bluuebunny/crossref_metadata_2025 huggingface dataset:
Differences in performance impairment due to brompheniramine maleate as a function of the sustained‐release system.
Authors: Millar K. , Standen PJ
Published: July 2012

1 study examined whether different sustained release systems would cause variation in the effect of an antihistamine, brompheniramine maleate 10 mg, upon mood and psychomotor performance. Two commercial preparations were examined, one giving linear release (LR) of the drug over time, the other releasing the drug in a non‐linear fashion (NLR). 2 Thirty‐six males were allocated to four separate groups receiving either the drug with LR, drug with NLR, placebo or drug‐free control. Single dosage of the drug occurred at 08.30 h and subjects completed mood inventories and performed serial choice reaction time and visual search tasks at 1 h, 2.75 h, 5.5 h and 7.25 h post dosage. 3 The NLR system significantly increased feelings of unco‐ordination at 2.75 h and significantly slowed reaction time at both 2.75 and 5.5 h post dosage. The LR system significantly slowed reaction time only at 5.5 h but increased pausing in serial choice performance at that time. Neither system impaired visual search. 4 Results suggest that two preparations having identical active constituents may vary in their effects on psychomotor performance and mood as a function of their sustained release systems. A system giving linear release of the drug can reduce the early post‐dosage performance decrement associated with a non‐linear release system.
Control of blood pressure and reduction of echocardiographically assessed left ventricular mass with one‐daily timolol.
Authors: Rowlands DB , Glover DR , Stallard TJ , Littler WA
Published: July 2012

1 Ten untreated hypertensive patients underwent 24 h continuous intra‐ arterial ambulatory monitoring of blood pressure (BP) and M‐mode echocardiography. 2 They were treated with once‐daily timolol and followed up at 2, 4, 8 and 12 weeks when dosage was titrated against BP control (indirect measurement) and degree of beta‐adrenoceptor antagonism (submaximal bicycle ergometry and sub‐lingual GTN). 3 Sixteen weeks after commencing therapy, nine patients underwent repeat continuous ambulatory monitoring of BP and M‐mode echocardiography. 4 Casual BP was significantly reduced during the follow‐up period at 2, 4, 8 and 12 weeks. 5 A reduction of BP was seen throughout the 24 h although this did not achieve statistical significance when sympathetic activity was low. 6 Echocardiographic measurement of left ventricular mass was significantly reduced after 16 weeks treatment.
RO 15‐1788 antagonises the central effects of diazepam in man without altering diazepam bioavailability.
Authors: Darragh A. , Lambe R. , Kenny M. , Brick I. , Taaffe W. , O'Boyle C.
Published: July 2012

1 In a double‐blind, placebo controlled study, the efficacy of Ro 15‐ 1788, a new benzodiazepine antagonist, in blocking the cognitive, psychomotor and subjective effects of diazepam, was investigated in a group of six healthy male volunteers. 2 The central effects of orally administered diazepam (40 mg) were most pronounced 1 h after dosing and persisted for 9 h with decreasing severity. 3 Concurrent oral administration of Ro 15‐1788 (200 mg) completely prevented the impairment in cognitive and psychomotor function observed after diazepam alone. 4 The duration of action of Ro 15‐1788 was shorter than that of diazepam. 5 Plasma diazepam levels after administration of the diazepam/antagonist combination were very similar to those observed following diazepam alone.
Comparison of two long‐acting preparations of metoprolol with conventional metoprolol and atenolol in healthy men during chronic dosing.
Authors: Freestone S. , Silas JH , Lennard MS , Ramsay LE
Published: July 2012

1 Eight healthy men received two long‐acting formulations of metoprolol 200 mg (SA Astra, SR Geigy), conventional metoprolol 200 mg and atenolol 100 mg once daily for 1 week each in balanced, crossover fashion. There was a washout period of at least a week between each phase. 2 On the last day of each phase, post‐exercise heart rate was recorded at intervals and compared to pretreatment values. Plasma metoprolol concentrations were measured. 3 The mean AUC was similar after each of the three formulations of metoprolol (relative bioavailability of SA and SR v conventional was 97%) but with SA and SR metoprolol the time to peak was significantly delayed by about 2 h. 4 In comparison to conventional metoprolol only metoprolol SA was associated with significantly higher plasma metoprolol concentrations at the end of a dosing interval (mean values: conventional, 25 ng/ml, SR 37 ng/ml, SA 51 ng/ml). 5 Mean (+/‐ s.d.) reduction in exercise tachycardia at the end of a dosing interval was significantly greater with atenolol (14.8 +/‐ 4.5%) and metoprolol SA (13.7 +/‐ 10.3%) than with metoprolol SR (10 +/‐ 8.4%) and conventional metoprolol (8.2 +/‐ 7.1%). 6 The variability in beta‐adrenoceptor blockade at 24 h was much greater with each of the three metoprolol formulations than that with atenolol. This was explained by the variability in metoprolol metabolism. 7 Oxidation phenotype testing with debrisoquine showed there were six extensive metabolisers and two poor metabolisers. The AUC, half‐life and response to metoprolol at 24 h were much greater in poor metabolisers. Response to atenolol was not influenced by phenotype.
Influence of cimetidine on oral diazepam elimination with measurement of subsequent cognitive change.
Authors: Gough PA , Curry SH , Araujo OE , Robinson JD , Dallman JJ
Published: July 2012

In a double‐blind crossover design, the effect of cimetidine on oral diazepam pharmacokinetics and an evaluation of cognitive function change was studied in seven healthy volunteers. Subjects randomly received placebo or cimetidine 300 mg orally every 6 h for a total of five doses prior to diazepam 10 mg. A significant increase in diazepam elimination half‐life from (mean +/‐ s.e. mean) 66.9 +/‐ 21.4 to 89.6 +/‐ 22.5 h (P = 0.006) and area under the plasma concentration‐time curve from 5.06 +/‐ 1.47 to 8.93 +/‐ 1.88 micrograms ml‐1 h (P = 0.028) was observed indicating a probable cimetidine induced inhibition of diazepam hepatic metabolism. Digit symbol substitution and visual analogue scales were used to measure the effect of an alteration of diazepam kinetics on cognitive function. An enhancement of pharmacological effect as reflected in digit symbol substitution scores and visual analogue scale measurements was not observed.
THE PHARMACOLOGY OF CENTRALLY ACTING ANTIHYPERTENSIVE DRUGS
Authors: VAN ZWIETEN P.A. , THOOLEN M.J.M.C. , TIMMERMANS P.B.M.W.M.
Published: July 2012

Aspects of centrally acting antihypertensive agents are reviewed with an emphasis on compounds acting on central α‐adrenoceptors, in the ponto‐medullary region of the brain. Central α‐adrenoceptors are stimulated by clonidine, guanfacine and also α‐methyldopa, which is presumed to act via α‐methylnoradrenaline, generated in vivo after biotransformation of α‐methyldopa in the brain. Stimulation of the central α‐adrenoceptors decreases peripheral sympathetic tone and thus a fall in blood pressure and bradycardia.

The central α‐adrenoceptors involved in the antihypertensive effect of clonidine, guanfacine and α‐methyldopa appear to be located at postsynaptic sites and of the α2 subtype.

The pharmacological basis of side effects, including withdrawal phenomena and drug interactions of the centrally acting antihypertensives is reviewed.
EFFECT OF METOPROLOL AND OF GUANFACINE ON AMBULATORY BLOOD PRESSURE AND ITS VARIATIONS
Authors: CLEMENT D.L. , CARDON E. , CASTRO M. , DE PUE N. , PACKET L. , VANMAELE G.O.
Published: July 2012

The effect of metoprolol (200 mg once daily) and guanfacine (2 mg once daily) on 12 h ambulatory blood pressure and heart rate was compared with placebo in a double‐blind cross‐over randomized protocol. Twenty‐six patients with moderate essential hypertension were studied.

Metoprolol significantly decreased both systolic and diastolic blood pressure; every point of the blood pressure curve over the 12 h was significantly lower with metoprolol than with placebo and the histograms of systolic and diastolic blood pressure were significantly shifted to the left.

Guanfacine significantly reduced systolic and diastolic blood pressure over the 12 h recording period. The antihypertensive effect lasted at least 24 h.

There was a significant decrease in heart rate with metoprolol but no significant effect on heart rate could be shown with guanfacine.

Neither metoprolol nor guanfacine caused a significant change in the amplitude of blood pressure variations regardless of whether variability was expressed as standard deviation of the mean, as variation coefficient or as range between the highest and the lowest blood pressure.
CARDIOVASCULAR EFFECTS OF WITHDRAWAL OF SOME CENTRALLY ACTING ANTIHYPERTENSIVE DRUGS IN THE RAT
Authors: THOOLEN M.J.M.C. , TIMMERMANS P.B.M.W.M. , VAN ZWIETEN P.A.
Published: July 2012

We have studied on the cardiovascular effects appearing after termination of 12 day continuous infusions with clonidine (500 μg/kg/day), guanfacine (10 mg/kg/day), azeoexole (B‐HT 933, 10 and 60 mg/kg/day) and α‐methyldopa (200 mg/kg/day) in conscious spontaneously hypertensive rats.

The infusions of the four drugs reduced the mean arterial pressure to approximately the same extent.

Following withdrawal of clonidine, a marked overshoot of heart rate and a period of blood pressure lability appeared, together with an elevation of the plasma noradrenaline concentration.

The severities of the withdrawal responses after cessation of infusion with clonidine and azepexole were comparable, whereas those observed after guanfacine and α‐methyldopa were of an insignificant degree.

Precipitation of the discontinuation symptoms by i.p. injection of yohimbine (3 and 10 mg/kg) at day 12 of the infusions resulted in equally severe responses in clonidine‐ and guanfacine‐treated animals, whereas those observed in α‐methyldopa treated rats were absent or much less severe.

Morphine and oxymetazoline suppress the appearance of blood pressure upswings after clonidine withdrawal when applied intracerebroventricularly (10 and 30 μg/kg, respectively). The withdrawal tachycardia is abolished by i.p. injection of 30 μg oxymetazoline/kg, but not by morphine (up to 10 mg/kg). 7 These results indicate, that cessation of prolonged α2 ‐adrenoceptor stimulation by imidazolines or azepexole leads to a cardiovascular withdrawal syndrome. Central as well as peripheral factors play a role in this phenomenon.
NEUROENDOCRINE ASPECTS OF CENTRALLY ACTING HYPOTENSIVE DRUGS
Authors: LAMBERTS S.W.J.
Published: July 2012

The effects of chronic treatment with methyldopa on plasma prolactin (PRL) levels and of the acute administration of guanfacine on growth hormone (GH) release in acromegalic patients were investigated.

Elevated plasma PRL concentrations were observed in five of eight patients during chronic treatment with methyldopa (750 mg/day) for 3–8 months. Three male patients complained of loss of libido and/or impotence. Addition of bromocriptine (7.5 mg/day) to methyldopa therapy normalized the PRL levels and sexual function, while it resulted in a further decrease in blood pressure.

Guanfacine as an acute test dose is a strong stimulator of GH secretion. We investigated the effect of guanfacine (2 mg orally) on plasma GH levels in six acromegalic patients. In five patients, the elevated plasma GH levels showed a paradoxical decrease from 90 to 180 min after the administration of the drug, while blood pressure remained unchanged.

Guanfacine appears to be a safe drug in patients with GH‐secreting pituitary tumours and may possibly be beneficial.
The effect of digoxin on 86rubidium uptake by erythrocytes from mothers and babies.
Authors: Kelly JG , McMillen RM , McDevitt DG
Published: July 2012

1 The uptake of 86rubidium by erythrocytes from mothers and babies has been used as a model system to investigate possible differences in sensitivity to digoxin in the very young. 2 While total 86rubidium uptake was not significantly different between mothers and babies, the digoxin‐sensitive proportion was higher in neonatal erythrocytes. Neonatal cells were less sensitive to digoxin, demonstrated by the requirement for a larger amount of digoxin to inhibit 86rubidium uptake and this was accompanied by an increase in numbers of specific erythrocyte binding sites for digoxin. 3 These results provide further evidence in support of the hypothesis of decreased sensitivity to digoxin in the very young.
Serum digoxin determination in outpatients‐need for standardization.
Authors: Jogestrand T , Nordlander R
Published: July 2012

1 Blood samples were taken from 30 outpatients for serum digoxin analysis before and after 5 min‐4 h of rest in the supine position. 2 The digoxin concentration increased significantly during rest and a steady‐state concentration was reached after approximately 2 h of rest. 3 The mean increase in serum digoxin after 2 h of rest was 23% with a considerable range, i.e. 0‐75% (0‐0.6 nmol/l). 4 On the analogy of a previous finding of a decrease in serum digoxin concentration during exercise in healthy subjects ingesting digoxin, the present results suggest that everyday physical activity affects the serum digoxin concentration. Standardized rest in the supine position prior to collecting blood samples from outpatients is therefore necessary for reliable serum digoxin determinations.
Acute haemodynamic effects of a new calcium antagonist, nicardipine, in man. A comparison with nifedipine.
Authors: Iliopoulou A , Turner P , Warrington SJ
Published: July 2012

1 The acute cardiovascular response to nicardipine was investigated using non invasive techniques in normal subjects. 2 In six subjects, i.v. nicardipine in an increasing dose (0.5‐20 mg) was compared with saline, under double‐blind conditions. A dose related increase in heart rate and fall in blood pressure were found. Pre‐ejection period (PEP) and PEP/left ventricular ejection time (LVET) ratio of the systolic time intervals were shortened in a clearly dose related manner. Total electromechanical systole index (QS2 I) was decreased and LVET index prolonged. 3 In four subjects increasing oral doses (10‐40 mg) of nicardipine, administered in a randomized double‐blind placebo control design, demonstrated the same pattern, marked changes being found with the 40 mg dose. 4 Comparison with nifedipine in a double‐blind‐placebo controlled balanced trial in six subjects confirmed that 40 mg nicardipine and 20 mg nifedipine exhibited similar effects. Maximum response was reached between 0.5 and 1.5 h, and changes in some cardiovascular variables were still evident at 3 h.
Effect of a 2 week course of oral salbutamol on adrenomedullary function in normal subjects.
Authors: Warren JB , Dalton N , Turner C
Published: July 2012

1 The adrenal medullary response to intravenous histamine infusions (0.1 and 0.4 micrograms kg‐1 min‐1 histamine base) was studied in six normal subjects. 2 After a 2 week course of oral salbutamol (8 mg slow release twice daily) plasma adrenaline levels, thought to reflect adrenomedullary function, were unchanged both at rest and in response to histamine infusion. 3 The present study does not support our original hypothesis that salbutamol may be capable of suppressing the adrenal medulla in normal subjects.
Effects of therapeutic drugs on lymphocyte transformation.
Authors: Williams WR , Davidson LA
Published: July 2012

1 Over 40 non‐steroidal drugs, routinely given on a long term therapeutic basis, were tested in lymphocyte transformation cultures at high therapeutic concentrations, or in serum cultures after short term oral drug administration. Lymphocyte transformation was assessed by measuring thymidine and 2‐deoxyuridine incorporation into DNA. 2 When added in vitro, salicylate significantly inhibited thymidine (48%, n = 35) and deoxyuridine incorporation (20%, n = 12). Thymidine incorporation was specifically inhibited by phenylbutazone (39%, n = 6) and chlorpropamide (48%, n = 5). Specific inhibition of deoxyuridine incorporation, indicative of impaired lymphocyte folate metabolism, was obtained following the addition of pyrimethamine (51%, n = 3) and to some extent by carbimazole (30%, n = 2). In serum cultures, pyrimethamine inhibited deoxyuridine incorporation (30%, n = 3) and chloroquine inhibited the incorporation of both thymidine (37%, n = 3) and deoxyuridine (46%, n = 3). 3 Most classes of drugs used long term are unlikely to cause any significant clinical effect, by impairing lymphocyte function. Caution may be warranted when high doses of salicylate, phenylbutazone, chloroquine, pyrimethamine, chloropropamide or combinations of these drugs are prescribed.
The interaction of canrenone with oestrogen and progesterone receptors in human uterine cytosol.
Authors: Fernandez MD , Carter GD , Palmer TN
Published: July 2012

1 Canrenone, the major active metabolite of spironolactone, decreased [3H]‐progesterone binding to isolated uterine cytosolic progesterone receptors. The inhibition was concentration‐dependent. 2 Canrenone did not alter [3H]‐oestradiol binding to isolated uterine cytosolic oestrogen receptors. 3 Canrenone inhibition of progesterone binding to isolated cytosolic receptors was strictly competitive: Kd (apparent dissociation constant for progesterone binding) was increased in a concentration‐dependent manner by canrenone, whereas Bmax (maximal number of progesterone binding sites/mg cytosolic protein) was unaltered. There was marked cooperativity in progesterone binding at high canrenone and low progesterone concentrations. The implication is that canrenone alters the subunit interaction of the receptor protein. 4 Kd for progesterone was 3.2 × 10(‐9)M. Ki (the inhibition constant for canrenone with respect to progesterone binding) was 300 × 10(‐9)M. Reports in the literature suggest that, following spironolactone administration, canrenone may rise to concentrations sufficiently high to inhibit progesterone binding. This action may contribute to the effect of spironolactone in inducing menstrual disturbances in female patients.
Optimal sampling times for minimum variance of clearance determination.
Authors: Dossing M , Volund A , Poulsen HE
Published: July 2012

1 Clearance of a substance that follows first order kinetics can be determined from multiple plasma concentrations (the standard method) or from only one plasma concentration and an assumed volume of distribution (the simplified method). 2 On the basis of statistical considerations it is shown that the variance of the clearance determined by the standard method has a minimum when the mean sampling time is equal to the reciprocal elimination constant. For the simplified method the variance of the clearance is minimal when the sampling time is equal to the reciprocal elimination constant multiplied by one plus the ratio between the squared coefficients of variation of the concentration and the volume of distribution. 3 The sampling times determined in this way are optimal in the sense that the variance of the clearance estimate will be larger for any alternative choice of the same number of sampling times. In practice, the optimal sampling times can only be determined approximately because the elimination constant is not known exactly. The loss in precision of the clearance estimation arising herefrom will be less if the elimination constant is underestimated than if it is overestimated to the same relative extent. 4 In theory, the simplified method with optimal sampling time will give a more precise clearance determination than the standard method, if the number of optimally spaced sampling times is less than one plus the ratio between the squared coefficients of variation of the concentration and volume of distribution. In studies where each subject serves as his own control and the coefficient of variation of the volume of distribution is relatively small the simplified method will be of higher precision unless the number of samples with the standard method is unusually large.
Benzodiazepines impair smooth pursuit eye movements.
Authors: Bittencourt PR , Wade P , Smith AT , Richens A
Published: July 2012

Five healthy male volunteers received single oral doses of 10 mg diazepam, 20 mg temazepam and placebo, in a double‐blind, randomised fashion. Smooth pursuit eye movement velocity and serum benzodiazepine concentration were measured before and after at 0.5,1,1.5,2,3,4,6,9 and 12 h after administration of the treatments. Significant decrease in smooth pursuit eye movement velocity as compared to placebo was observed between 0.5‐2 h after temazepam, and between 1‐2 h after diazepam. Smooth pursuit eye movement velocity was log‐linearly correlated with serum temazepam and diazepam concentration. The results demonstrate the relationship between serum benzodiazepine concentration and its effect on an objective measure of oculomotor performance.
The effect of propranolol on CSF amine metabolites in psychiatric patients.
Authors: King DJ , Cooper SJ , Liddle J
Published: July 2012

In view of the central side effects of beta‐adrenoceptor blocking agents and their alleged antipsychotic action in the absence of DA receptor blockade, it is important to establish which neurotransmitters are likely to be involved. Previous animal and patient studies have, however, produced conflicting data on this point. The changes in CSF HVA, 5HIAA and MHPG during treatment with propranolol (960 mg/day) in chronic schizophrenic patients were monitored on four occasions over 30 days. Clinical changes were monitored by the Wing and Krawiecka Scales and motor activity was assessed by pedometer. CSF HVA levels were significantly increased by propranolol and the rise continued throughout the 30 day period. There were no significant changes in the other metabolites. There was no evidence of any therapeutic benefit from propranolol treatment in these patients. These findings may explain the central side‐effects and occasional reports of schizophreniform psychosis after propranolol, since an increase in DA turnover occurs without DA receptor blockade.
Antihypertensive effect of propranolol at rest and during exercise.
Authors: Leenen FH , Boer P , Mees Dorhout EJ
Published: July 2012

In eight patients with normal‐renin, moderate hypertension, the antihypertensive effects of increasing doses of propranolol (80, 160, 320 and, in three patients, 640 mg/day, each dose for 2 weeks) were evaluated at rest and during exercise in relation to the degree of beta‐ adrenoceptor blockade induced. A significant decrease (11 +/‐ 4 mm Hg) in systolic blood pressure was found after propranolol 80 mg/day. Systolic blood pressure showed a fall of 16 +/‐ 4 mm Hg after 160 mg/day, but no further decrease was measured at higher doses. Diastolic blood pressure showed a significant drop (by 9 +/‐ 3 mm Hg) after propranolol 80 mg/day; a decrease by 12 +/‐ 3 mm Hg after propranolol 160 mg/day, but no further decreases at higher doses. PRA and the rise of systolic blood pressure during bicycle exercise were suppressed to a similar extent by propranolol 80 ng and the higher doses. At 80 mg daily exercise tachycardia was reduced by 18%, at 160 mg by 28%, and at the 2 higher doses by 32%. These results suggest that relatively low doses of propranolol (80‐160 mg daily) induce most of the antihypertensive effect of propranolol not only at rest but also during exercise. Complete cardiac chronotropic beta‐adrenoceptor blockade may not be necessary for the full hypotensive effect.
Effects of feeding on the systemic clearance of indocyanine green and propranolol blood concentrations and plasma binding.
Authors: Feely J , Nadeau J , Wood AJ
Published: July 2012

In six healthy subjects a 250 g steak significantly increased the systemic clearance of indocyanine green. During a steady‐state infusion of propranolol there was a rapid decrease (mean 35%) in blood propranolol concentrations within 5 min of feeding and levels were reduced for 30 min before gradually returning towards the pre‐feeding. These results suggest that the systemic clearance of high extraction drugs may be increased immediately following food.
Determinants of the plasma protein binding of theophylline in health.
Authors: Buss D , Leopold D , Smith AP , Routledge PA
Published: July 2012

1 The plasma protein binding of theophylline was determined after addition of [14C]‐theophylline (15 micrograms/ml) to plasma from 24 healthy drug‐free volunteers and equilibrium dialysis for 2 h at 37 degrees C. 2 The percentage of drug unbound was 60.0% +/‐ 2.2% (s.d.) with very little variation between individuals. The binding ratio of theophylline was not significantly related to the plasma albumin or alpha 1‐acid glycoprotein (AAG) concentrations but was significantly, although weakly, negatively related to the logarithm of the non‐ esterified fatty acid concentration (NEFA) (r = 0.443, P less than 0.05). 3 Intravenous administration of heparin (1000 units) caused a significant rise in plasma NEFA concentration and in the percentage of drug unbound in plasma after equilibrium dialysis. 4 In human serum albumin solutions, the binding ratio of theophylline was significantly related to the albumin concentration and at the albumin concentration seen in the 24 normal subjects, the percentage of drug unbound was almost identical. Addition of AAG in physiological concentrations did not enhance theophylline binding but oleic acid, and to a lesser extent palmitic acid, reduced binding significantly. 5 The percentage of theophylline unbound in plasma varied markedly with pH so that at pH7 the percentage unbound was 52% greater than at pH 8. There was no evidence of concentration dependence of binding up to 140 micrograms/ml theophylline. 6 Theophylline appears to bind almost exclusively to albumin and its plasma protein binding varies little in healthy subjects, showing no concentration‐dependence over the therapeutic range of concentrations. The binding is affected by pH and by NEFA concentration, however, and these factors may be of greater importance in disease states. Caution should be employed in the use of heparin in studies of plasma protein binding of theophylline.
Contribution of the vagus to the haemodynamic responses following intravenous boluses of isoprenaline.
Authors: Arnold JM , McDevitt DG
Published: July 2012

1 Eight healthy subjects (six male, two female, aged 18‐21 years) received graded intravenous bolus injections of isoprenaline sulphate. Heart rate and intra‐arterial blood pressure were continuously monitored PRE‐ and POST‐atropine (0.04 mg/kg). 2 PRE‐atropine, an increase in heart rate of 25 beats/min was produced by 2.15 +/‐ 0.53 micrograms of isoprenaline and was associated with a fall in mean, systolic and diastolic pressures (18.9 +/‐ 2.8, 17.7 +/‐ 3.4 and 20.4 +/‐ 2.3 mm Hg respectively). 3 POST‐atropine, the heart rate dose response curve was shifted to the right so that the dose of isoprenaline which increased heart rate 25 beats/min PRE‐atropine, produced a significantly smaller heart rate rise of 20.3 +/‐ 1.7 beats/min (P less than 0.001). This was associated with a shift of the blood pressure dose‐response curves to the left, and larger falls in mean, systolic and diastolic pressures (30.9 +/‐ 2.8, 31.8 +/‐ 3.3, 30.1 +/‐ 3.3 mm Hg respectively; P less than 0.01). 4 It is concluded that there is a significant contribution from a reflex withdrawal of cardiac vagal tone, to the tachycardia produced by a bolus of isoprenaline.
Variations in drug free fraction during alcohol withdrawal.
Authors: Sandor P , Naranjo CA , Khouw V , Sellers EM
Published: July 2012

1 Free fractions of diazepam, propranolol and warfarin were determined in 15 male chronic alcoholics in alcohol withdrawal. 2 On admission the mean free fraction of diazepam was 25% above and propranolol 44% below the limits of normal range, while the mean warfarin free fraction was in high normal range. One week later mean free fraction of diazepam declined by 20% while propranolol and warfarin increased by 24% and 19% respectively (P less than 0.05). 3 Propranolol free fraction and alpha 1‐AGP concentrations were highly correlated (linear r = −0.83, P less than 0.001). In contrast the sources of variation in diazepam and warfarin free fraction were more complex and less certain. 4 Statistically significant changes of drug free fractions in serum of chronic alcoholics were observed during alcohol withdrawal. The extent and direction of these changes differed for various classes of drugs and their potential causes appear to be quite different. 5 Clinically important changes in drug effect may be present acutely, within the dosing interval, as a result of altered drug binding. These are more likely when the clinical response is closely related to drug concentration and will occur within the dosing interval due to larger fluctuations in free drug concentration, even though the average free drug concentration will remain unchanged. 6 Total drug level changes will be observed during alcohol withdrawal even in absence of detectable changes of drug metabolism.
The influence of food intake on the bioavailability of timegadine, a novel non‐steroidal anti‐inflammatory drug.
Authors: George S , Dauwe K , McBurney A , Ward J
Published: July 2012

The effects of food ingestion on the absorption of timegadine, a recently synthesised non‐steroidal anti‐inflammatory drug, was studied in ten healthy volunteers. It was found that food enhanced the absorption of timegadine as shown by increased peak plasma concentrations (Cmax), decreased time taken to achieve these concentrations (tmax), and increased area under the plasma concentration time curve (AUC).
Dose‐response curves to inhaled beta‐adrenoceptor agonists in normal and asthmatic subjects.
Authors: Barnes PJ , Pride NB
Published: July 2012

We have compared bronchodilator dose‐response curves to inhaled salbutamol in seven normal and eight asthmatic subjects. In all normal subjects maximal bronchodilatation measured by partial flow volume curves was achieved at a cumulative dose of 110 micrograms. The dose necessary to produce half maximal response (ED50) was 23 +/‐ 2 micrograms (mean +/‐ s.e. mean) with a range of 18‐28 micrograms. In asthmatic subjects maximal bronchodilatation measured by FEV1 and by maximal flow volume curves was achieved at significantly higher (P less than 0.01) doses of salbutamol with a mean ED50 of 83 +/‐ 28 micrograms and range of 25‐251 micrograms. There was a significant (P less than 0.05) correlation between ED50 and % predicted baseline FEV1. This is more likely to reflect impaired access of drug for airway beta‐ adrenoceptors than impaired beta‐adrenoceptor function in asthma. In five asthmatic subjects dose‐response curves to salbutamol and isoprenaline were compared and found to be similar, thus providing no evidence that salbutamol is a partial agonist in vivo, as it appears to be in vitro.
Effects of terbutaline sulphate aerosol on bronchodilator response and lung mucociliary clearance in patients with mild stable asthma.
Authors: Bateman JR , Pavia D , Sheahan NF , Newman SP , Clarke SW
Published: July 2012

Ventilatory function and whole lung mucociliary clearance have been assessed in 10 patients with mild stable asthma following inhalation of 1 mg of the beta‐adrenergic receptor agonist terbutaline sulphate (Bricanyl, Astra Pharmaceuticals) from a metered dose inhaler (MDI). Compared to placebo inhalation, terbutaline produced marked bronchodilatation (mean percentage increase in FEV1 14%, P less than 0.01). Mucociliary clearance (measured by the in vivo radioaerosol technique) was assessed on three occasions‐control, followed by placebo or terbutaline studies in a double‐blind, cross‐over manner. Particles were removed from the lung at a similar rate in all three studies. The mean (+/‐ s.e. mean) percentage of aerosol retained in the lungs after 6 h was 58 +/‐ 5%, 57% +/‐ 5% and 57 +/‐ 4% for control, placebo and drug studies respectively. It is concluded that terbutaline sulphate, given as a 1 mg acute dose, does not enhance mucociliary clearance in mild stable asthmatics, although it produces marked bronchodilatation.
A comparison of once daily atenolol and metoprolol SA in mild to moderate hypertension.
Authors: Morley CA , Cavalcanti C , Perrins EJ , Sutton R
Published: July 2012

Atenolol 100 mg once daily and metoprolol SA 200 mg once daily were compared in 20 patients with mild to moderate hypertension, in a randomised, double‐blind cross‐over trial. Blood pressure and heart rate were compared at rest and during maximal exercise on a bicycle ergometer at 2 and 24 h post‐dose. Blood pressure control was similar with both drugs, except at 2 h when systolic blood pressure was significantly lower with atenolol. Blood pressure and heart rate were less well controlled at 24 h than at 2 h with both drugs, but the majority of patients were still considered adequately controlled at 24 h. Atenolol and metoprolol SA can be considered equally effective in the treatment of mild to moderate hypertension and can be recommended as a once daily regime.
Cardiovascular and platelet effects in man of BW 245C, a stable mimic of epoprostenol (PGI2).
Authors: Orchard MA , Ritter JM , Shepherd GL , Lewis PJ
Published: July 2012

1 BW 245C is a stable hydantoin prostaglandin analogue with a biological action similar to epoprostenol (PGI2). 2 Intravenous BW 245C (1,2 and 4 ng kg‐1 min‐1) produced a progressive increase in heart rate and pulse pressure in four healthy male volunteers. 3 These changes in heart rate and pulse pressure were accompanied by reduced ex vivo platelet aggregation to submaximal concentrations of ADP. 4 In man, BW 245C has a profile of action and potency similar to PGI2. However, it has a longer duration of action than PGI2.
The pharmacodynamics and pharmacokinetics of conventional and long‐ acting propranolol in patients with moderate hypertension.
Authors: Serlin MJ , Orme ML , MacIver M , Green GJ , Sibeon RG , Breckenridge AM
Published: July 2012

1 The effects on heart rate and blood pressure after single and multiple dosing (1 month) of a long acting formulation of propranolol 160 mg daily, and conventional propranolol, 80 mg twice daily, or 160 mg daily were compared in 11 moderately hypertensive subjects previously shown to respond to propranolol. 2 After acute dosing all three treatments produced significant reduction in blood pressure. After multiple dosing all three treatments maintained significant reductions in lying, standing and exercise heart rate and blood pressure throughout the 24 h. At 24 h, after multiple dosing, the fall in resting and standing systolic BP was significantly greater with LA propranolol than with conventional propranolol 80 mg twice daily or conventional propranolol 160 mg once daily (P at least less than 0.05). 3 The plasma propranolol concentration time curve after LA propranolol showed slowed absorption, and the area under the curve was significantly lower than after conventional propranolol (acute dosing; LA propranolol 160 mg 560 mg ml‐1 h, conventional propranolol 80 mg twice daily 1135 mg ml‐1 h, conventional propranolol 160 mg daily 1414 mg ml‐1 h).
Reorientation of prostaglandin endoperoxide metabolism by a thromboxane synthetase inhibitor: in vitro and clinical observations.
Authors: Vermylen J , Deckmyn H
Published: July 2012

1 Work with dazoxiben in vitro and in vivo suggests that a diminished capacity of platelets to synthesize thromboxane A2 results in a reorientation of the metabolism of cyclic endoperoxides. 2 Platelets of patients with congenital thromboxane synthetase deficiency show the same phenomenon. 3 In the presence of endothelium or leukocytes which have prostacyclin synthetase capacity, significant amounts of prostacyclin can be generated if thromboxane synthesis is blocked. 4 The local generation of aggregation inhibiting prostaglandins in areas of vascular damage may be an interesting therapeutic concept. 5 Pilot clinical studies of thromboxane synthetase inhibitor dazoxiben (UK 37248) in a small number of patients with peripheral arterial disease did not reveal major or consistent haemodynamic changes. 6 Attention is directed towards optimizing pharmacologically the generation and efficacy of the inhibitory prostaglandins produced when thromboxane synthetase is inhibited.
Effects of dazoxiben on arrhythmias and ventricular fibrillation induced by coronary artery occlusion and reperfusion in anaesthetised greyhounds.
Authors: Coker SJ , Parratt JR
Published: July 2012

1 The effects of the thromboxane synthetase inhibitor dazoxiben (UK 37248) on haemodynamics, blood gases, thromboxane and prostacyclin release and on arrhythmias were examined in anaesthetised greyhounds subject to acute coronary artery occlusion and reperfusion. 2 Ten minutes after the administration of UK 37248 2 mg/kg intravenously, the plasma concentration of thromboxane B2 in the coronary sinus was significantly reduced whereas the 6‐keto‐prostaglandin F1 alpha concentration was increased. 3 UK 37248 did not significantly alter the number of arrhythmias or the incidence of ventricular fibrillation resulting from coronary artery occlusion. There was evidence, however, that in some drug‐treated animals there may have been incomplete inhibition of thromboxane synthesis during coronary artery occlusion. 4 A further dose of 1 mg/kg UK 37248 was administered intravenously 5 min before the release of the 40 min coronary artery occlusion. Seven out of eight control dogs died in ventricular fibrillation following reperfusion whereas only one out of eight drug‐treated animals fibrillated. 5 This latter result suggests that thromboxane may be an important factor in reperfusion induced ventricular fibrillation and that dazoxiben may be a useful drug in clinically related situations.
Prevention of extension of ischaemic damage following acute myocardial ischaemia by dazoxiben, a new thromboxane synthetase inhibitor.
Authors: Burke SE , Lefer AM , Smith GM , Smith JB
Published: July 2012

1 Dazoxiben, a new thromboxane synthetase inhibitor, at an infusion rate of 5 mg/kg/h inhibited the ischaemia‐induced increase in circulating thromboxane B2 in cats. 2 Dazoxiben also restored the S‐T segment of the electrocardiogram toward normal values after the onset of ischaemia, and prevented the rise in plasma creatine kinase activity usually observed during myocardial ischaemia. 3 Associated with the above changes were reduced loss of myocardial creatine kinase activity and amino‐nitrogen concentration in the ischaemic region of those cats treated with dazoxiben. 4 No significant effects of dazoxiben were observed on heart rate, mean arterial blood pressure or the product of the two, the pressure‐rate index. Therefore, dazoxiben does not protect by reducing myocardial oxygen demand. 5 The mechanism of the protective action of dazoxiben in acute myocardial ischaemia seems to be either due to prevention of the constrictor and cytolytic actions of thromboxane A2 or to metabolic and cellular actions of dazoxiben unrelated to thromboxane synthetase inhibition.
5‐hydroxytryptamine and depression: a model for the interaction of normal variance with pathology.
Authors: Goodwin FK , Post RM
Published: July 2012

1 Theories linking 5‐hydroxytryptamine (5‐HT) with depression are briefly reviewed. The various experimental strategies adopted to investigate this relationship, examination of autopsy data, CSF metabolite data, 5‐HT re‐uptake patterns in human blood platelets and imipramine binding studies in human platelets, are discussed. 2 Recent studies of 5‐hydroxyindole acetic acid (5‐HIAA) levels in cerebrospinal fluid have revealed a linkage between low 5‐HIAA levels and suicide, aggression and impulsivity. Decreases in the number of imipramine binding sites have also been found in brains of suicide victims. 3 The available data lead to the conclusion that decreased 5‐ hydroxytryptaminergic function may be associated with an increased risk of depression, suicide, and some types of aggression.
Pharmacokinetics of ketoprofen in the elderly.
Authors: Advenier C , Roux A , Gobert C , Massias P , Varoquaux O , Flouvat B
Published: July 2012

Pharmacokinetic constants of ketoprofen (Orodis, Profenid) were determined in 10 young adults (24.9 +/‐ 1.3 years) and seven elderly patients (86.3 +/‐ 2.4). Following oral administration of a 150 mg dose of ketoprofen, no difference in tmax was observed between the two groups. However, compared with younger subjects elderly patients showed a significant increase in t1/2,z (2.72 +/‐ 0.22 vs 1.77 +/‐ 0.16 h; P less than 0.01) and AUC (70.4 +/‐ 6.4 vs 29.13 +/‐ 2.02 mg l‐1 h; P less than 0.001), a non‐significant reduction of Vd/F per kg bodyweight (0.145 +/‐ 0.016 vs 0.213 +/‐ 0.028 l kg‐1) and a decrease in total clearance CLT/F (0.037 +/‐ 0.002 vs 0.071 +/‐ 0.004 l h‐1 kg‐1, P less than 0.05). These results suggest that the glucuroconjugation of ketoprofen is slowed down by age.
Sustained release disopyramide compared to plain capsules after change‐ over from intravenous infusion.
Authors: Lien E , Bakke OM
Published: July 2012

The plasma concentration profile of disopyramide was examined in 13 patients with arrhythmias following acute myocardial infarction. Intravenous loading doses of 1.5 mg/kg followed by 0.7 mg/kg and then infusion of 0.3 mg kg‐1h‐1 resulted in final concentrations between 2.4 and 4.9 mg l. Change‐over to oral therapy with disopyramide sustained release (SR) tablets was smooth, and therapeutic plasma concentrations were maintained throughout. Comparison of the plasma concentrations in a subsequent cross‐over study with disopyramide plain capsules 150 mg every 6 h and SR tablets 250 mg every 12 h, each being administered for 3 days to attain a steady state, showed that the bioavailability and the variation of the plasma concentration were similar with both regimens. In patients with body weight between 62 and 92 kg disopyramide SR tablets 250 mg every 12 h matched the preceding infusion rate of 0.3 mg kg‐1h‐1 resulting in plasma concentrations close to steady state already on the first day of oral therapy. The absorption of disopyramide SR tablets is only moderately delayed, and the preparation can be used twice daily in direct succession of intravenous infusion.
Drug binding in sera deficient in lipoproteins, albumin or orosomucoid.
Authors: Pike E , Kierulf P , Skuterud B , Bredesen JE , Lunde PK
Published: July 2012

The relative role of lipoproteins, albumin and orosomucoid in the serum binding variation of various drugs was examined by separate removal of these proteins. Lipoproteins were removed from serum by ultracentrifugation, albumin by affinity chromatography and orosomucoid by immunoprecipitation. Removal of the lipoproteins did not affect the serum binding of the acidic (phenytoin) and neutral (digitoxin) drugs tested, nor the basic drugs disopyramide, quinidine or propranolol. A reduction in binding of amitryptyline, nortriptyline, doxepin and desmethyldoxepin was observed. Removal of albumin did, with some exception for nortriptyline, not affect the serum binding of the basic drugs tested. A pronounced reduction in the binding of phenytoin and digitoxin was observed. Removal of orosomucoid did not affect the binding of the acidic and neutral drugs tested. A reduction in the binding of all the basic drugs tested was observed, especially for disopyramide whose binding almost disappeared. Quinidine, propranolol, phenytoin and digitoxin all bound to isolated lipoproteins, but the removal of lipoproteins had no effect on the total serum binding for these drugs. Hence, the use of deficient sera provides valuable information as to the quantitative role of the various proteins in drug binding, whereas studies using purified proteins are often necessary to examine the mechanisms of the drug protein interactions.
The acute and chronic effects of H1 receptor blockade with astemizole on indocyanine green clearance.
Authors: Bateman DN , Chapman PH , Rawlins MD
Published: July 2012

The effects of acute and chronic (3 months) dosing with astemizole on indocyanine green kinetics have been investigated in normal volunteers and patients. A single dose of astemizole 40 mg produced significant reduction in indocyanine green clearance (P less than 0.02) and volume of distribution (P less than 0.02) when assessed at 48 h, but not at 24 h. In six volunteers who did not receive astemizole there was no significant change in indocyanine green kinetics over a 48 h period. In seven patients on chronic treatment with astemizole there was no significant change in indocyanine green kinetics when these were measured at 1 month and 3 months and compared to pre‐treatment values. The change in indocyanine green clearance and volume of distribution following acute astemizole treatment did not correlate with H1‐receptor antagonism. Change in indocyanine green clearance following acute drug administration may not be due to changes in liver blood flow and should therefore be interpreted with caution.
The effects of chronic renal insufficiency on the pharmacokinetics of doxycycline in man.
Authors: Houin G , Brunner F , Nebout T , Cherfaoui M , Lagrue G , Tillement JP
Published: July 2012

The pharmacokinetics as well as erythrocyte and plasma protein binding of doxycycline were studied in fifteen patients with various renal function impairments after oral doxycycline polyphosphate single administration. Plasma half‐life (t 1/2), area under the plasma concentration‐time curve (AUC), urinary excretion, renal clearance, erythrocyte and plasma protein binding (%) were regressed vs creatinine clearance. No significant correlations were observed between t 1/2 or AUC and renal function nor plasma protein binding and plasma albumin concentrations. Significant correlations were obtained between urinary excretion, renal clearance, erythrocyte binding, plasma protein binding and creatinine clearance. Significant correlation was obtained between haematocrit and erythrocyte binding. Constancy of overall elimination parameters in renal failure is due to parallel increase in plasma free fraction of doxycycline.
Acebutolol pharmacokinetics in renal failure.
Authors: Smith RS , Warren DJ , Renwick AG , George CF
Published: July 2012

Acebutolol was administered orally in a single dose of 200 mg to 17 individuals whose renal function varied markedly. The plasma half‐life and elimination rate constant for acebutolol showed a four‐fold variation but these did not correlate with the degree of renal impairment. However, there was a good correlation between the renal clearance of creatinine and that of acebutolol (P less than 0.001). The half‐life and elimination rate of the acetyl metabolite, diacetolol, were subject to 10‐fold inter‐individual variability which correlated significantly with the creatinine clearance and serum creatinine concentration. The AUC for the acetyl metabolite showed a 40‐fold individual variation which also correlated with renal function. It is concluded that renal elimination is the principal route of excretion for diacetolol but not the parent compound, acebutolol.