in MI patients. 5 Pharmacokinetic modelling suggested that at least some of the rise in blood lignocaine concentration was due to reduced clearance resulting from enhanced plasma binding. 6 We conclude that the rise in AAG following MI is responsible for increased plasma binding and drug redistribution within blood. These changes, together with a reduction in lignocaine clearance, can explain much of the phenomenon of lignocaine accumulation in MI.
Maternal kinetics and transplacental passage of pethidine during labour.
Authors: Tomson G , Garle RI , Thalme B , Nisell H , Nylund L , Rane A
Published: July 2012

1 Pethidine is commonly used in single doses as an analgesic in obstetrics. Plasma concentration‐time profiles of pethidine after intramuscular administration of 1.5 mg/kg body weight to 16 pregnant women during labour were investigated. There was only a two‐fold variation in peak plasma concentration (300‐650 ng/ml). The mean (+/‐ s.d.) value of the apparent plasma half‐life of pethidine was 3.4 (+/‐ 1.0) h which is not different from that in healthy controls. norpethidine plasma levels were not measurable (less than 10 ng/ml). 2 The placental transfer transfer of pethidine was studied at delivery in samples from the umbilical cord vessels and from a maternal peripheral vein. In another 14 patients serial determinations of pethidine concentration were made in foetal scalp blood and maternal venous blood simultaneously during the different stages of labour. The foeto‐ maternal drug ratio varied between 0.35 and 1.5 with a positive correlation between ratio and dose delivery time interval. The concentration of pethidine in umbilical cord plasma or blood varied between 60 and 400 ng/ml with dose‐delivery time intervals of 30 min to 10.5 h. The foetal concentration of pethidine reached a peak‐plateau value between 1‐5 h after dose.
The short term effects of propranolol, atenolol and labetalol on antipyrine kinetics in normal subjects.
Authors: Daneshmend TK , Roberts CJ
Published: July 2012

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.
Alinidine pharmacokinetics following acute and chronic dosing.
Authors: Harron DW , Arndts D , Shanks RG
Published: July 2012

1 Alinidine (N‐allyl clonidine) pharmacokinetics were investigated in healthy volunteers following acute administration of 40 mg orally and intravenously (i.v.) and chronic administration of 40 mg daily and twice daily for 8 days. 2 After acute oral administration the following values were obtained; Cmax – 166.5 +/‐ 18.5 ng/ml at 1.8 +/‐ 0.7 h (mean +/‐ s.d., n = 5); AUC – 1122.9 ng ml‐1 h; VdSS – 190.71 and T1/2 – 4.2 h, and after i.v. administration: AUC – 1046.7 ng ml‐1 h; VdSS – 190.71 and T1/2 4.2 h. 3 Clonidine was identified in plasma and urine samples following oral and i.v. administration; clonidine Cmax was 0.26 +/‐ 0.06 ng/ml at 8.4 +/‐ 2.2 h and 0.5 +/‐ 0.2 ng/ml at 4.8 +/‐ 2.5 following oral and i.v. alinidine respectively. Urinary excretion of clonidine represented 0.1% of the administered dose of alinidine. 4 During administration of alinidine 40 mg daily for 8 days, peak and trough plasma levels reached steady state after day 2 (223.1 +/‐ 123.9 and 9.03 +/‐ 6.7 ng/ml respectively). During alinidine 40 mg twice daily for 8 days peak and trough plasma levels on day 2 were 356.2 +/‐ 92.0 and 80.0 +/‐ 35.8 ng/ml respectively, these levels did not change (P greater than 0.05) between days 2 and 8. Urine elimination of alinidine did not change (P greater than 0.05) between days 5, 6, 7 and 8. 5 Clonidine plasma concentration following alinidine 40 mg daily and twice daily were 0.47 +/‐ 0.18 and 0.84 +/‐ 0.21 ng/ml respectively 2 h after administration on day 2 and did not change (P less than 0.05) between days 2‐8. 6 It is unlikely that clonidine formed from alinidine contributes to the pharmacological action of alinidine.
Xipamide and cyclopenthiazide in essential hypertension–comparative effects on blood pressure and plasma potassium.
Authors: MacGregor GA , Banks RA , Markandu ND , Roulston J
Published: July 2012

1 The blood pressure lowering effect of xipamide, a non‐thiazide diuretic given for 6 weeks was compared in a randomised cross‐over trial with that of cyclopenthiazide in 14 patients with essential hypertension. 2 Xipamide 10 or 20 mg given once daily was as effective in lowering supine blood pressure as daily cyclopenthiazide 0.5 mg. There was no difference in the blood pressure lowering effect of 10 mg xipamide daily for 2 weeks compared to 20 mg daily given for a further 4 weeks. 3 Plasma potassium was reduced by both drugs, but markedly more after both 10 mg and 20 mg xipamide than after cyclopenthiazide 0.5 mg. By the sixth week of treatment 13 of 14 patients on xipamide but only 6 of 14 on cyclopenthiazide has plasma potassium concentrations of, or less than, 3.5 mmol/l. The fall in plasma potassium was significantly greater and the final plasma potassium concentration was significantly lower after either dose of xipamide than after cyclopenthiazide. 4 These results suggest that 10 mg or 20 mg of xipamide daily is effective in lowering blood pressure in hypertensive patients but is associated with hypokalaemia. In view of recent evidence linking diuretic‐induced hypokalaemia with cardiac dysrhythmias in patients with essential hypertension we would suggest that thiazide diuretics be used in preference to xipamide for the routine management of essential hypertension. Our results also suggest that the currently recommended dose of xipamide (20 mg) for the treatment of hypertension is excessive, and lower amounts than 10 mg per day might possibly be as effective in lowering blood pressure with less adverse metabolic consequences.
Prazosin first dose phenomenon during combined treatment with a beta‐ adrenoceptor blocker in hypertensive patients.
Authors: Seideman P , Grahnen A , Haglund K , Lindstrom B , Von Bahr C
Published: July 2012

1 The antihypertensive effect of prazosin has been studied in three groups of hypertensive patients. 2 The drug caused a significant reduction of blood pressure both as monotherapy and combined with alprenolol. 3 The effect of prazosin on blood pressure was more marked at the first dose and especially in combination with alprenolol. 4 No pharmacokinetic interaction between prazosin and alprenolol was observed. 5 Prazosin exhibits an exaggerated first dose effect together with alprenolol. Smaller starting doses of prazosin in combination therapy with beta‐adrenoceptor blockers are warranted.
Comparison of labetalol with other anti‐hypertensive drugs.
Authors: Prichard BN , Richards DA
Published: July 2012

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.
Intravenous labetalol in the treatment of severe hypertension.
Authors: Cumming AM , Brown JJ , Lever AF , Robertson JI
Published: July 2012

1 We have compared, in patients with severe hypertension, the administration of intravenous labetalol by single rapid injection, by repeated bolus injections, and by incremental infusion. 2 Incremental infusion was the most consistently (albeit not invariably) effective method, and that least prone to cause side‐effects. 3 An occasional very marked decrease in blood pressure was seen with all these techniques but least often with incremental infusion. Thus close and continuous supervision is mandatory. 4 All three methods produced slight but significant decreases in heart rate, and in plasma angiotensin II and aldosterone. 5 Intravenous labetalol was also effective in controlling hypertensive crises of phaeochromocytoma and those following the withdrawal of clonidine. 6 In a total of 70 severely hypertensive patients given intravenous labetalol, none showed adverse neurological or cardiological sequelae.
Effects of combined alpha‐ and beta‐blockade by labetalol in patients with coronary artery disease.
Authors: Condorelli M , Brevetti G , Chiariello M , Miceli D , Lavecchia G , Paudice G , Verrienti S
Published: July 2012

1 The effect of labetalol 100 mg orally twice daily on exercise tolerance has been compared with placebo in 19 normotensive subjects with angiographic evidence of coronary artery disease. 2 Labetalol, at the same work load as during placebo exercise, significantly reduced systolic and diastolic blood pressures, as well as heart rate and rate‐ pressure product. 3 Similarly, ST segment depression was reduced by labetalol from 2.0 +/‐ 0.4 to 1.36 +/‐ 0.6 mm (P less than 0.001), thus enabling an increase in exercise tolerance from a control value of 83.7 +/‐ 18 to 95.3 +/‐ 19 W (P less than 0.005). 4 In seven other patients, also with coronary artery disease, the haemodynamic effects of a single 0.6 mg/kg intravenous dose of the drug was evaluated during exercise. 5 Compared with conditions during control exercise, labetalol induced a significant reduction in rate‐pressure product from 17228 +/‐ 2375 to 13445 +/‐ 2404 mmHg/min (P less than 0.005) and in peripheral vascular resistance from 612.0 +/‐ 61.2 to 512.7 +/‐ 36.2 dyn cm‐5 m‐2 (P less than 0.0025). These events were not accompanied by any change in cardiac index and in dP/dT left ventricular end‐diastolic pressure (LVEDP) ratio. 6 These data suggest that labetalol may induce reduction in myocardial oxygen consumption, thereby increasing exercise tolerance in patients with coronary artery disease, without impairment of left ventricular performance.
Comparison of beta‐adrenoceptor blockers under maximal exercise (pindolol v metoprolol v atenolol).
Authors: Erikssen J , Thaulow E , Mundal R , Opstad P , Nitter‐Hauge S
Published: July 2012

1 The time‐related, comparative beta‐adrenoceptor blocking effect of metoprolol 150 mg twice daily, atenolol 100 mg once daily and pindolol 7.5 mg twice daily on heart rate, blood pressure, work performance, blood lactate, free fatty acids and plasma catecholamines was studied in ten males aged 19–25 years by means of repeated maximal bicycle exercise tests. 2 At steady state several differences in effects were noted among the drugs. These could be explained by differences in beta 1‐selectivity, potency of the chosen drug‐doses and intrinsic sympathomimetic activity (ISA). 3 This study emphasizes the importance of including strong sympathetic stimuli in any model used for comparing beta‐adrenoceptor blockers with and without ISA in order not to underrate the effects of beta‐adrenoceptor blockers with ISA. 4 In the chosen doses pindolol was more effective, and atenolol less effective than metoprolol in suppressing heart rate and blood pressure responses to maximal exercise.