bluuebunny/crossref_metadata_2025 huggingface dataset:
Regional circulatory response to converting‐enzyme inhibition in congestive heart failure.
Authors: Faxon DP , Creager MA , Halperin JL
Published: July 2012

1 To determine the distribution of flow, the regional haemodynamic response to 100 mg of captopril was determined in 36 patients with refractory cardiac heart failure. Measurements included forearm blood flow by venous occlusion plethysmography (eight patients), splanchnic blood flow by indocyanine green clearance (10 patients), and coronary blood flow by thermodilution (12 patients). 2 Cardiac index significantly rose in one hour (1.9 +/‐ 0.1 to 2.2 +/‐ 0.1 1/m/m2, p less than 0.01) while forearm blood flow rose slightly (2.9 +/‐ 0.8 to 3.2 +/‐ 0.3 ml/100 ml/min). Renal blood flow rose significantly by 30% (344 +/‐ 48 to 533 +/‐ 82 ml/min, p less than 0.02). Despite a fall in rate pressure product (8.8 +/‐ 0.7 to 7.1 +/‐ 0.5 mm Hg bt x 10(3), p less than 0.02), coronary blood flow did not significantly change (160 +/‐ 20 to 133 +/‐ 12 ml/min), indicating an improved supply‐demand relationship. 3 External myocardial efficiency improved (19 +/‐ 3 to 26 +/‐ 6%, p less than 0.05). Coronary blood flow is unaffected and converting‐enzyme inhibitor improves myocardial efficiency. This strategic reduction in vascular impedence distinguishes converting‐ enzyme inhibitors as a unique class of vasodilators in the treatment of coronary heart failure.
The effects of ampicillin oral contraceptive steroids in women.
Authors: Back DJ , Breckenridge AM , MacIver M. , Orme M. , Rowe PH , Staiger C. , Thomas E. , Tjia J.
Published: July 2012

1 Thirteen women taking long term oral contraceptive steroids were studied while taking ampicillin (500 mg three times daily) and compared to a control cycle while not taking ampicillin. 2 There were no significant changes in the plasma concentrations of ethinyloestradiol, levonorgestrel, follicle stimulating hormone or progesterone, although lower concentrations of ethinyloestradiol were noted in two women. 3 We conclude that most patients taking oral contraceptive steroids do not need to take alternative contraceptive precautions while taking ampicillin.
Plasma levels of (+) and (−)−propranolol and 4‐hydroxypropranolol after administration of racemic (+/‐)‐propranolol in man.
Authors: Von Bahr C. , Hermansson J. , Tawara K.
Published: July 2012

1 We have given fifteen healthy volunteers single doses of racemic (+/‐)‐propranolol orally (40 mg) and intravenously (5‐10 mg) to find out how large the variation was of the ratio between (−)− and (+)‐ propranolol plasma levels in relation to that of total levels of propranolol and 4‐hydroxypropranolol. 2 Total propranolol (+/‐)‐levels 2 h after a 40 mg oral dose of (+/‐)‐propranolol varied from 21 to 580 nmol/l and those of 4‐hydroxypropranolol from 0 to 33 nmol/l. Their levels did not correlate. The ratio between (−)− and (+)‐propranolol levels varied from 0.99 to 2.04. The plasma half‐lives of the two isomers were usually similar. 3 We conclude that in most single doses studies on relationships between plasma concentrations and effects (beta‐adrenoceptor blockade) it is not necessary to quantitate (+)‐ and (−)−propranolol levels separately since total (+/‐) plasma propranolol levels varied much more than the ratio between (−)− and (+)‐propranolol.
A study of nadolol to determine its effect on ambulatory blood pressure over 24 hours, and during exercise testing.
Authors: Hornung RS , Gould BA , Kieso H. , Raftery EB
Published: July 2012

1 The effect of once daily nadolol therapy in sixteen ambulant patients with essential hypertension has been closely assessed during exercise and over 24 h by continuous intra‐arterial recording. 2 The drug was well tolerated and showed similar efficacy to other beta‐adrenoceptor blocking agents. Whilst blood pressure reduction was observed throughout the whole day, it was not uniform and lost significance during the morning period when blood pressure levels were highest. 3 This provides further evidence that the antihypertensive action of a beta‐adrenoceptor drug over 24 h cannot be predicted from its plasma half‐life which, with regard to nadolol, is up to 24 h. 4 An explanation for the loss of blood pressure control during the morning may be that the rapid rise in blood pressure leading to the peak levels at this time may be mediated through alpha‐ rather than beta‐adrenergic receptors at the periphery.
Pharmacokinetics of azapropazone in the elderly.
Authors: Ritch AE , Perera WN , Jones CJ
Published: July 2012

Plasma concentrations of azapropazone have been measured in young and elderly subjects after a single dose of 600 mg azapropazone. Maximum concentrations were higher in the elderly. Renal function was impaired in the older subjects. Mean azapropazone clearance was significantly reduced (P less than 0.001) in the old, compared to the young. Elimination half‐life was prolonged but the difference did not reach statistical significance due to the wide variation of the values in the elderly. The volume of distribution of azapropazone and degree of adipose tissue did not differ between the two groups. Azapropazone clearance correlated well with creatinine clearance (P less than 0.001) when all the subjects were included and for the younger subjects only but not for the elderly patients alone. The addition of fat mass into the regression equation improved the relationship in all groups but in the older group levels of statistical significance were not achieved. Reasons for the difference between young and old are discussed. The effects of age on the pharmacokinetics of azapropazone suggest that therapeutic plasma levels may be achieved with a dose of 600 mg daily.
REGULATION OF α‐ AND β‐ADRENOCEPTOR RESPONSIVENESS. STUDIES IN PATIENTS WITH CHRONIC AUTONOMIC FAILURE
Authors: VELD A.J. MAN IN ‘T , BOOMSMA F. , SCHALEKAMP M. A.D.H.
Published: July 2012

Seven patients with severe orthostatic hypotension due to peripheral autonomic neuropathy were studied.

In four patients, heart rate did not change after the β‐adrenoceptor antagonists propranolol or metoprolol. After the partial β‐adrenoceptor agonist pindolol heart rate rose in a dose‐dependent manner. After α‐adrenoceptor antagonists phentolamine and yohimbine heart rate and blood pressure did not change, which confirmed that these patients were indeed sympathetically denervated.

The non‐selective β‐adrenoceptor agonist isoprenaline and the β2‐selective β‐adrenoceptor agonist salbutamol increased heart rate and lowered arterial pressure, whereas the β1‐adrenoceptor agonist prenalterol increased both heart rate and arterial pressure. After treatment with pindolol, the patient was desensitized for the chronotropic effects of the β‐adrenoceptor agonists in the order: salbutamol > isoprenaline > prenalterol. The desensitization of the depressor effects of the β‐adrenoceptor agonists was in the order isoprenaline > salbutamol. These data suggest preferential cardiovascular β2‐adrenoceptor sensitization in patients with chronic autonomic failure, which can be reversed by treatment with pindolol. They also provide in vivo evidence for the existence of cardiac chronotropic β2‐adrenoceptors in man.

The α‐adrenoceptor agonists methoxamine, phenylephrine, noradrenaline, clonidine and guanfacine increased arterial pressure. The vascular reactivity for the different α‐adrenoceptor agonists differed markedly, as was shown by the declining steepness of the dose‐response curves in the order methoxamine and phenylephrine > noradrenaline > clonidine > guanfacine. The pressor profiles of these agonists were also different. These data suggest, that different α‐adrenoceptor populations are involved in the contractile responses to these α‐agonists, being methoxamine and phenylephrine a1, noradrenaline α1 > α2 and clonidine and guanfacine α2 > α1.

Two patients were treated with clonidine, slow release, 250 μg daily, which increased supine and standing arterial pressure and relieved orthostatic symptoms. In one patient the pressor‐depressor response to adrenaline was converted to a pure pressor response after clonidine, which contrasted with a pure pressor response to adrenaline after treatment with pindolol. Treatment with clonidine shifted the dose‐response curves of the α‐adrenoceptor agonists in the order clonidine > noradrenaline > phenylephrine, suggesting preferential α2‐adrenoceptor desensitization by clonidine in this patient.

These data provide further evidence for the view that α1‐β1 and α2‐β2‐adrenoceptor sensitivity and/or responsiveness are independently regulated and lend support to the hypothesis that peripheral α2‐β2‐adrenoceptors are not innervated.
Observations on the mechanism underlying the differences in exercise and isoprenaline tachycardia after cardioselective and non‐selective beta‐adrenoceptor antagonists.
Authors: McGibney D , Singleton W , Silke B , Taylor SH
Published: July 2012

1 Differences in ability to attenuate isoprenaline tachycardia between the cardioselective beta‐adrenoceptor antagonist atenolol and the non‐ selective drug propranolol, when administered in equivalent anti‐ exercise tachycardia oral doses, were measured in four normal volunteers. 2 Propranolol at all dose comparisons showed a greater potency in antagonism of isoprenaline tachycardia than atenolol; this ranged from 6 at the lowest doses (40 and 50 mg respectively) to 13 at the highest doses (320 and 400 mg respectively). 3 After doses of each drug which produced equal inhibition of exercise tachycardia, isoprenaline induced a greater increase in heart rate and greater decrease in diastolic blood pressure after pre‐treatment with atenolol than after propranolol. 4 The contribution of this isoprenaline induced vasodilatation to the reduced tachycardia response, 1 h after 25 mg oral atenolol, was measured in the same four subjects by correction of the hypotension with an intravenous angiotensin infusion. Reversal by angiotensin of the 17 mm Hg average fall in diastolic blood pressure during the sustained isoprenaline infusion did not reduce the tachycardia. 5 The hypotension that results from isoprenaline stimulation of unblocked vasodilator beta 2‐adrenoceptors in normal subjects pre‐treated with atenolol appears to make a negligible contribution to the tachycardia response and does not explain the different abilities of cardioselective and non‐selective beta‐ adrenoceptor blocking drugs to antagonise isoprenaline tachycardia. Our results are compatible with the presence of beta 2‐adrenoceptors in human atria.
Relationship between myocardial uptake and actions in heart failure of methyldigoxin.
Authors: Hayward R , Greenwood H , Stephens J , Hamer J
Published: July 2012

1 Problems have been encountered in recent years in confirming useful benefit to patients with heart failure and sinus rhythm from acute exposure to digitalis glycosides, though effectiveness of these preparations upon cardiac contractile performance is indisputable. Undesired effects such as those upon systemic vascular resistance have been invoked to explain this. 2 Detailed haemodynamic responses have been studied by cardiac catheterisation in nine such patients for 30 min after intravenous methyldigoxin infusion. Myocardial glycoside uptake was simultaneously assessed. 3 Methyldigoxin uptake by the heart was rapid, passing its peak within 20 min, and was followed by substantial elution. 4 A small progressive and significant increase in cardiac output was observed, though left ventricular filling pressures were not significantly reduced after methyldigoxin. Cardiac contractile function as assessed by left ventricular maximum dP/dt, measured in six patients, showed consistent improvement.
Rate of entrance of benzodiazepines into the brain determined by eye movement recording.
Authors: Tedeschi G , Smith AT , Dhillon S , Richens A
Published: July 2012

1 Peak saccadic velocity of horizontal eye movements, saccade duration at 30 degrees of amplitude and saccade reaction time were measured in six drug free male subjects. 2 In two separate experiments, intravenous doses of diazepam (5 mg), lorazepam (2 mg), chlordiazepoxide (25 mg) and placebo were given, and eye movement recordings were made before and at frequent intervals after drug administration. 3 All the benzodiazepines produced a significant impairment of peak saccadic velocity and saccade duration. Only lorazepam significantly affected saccade reaction time. 4 Time to achieve maximum effect was 10 min after diazepam, 29 min after lorazepam and 42 min after chlordiazepoxide.
Effect of inhibitors of prostaglandin synthesis on hepatic drug clearance.
Authors: Feely J , Wood AJ
Published: July 2012

The effect of inhibition of prostaglandin synthesis on the systemic clearance of indocyanine green and antipyrine was studied in seven subjects. Antipyrine clearance was not altered by indomethacin suggesting that oxidative metabolism was not affected. Both aspirin and indomethacin decreased the clearance of indocyanine green presumably by reducing liver blood flow. These results suggest that an effect of inhibitors of prostaglandin synthesis on hepatic drug clearance is likely to be confined to high clearance drugs when given systemically.
Local and systemic effects of pindolol eye drops.
Authors: Mekki QA , Penhall R , Edgar DF , Stewart‐Jones JH , Turner P
Published: July 2012

Local (reduction of intraocular pressure) and systemic (inhibition of exercise‐induced tachycardia) effects of 1% and 0.25% pindolol eye drops have been studied in a balanced cross‐over double‐blind trial in 12 healthy volunteers. Both concentrations produced a comparable reduction in intraocular pressure while the inhibition of exercise tachycardia was significantly less with the lower concentration.
Secondary metabolism of theophylline biotransformation products in man‐ route of formation of 1‐methyluric acid.
Authors: Birkett DJ , Miners JO , Attwood J
Published: July 2012

The route of formation of 1‐methyluric acid (1MU) from theophylline has been investigated by i.v. administration of 1‐methylxanthine (1MX) before and after allopurinol treatment and of 1,3‐dimethyluric acid (1,3DMU) to healthy male volunteers. 1,3DMU was recovered unchanged in urine and was not demethylated to 1MU. By contrast after administration of 1MX the major part of the dose was recovered as 1MU. After allopurinol this was reversed with most of the 1MX dose being excreted unchanged and only a minor amount as 1MU. The results show that 1MU derived from theophylline is formed by an initial 3‐demethylation to 1MX and then a rapid xanthine oxidase mediated 8‐oxidation. No 1MU is formed by 3‐demethylation of 1,3DMU.
The effects of diazepam and oxprenolol on short term memory in individuals of high and low state anxiety.
Authors: Desai N , Taylor‐Davies A , Barnett DB
Published: July 2012

1 The effect of oral doses of diazepam (5 mg) and oxprenolol (80 mg) on short term memory of normal individuals stratified for ‘state’ anxiety levels has been investigated. 2 Normal student volunteers were stratified into high and low anxiety groups on the basis of responses to the Spielberger ‘A‐state’ scale. Subjects were then randomly administered active drug or placebo and given a form of running memory test performed under a variety of conditions in which variable rate of item presentation and articulatory suppression were used. 3 Diazepam significantly reduced the errors of recall in the running memory test in the high anxiety group and produced a distinct separation of response from the low anxiety group under the test conditions of slow item presentation with articulatory suppression. Oxprenolol had no effect on the short term memory test in either high or low anxiety groups in any experimental test situation. 4 These results are compared to previous work in which generally a deleterious effect of diazepam on short term memory in normal volunteers has been reported. The implications of these findings are further discussed in relationship to possible models of memory function.
Alcuronium kinetics in patients undergoing cardiopulmonary bypass surgery.
Authors: Walker JS , Brown KF , Shanks CA
Published: July 2012

1 The disposition of alcuronium was investigated in 10 patients undergoing surgery involving cardiopulmonary bypass (CPB) and compared with results from a group of non‐cardiac patients studied previously. 2 After intravenous administration of a combined bolus and infusion dosage regimen, plasma concentrations fell in a bi‐exponential fashion to a mean value of 0.55 micrograms/ml immediately before the start of extracorporeal circulation. 3 During CPB an apparent steady‐state of alcuronium was reached immediately after commencement of CPB, however plasma concentrations were some 50% higher than those noted prior to commencement of CPB and those predicted using previous pharmacokinetic data from normal surgical patients. 4 Once CPB was completed and the alcuronium infusion terminated, post‐infusion alcuronium plasma concentrations again appeared to decline bi‐exponentially with time. 5 Of the pharmacokinetic parameters which were calculated model‐ independently, the apparent volume of distribution (Vss) was unchanged (329 vs 313 ml/kg) and the elimination half‐life (t1/2,z) (532 vs 199 min) was prolonged and the plasma clearance (CL) (0.8 vs 1.34 ml min‐ 1kg‐1) markedly reduced in these patients compared to non‐cardiac surgical patients. 6 As a result of these changes in alcuronium concentration during CPB and the diminished elimination of alcuronium following CPB, a closer monitoring of neuromuscular function may be necessary in cardiac patients undergoing CPB.
The pharmacokinetics and pharmacodynamics of the diuretic bumetanide in hepatic and renal disease.
Authors: Marcantonio LA , Auld WH , Murdoch WR , Purohit R , Skellern GG , Howes CA
Published: July 2012

1 Bumetanide (1 mg) was given orally and intravenously to a group of patients with chronic renal failure (n = 6) and to another group with cirrhosis of the liver (n = 8). 2 The pharmacokinetics, using a two‐ compartment model, and the pharmacodynamics of the drug in these patients were compared with those previously obtained for normal subjects. 3 In the renal group serum bumetanide concentrations were higher than for the normal subjects and the terminal half‐lives were significantly prolonged (P less than 0.001). A decreased whole body clearance was attributable to a low renal clearance of drug, the non‐ renal clearance being significantly increased (P less than 0.01). 4 For the patients with liver disease, serum bumetanide concentrations were higher than for the renal group, and the terminal half‐lives were significantly further prolonged (P less than 0.001). Both non‐renal and renal clearances were significantly reduced (P less than 0.001). 5 Absorption rates were not significantly altered in either group and the values of F (bioavailability) were 0.82 and 0.95 for the patients with renal disease and hepatic disease, respectively. 6 A poor pharmacodynamic response and a reduced bumetanide excretion rate were observed for the patients with chronic renal failure, whereas with hepatic disease normal bumetanide excretion rates were observed with an impaired diuretic response.
The role of naloxone infusions in the treatment of overdoses of long half‐life narcotic agonists: application to nor‐methadone.
Authors: Gourlay GK , Coulthard K
Published: July 2012

This report describes the use of a naloxone infusion at a rate of 300 micrograms/h to provide constant antagonism of the respiratory depressant effects of a near fatal nor‐methadone dose in a 2 year old boy. The terminal half‐life for nor‐methadone was calculated to be 13.5 h. The results indicate that a single dose of a narcotic antagonist with a short half‐life (e.g. naloxone) will probably be inadequate to provide long lasting reversal of the effects of overdoses of long half‐ life narcotic agonists, and that continuous infusion may be the preferable to repeated bolus doses.
A comparison of the in vivo effects of ketotifen, clemastine, chlorpheniramine and sodium cromoglycate on histamine and allergen induced weals in human skin.
Authors: Phillips MJ , Thomas Meyrick RH , Moodley I , Davies RJ
Published: July 2012

The effect of ketotifen was compared with that of clemastine and chlorpheniramine, known antihistamines, and sodium cromoglycate, a drug considered to have mast cell “stabilizing” properties on histamine and allergen wealing reactions in human skin, in random order, double‐ blind, placebo controlled studies. Ketotifen was significantly more potent in the inhibition of both histamine (P less than 0.001) and allergen (P less than 0.001) skin wealing reactions than either clemastine or chlorpheniramine. Sodium cromoglycate had no significant effect on either histamine or allergen skin wealing reactions in any of the concentrations tested. However ketotifen, like clemastine, had a significantly greater inhibitory effect on histamine than on allergen induced weals (P less than 0.001) and both drugs were shown to act as competitive antagonists of histamine. Ketotifen has been shown to be a potent anti‐histamine but there is no evidence from these in vivo studies to suggest that it has any additional inhibitory activity on release of mediators from mast cells in human skin.
Pharmacokinetics of promethazine and its sulphoxide metabolite after intravenous and oral administration to man.
Authors: Taylor G , Houston JB , Shaffer J , Mawer G
Published: July 2012

Blood concentrations of promethazine and promethazine sulphoxide have been measured following oral and intravenous administration of promethazine to seven healthy male volunteers. Promethazine disposition is characterised by a large volume of distribution (1970 1) and a high blood clearance (1.141 min‐1). Less than 1% of the dose is excreted unchanged in the urine, therefore total body clearance is essentially metabolic clearance. In accord with this high clearance the oral availability of promethazine is only 25%. The absorption of promethazine from the gastrointestinal tract exceeds 80% in most subjects. Minimal metabolism by the gastrointestinal mucosa is implicated. Promethazine sulphoxide pharmacokinetics are consistent with a pronounced first pass effect. Although the area under the curve for this metabolite is not route dependent, there is a marked alteration in the shape of the metabolite curve when oral and intravenous data are compared. Evidence is presented to support the hypothesis that S‐oxidation of promethazine is predominantly an hepatic event. The conclusions of previous investigators with regard to the role of the gut mucosa in S‐oxidation of phenothiazines is critically assessed.
Reduced clearance of triazolam in old age: relation to antipyrine oxidizing capacity.
Authors: Greenblatt DJ , Divoll M , Abernethy DR , Moschitto LJ , Smith RB , Shader RI
Published: July 2012

Thirty‐three healthy male and female volunteers aged 21 to 87 years received a single 0.5 mg oral dose of triazolam. Plasma triazolam concentrations were measured in multiple samples drawn during 24 h after the dose. Mean triazolam elimination half‐life was not significantly different between young and elderly men (3.0 vs 4.6 h), nor between young and elderly women (2.7 vs 3.2 h). However, apparent oral clearance of triazolam was significantly reduced in elderly as compared to young groups of both sexes, leading to higher peak plasma concentrations and increased total area under the curve. Values of half‐ life and clearance of antipyrine, a low‐extraction hepatically oxidized compound, were poorly correlated with those of triazolam (r = 0.34 and 0.44, respectively), suggesting different mechanisms controlling age‐ related changes in clearance of these two hepatically oxidized drugs.
The pharmacokinetics and diuretic effects of piretanide in chronic renal insufficiency.
Authors: Berg KJ , Walstad RA , Bergh K
Published: July 2012

The pharmacokinetics of piretanide, a new loop diuretic, were studied in four patients with GFR 4.7‐14.8 ml/min. An oral dose of piretanide 18 mg was given at 08.00 h in two patients and at 08.00 h and 14.00 h in two. Blood samples were drawn after 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h. Serum concentrations of piretanide were estimated by radioimmunoassay. The peak serum concentration of piretanide (1‐2 h after drug administration) was 510‐880 ng/ml, independent of renal function. Elimination half life (t1/2) was 1.2‐4.1 h, area under the curves (AUC(0,24)) 1.63‐2.44 micrograms ml‐1 h, volume of distribution (Vz) 0.30–0.741#kg, total plasma clearance (CL) 122.8‐184.0 ml/min and renal clearance (CLR) 1.5‐5.2 ml/min. The clinical effects of oral treatment with piretanide 18 mg twice daily were compared with bumetanide 3 mg twice daily in eight patients with renal failure (GFR 2.2‐24.5 ml/min). Both drugs equally increased the 24 h output of urine (delta V), sodium (delta UNaV), chloride (delta UC1V), potassium (delta UKV) and calcium (delta UCaV). Fractional excretion of sodium (ENa%) was doubled by piretanide in patients with GFR less than 8 ml/min while a five fold increase was found in patients with GFR greater than 8 ml/min. The onset of effect was the same for both drugs, but the duration exceeded 6 h only for piretanide. Both drugs were most effective on the first of two consecutive treatment days. Delta UC1V was always greater than delta UNaV and urinary phosphate excretion was unchanged, as expected of a loop diuretic without significant proximal effects. Metabolic or clinical side effects were not noticed.
Effects of codeine on the respiratory responses to exercise in healthy subjects.
Authors: Stark RD , Morton PB , Sharman P , Percival PG , Lewis JA
Published: July 2012

In six healthy subjects, respiration and the sensation of breathlessness were assessed during submaximal exercise and the subsequent recovery. The overall responses were expressed by the relationship of breathlessness to minute volume. Because of the high subjective component in the assessments, validation of the method in these particular subjects was an integral part of the study. The relationship of breathlessness to ventilation during identical periods of exercise was highly reproducible and sensitivity was demonstrated by an alteration in this relationship in the presence of an inspiratory resistance. Codeine at a dose of 60 mg by mouth was compared with placebo, each treatment being given on two occasions. The study was conducted in a double‐blind fashion with randomization of the order of treatments. Codeine at this dose allowed higher levels of carbon dioxide to be tolerated during breath‐holding; oxygen uptakes at rest and during exercise were unaffected. Ventilation and breathlessness at the end of exercise were each slightly but significantly reduced by codeine but the relationship between breathlessness and ventilation was not changed. Codeine did not prevent detection of an inspiratory resistance.
An intensive drug monitoring study suggesting possible clinical irrelevance of impaired drug disposition in liver disease.
Authors: Naranjo CA , Busto U , Janecek E , Ruiz I , Roach CA , Kaplan K
Published: July 2012

1 Liver disease can alter the disposition and clinical effects of drugs. However, even though altered drug disposition occurs, there is no clinical evidence relating it to an increased susceptibility to adverse drug reactions (ADRs). 2 An intensive prospective drug monitoring study of 2,582 hospitalized patients was conducted. The adverse drug reactions probability scale (APS) was used to assess ADRs. Only non‐mild, definite or probable ADRs (APS greater than or equal to 5) were included. Severity of liver dysfunction was assessed by a composite clinical and laboratory index (CCLI). 3 The frequency of ADRs was higher in 402 patients with cirrhosis (27.4%) than in 661 with renal dysfunction (22.8%) and in 249 with other parenchymatous liver diseases (13.7%) or in 1,270 patients with neither liver diseases nor renal dysfunction (10.9%) (chi 2 3 = 85.53, P less than 0.001). The frequency of ADRs in cirrhotics was highly correlated with the severity of the liver dysfunction measured by CCLI (r = 0.82, P less than 0.001). 4 Drugs predominantly eliminated by liver metabolism were not among those most commonly inducing ADRs or those causing severe reactions in cirrhotics. Thus, frusemide caused the most common and the most severe ADRs, whereas reactions induced by sedatives were uncommon. Drug‐induced hepatic encephalopathy was more common in cirrhotics receiving diuretics (13.3%) than in those receiving sedatives (1.8%) (chi 2 y.c. = 5.29, P less than 0.025). Patients with alcoholic liver disease had more drug‐induced hepatic encephalopathy (7.7%) than those with non‐alcoholic liver disease (1.2%) (chi 2 y.c. = 11.86, P less than 0.001). 5 These results indicate that susceptibility to ADRs is increased only in severe cirrhosis and that the most common and severe ADRs seem more likely related to enhanced pharmacodynamic action than to impaired drug disposition.
Labetalol disposition and concentration‐effect relationships during pregnancy.
Authors: Rubin PC , Butters L , Kelman AW , Fitzsimons C , Reid JL
Published: July 2012

1 Labetalol pharmacokinetics and concentration‐effect relationships following intravenous administration have been studied in 10 women during the last trimester of pregnancies complicated by hypertension, in seven of these women postpartum (when normotensive) and in 10 normotensive female volunteers. 2 The clearance and volume of distribution of labetalol were the same in all three groups. Clearance values (1 min‐1) were: pregnant, 2.16 (range 1.54‐3.14); postpartum 2.35 (1.56‐3.85); controls 1.96 (0.98‐2.61). Volumes of distribution (1) were: pregnant 274 (250‐547); postpartum 407 (248‐701); controls 234 (186‐415). 3 A linear model relating labetalol concentration to effect successfully described the antihypertensive action of labetalol in the pregnant patients. Supine systolic blood pressure fell by 0.38 (0.14‐0.91) mm Hg per ng ml‐1 of labetalol and diastolic by 0.36 (0.21‐ 1.14) mm Hg per ng ml‐1 of labetalol. In the other two groups labetalol did not lower pressure sufficiently to allow modelling to be performed. 4 We conclude that pregnancy does not alter the clearance or volume of distribution of labetalol. Modelling techniques can be applied successfully to drug induced blood pressure changes during pregnancy.
Disposition of chloroquine in man after single intravenous and oral doses.
Authors: Gustafsson LL , Walker O , Alvan G , Beermann B , Estevez F , Gleisner L , Lindstrom B , Sjoqvist F
Published: July 2012

1 Chloroquine was given in 300 mg single doses as an i.v. infusion, an oral solution and as tablets at intervals of at least 56 days to 11 healthy volunteers. Concentrations of chloroquine and its metabolite desethylchloroquine were measured in plasma, erythrocytes and urine using h.p.l.c. 2 Chloroquine was detectable in all plasma samples up to 23 days and occasionally up to 52 days after dosage. Urinary concentrations were monitored up to 119 days. The disposition pattern was multiexponential reflecting extensive tissue binding of the drug. 3 After i.v. dosing the volume of distribution ranged from 116 to 285 l/kg and the apparent terminal half‐life from 146 to 333 h. Total plasma clearance +/‐ s.d. was 712 +/‐ 166 ml/min and renal clearance 412 +/‐ 139 ml/min. The mean estimated urinary recovery of chloroquine was 47%, 42% and 46% after i.v., oral solution and tablets indicating nearly complete bioavailability. The corresponding figures for the metabolite were 7%, 10% and 12%. 4 The disposition of chloroquine in erythrocytes was parallel to that in plasma. The concentrations in erythrocytes were consistently 2 to 5 times higher than in plasma. 5 Subjective side effects like difficulties with swallowing and accommodation, diplopia and fatigue occurred during intravenous infusion and were closely related to plasma concentrations. No effect was seen on the electrocardiogram, mean arterial blood pressure and pulse rate. No adverse reactions were observed after the oral doses. High frequency audiometry did not reveal any significant hearing impairment for the group as a whole.
Paracetamol absorption from Paramax, Panadol and Solpadeine.
Authors: Dougall JR , Cunningham B , Nimmo WS
Published: July 2012

Plasma paracetamol concentrations were measured after oral administration of three pharmaceutical preparations to four healthy volunteers. The formulations were Paramax (paracetamol with metoclopramide), Solpadeine (paracetamol with codeine and caffeine) and Panadol (paracetamol alone). After Solpadeine, concentrations at 15 min were significantly higher than after Panadol. Absorption of paracetamol from Paramax tablets did not differ significantly from Solpadeine or Panadol.
Absorption of beta‐adrenoceptor antagonists to Amberlite resin.
Authors: Heath A , Gabrielsson M , Redgardh CG
Published: July 2012

The adsorption of beta‐adrenoceptor blockers and the partial beta‐ adrenoceptor agonist prenalterol was studied in an in vitro haemoperfusion (HP) model. Metoprolol, alprenolol, propranolol and prenalterol adsorb well from the blood to the resin with extraction ratios nearing 1.0. Extraction ratio for practolol was 0.68 and for atenolol 0.49. Protein binding has little effect on the degree of adsorption, which is more dependent on water solubility.
Uses and abuses of analysis of variance.
Authors: Evans SJ
Published: July 2012

Analysis of variance is a term often quoted to explain the analysis of data in experiments and clinical trials. The relevance of its methodology to clinical trials is shown and an explanation of the principles of the technique is given. The assumptions necessary are examined and the problems caused by their violation are discussed. The dangers of misuse are given with some suggestions for alternative approaches.
The characteristics of [3H]‐ouabain binding to human lymphocytes.
Authors: Pedersen KE , Klitgaard NA
Published: July 2012

The kinetic characteristics of [3H]‐ouabain binding to human lymphocytes and mixtures of mononucleated cells, and the maximum [3H]‐ ouabain binding capacities of these cells were studied. The [3H]‐ ouabain binding was compatible with a single class of receptors with a high affinity for the drug. No signs of positive or negative cooperativity could be demonstrated. In six experiments with pure lymphocyte preparations, the association and dissociation rate constants were 3.08 +/‐ 0.34 × 10(4)/M/S and 1.58 +/‐ 0.50 × 10(‐4)/S. The dissociation constant derived from equilibrium studies on lymphocytes was 0.68 +/‐ 0.21 × 10(‐8) M, which was identical to that of mononucleated cells. In healthy subjects the maximum [3H]‐ouabain binding capacities, which reflect the number of sodium/potassium pump sites were 43154 +/‐ 8037 molecules/cell (n = 25) in lymphocytes and 75474 +/‐ 6764 (n = 9) molecules/cell in mixtures of mononucleated cells. Direct determination of the [3H]‐ouabain binding capacity of lymphocytes can be performed with acceptable accuracy and precision using 30 ml whole blood. Provided high cell purity, this method may be useful, when studying sodium/potassium pump function in clinical settings.
The influence of antacid on the absorption of two different sustained‐ release formulations of theophylline.
Authors: Myhre KI , Walstad RA
Published: July 2012

Twelve healthy volunteers were treated with two different sustained‐ release formulations of theophylline (Nuelin Depot 350 mg and Theo‐Dur 300 mg) twice daily in an open cross‐over study. The serum levels in steady state without and with concomitant administration of antacid were studied. Antacid did not influence the serum theophylline levels in the Theo‐Dur treatment period, while in the Nuelin Depot treatment period antacids caused a significantly larger increase in serum levels of theophylline after drug intake. The difference between morning and peak concentrations were also much higher with the combination Nuelin Depot/antacid. This implies that physicochemical factors such as gastrointestinal fluid pH might influence the degradation and/or absorption of some slow‐release theophylline formulations as reflected in serum concentrations, and thereby contribute to the therapeutic and side effects of such drugs.
Pharmacokinetic investigation of the interaction of azapropazone with phenytoin.
Authors: Geaney DP , Carver JG , Davies CL , Aronson JK
Published: July 2012

We have investigated the interaction of azapropazone with phenytoin in five healthy volunteers. From steady‐state plasma phenytoin concentrations of about 17 mumol/l there was at least a two‐fold increase following the introduction of azapropazone. The main mechanism of the interaction was a decrease in phenytoin clearance, attributable to competitive inhibition by azapropazone of phenytoin p‐hydroxylation. Protein‐binding of phenytoin in the plasma (as assessed by salivary phenytoin concentrations) was significantly reduced from 92 to 90% by azapropazone and similar changes occurred in in vitro studies of [3H]‐ phenytoin protein binding.
Conversion in vitro of urinary (+)‐penicillamine to its major metabolites, PSSP and PSSC.
Authors: Carruthers G , Weir D , Freeman D , Harth M
Published: July 2012

To investigate the discrepancy between the apparent pharmacokinetic disposition of (+)‐penicillamine in plasma and urine, the spontaneous degradation of (+)‐penicillamine was studied in acidified and non‐ acidified urine. Degradation was prevented by acidification. The oxidized metabolites were converted to reduced (+)‐penicillamine by electrolysis.
Evidence for a dual action of sulphinpyrazone on drug metabolism in man: theophylline‐sulphinpyrazone interaction.
Authors: Birkett DJ , Miners JO , Attwood J
Published: July 2012

The effects of sulphinpyrazone administration on the metabolic and renal clearances of theophylline in man were investigated. Sulphinpyrazone increased total plasma theophylline clearance by 22%. This was the sum of increases in metabolic clearances by 3‐ demethylation (32%), 1‐demethylation (30%) and 8‐oxidation (22%) and of a decrease in renal clearance (27%). It is proposed that sulphinpyrazone has differential effects on at least two forms of cytochrome P‐450 inhibiting one enzyme or group of enzymes which metabolises tolbutamide, phenytoin and S(‐)warfarin and inducing a form (or forms) which metabolises theophylline, antipyrine and R(+)warfarin.
Oral verapamil does not affect glucose tolerance in non‐diabetics.
Authors: Semple CG , Thomson JA , Beastall GH , Lorimer AR
Published: July 2012

Verapamil, a calcium antagonist used to treat angina pectoris, inhibits insulin release in vitro and, when administered intravenously to humans, decreases glucose tolerance. Oral verapamil, 120 mg/day for 1 week increasing thereafter to 240 mg/day in divided doses, was given to nine non‐diabetic patients with angina pectoris for 4 weeks. The glucose and insulin responses to a standard glucose load showed no significant difference before and after verapamil. Oral verapamil in the doses used in this study had no significant effect on glucose tolerance in non‐diabetics.
Effect of dazoxiben on arterial graft thrombosis in the baboon.
Authors: Hanson SR , Harker LA
Published: July 2012

1 The thromboxane A2 synthetase inhibitor dazoxiben (UK 37248) was given orally to normal male baboons to determine its effect on platelet function in forming haemostatic plugs, and its capacity to prevent arteriovenous shunt and vascular graft thrombosis. 2 The standard template bleeding time was prolonged significantly at all doses ranging from 10‐100 mg/kg (P less than 0.02 in all cases). 3 Doses ranging from 20‐100 mg/kg daily did not normalize shortened platelet survival time or increased platelet destruction associated with chronic thrombogenic arteriovenous cannulae (P greater than 0.5). 4 A dose of 50 mg/kg did not reduce the rate or extent of acute platelet deposition on to Dacron vascular grafts (P greater than 0.5). 5 Despite significant inhibition of the platelets' capacity to form haemostatic plugs dazoxiben alone is ineffective in the prevention of prosthesis‐related arterial thrombosis in the doses studied.
Use of a thromboxane synthetase inhibitor, dazoxiben, during haemodialysis.
Authors: Dodd NJ , Gordge MP , Weston MJ
Published: July 2012

1 We have assessed the thromboxane synthetase inhibitor, dazoxiben (UK 37248), during dialysis in a double‐blind, placebo‐controlled crossover study. 2 Thromboxane generation was markedly inhibited, and there was an increase in serum 6‐keto prostaglandin F1 alpha levels during active treatment studies. 3 We were unable to demonstrate any reduction of platelet activation, or dialyser fibrin deposition, nor were heparin requirements altered by the drug. 4 Dazoxiben had no adverse effects.
Effects of dazoxiben on transcardiac thromboxane levels and haemodynamics in coronary heart disease.
Authors: Hutton I , Tweddel AC , Rankin AC , Walker ID , Davidson JF
Published: July 2012

1 Plasma thromboxane levels were obtained from both the coronary sinus and aorta in patients with stable angina pectoris paced to angina, and in unstable angina patients before and after dazoxiben 100 mg. 2 Although there was a wide range of values in the different groups, dazoxiben significantly reduced plasma thromboxane levels in all patients. 3 Dazoxiben had no adverse effect on coronary and systemic haemodynamics, and atrial pacing time to angina was increased from 245 +/‐ 41 to 308 +/‐ 48s (P less than 0.01).
Neuroendocrine studies with fluvoxamine: animal data.
Authors: Cella S , Penalva A , Locatelli V , Novelli A , Cocchi D , Muller EE
Published: July 2012

1 Administration of the potent 5‐hydroxytryptamine (5‐HT) re‐uptake inhibitor fluvoxamine (25 mg/kg i.p. for 14 days) to adult cycling female rats did not alter either the number of oestrous episodes or the plasma concentrations of luteinizing hormone determined on days 2, 9 and 14 of treatment. 2 Fluvoxamine (25 mg/kg i.p.) induced in male rats a clear‐cut lowering of beta‐endorphin‐like immunoreactivity from the anterior pituitary, but not the neurointermediate lobe, and increased concomitantly plasma levels of beta‐endorphin and beta‐lipotropin. 3 Fluvoxamine (12.5 and 25 mg/kg i.p.) stimulated, although not strikingly, prolactin (PRL) secretion in adult male rats, and at 25 mg/kg i.p. potentiated the PRL‐releasing effect of 5‐hydroxytryptophan (30 mg/kg i.p.). 4 In male rats treated daily with fluvoxamine (25 mg/kg i.p.) the PRL‐releasing effect of an additional acute fluvoxamine administration (same dose) was abolished after 4 days maintenance treatment. One week after withdrawal of maintenance, which had been given for 14 days, the challenge dose of fluvoxamine was still unable to raise plasma PRL levels. 5 The endocrine effects of acute fluvoxamine administration are compatible with activation of 5‐HT neurotransmission in the central nervous system. The mechanism(s) underlying tolerance to the PRL‐releasing action of the drug is presently obscure. Its elucidation should provide insight into the mechanism of action of antidepressant drugs affecting 5‐HT function.
Drug plasma levels and platelet 5‐HT uptake inhibition during long‐term treatment with fluvoxamine or lithium in patients with affective disorders.
Authors: Wood K , Swade C , Abou‐Saleh M , Milln P , Coppen A
Published: July 2012

1 Plasma levels and platelet 5‐HT uptake characteristics were determined at baseline and at various times during a long‐term study comparing fluvoxamine and lithium prophylaxis. 2 In the fluvoxamine‐ treated patients after 12 and 24 weeks of treatment, Km was significantly increased and y, the mean overall uptake, significantly decreased compared to the patients' own baseline values and to lithium treatment. No significant change was noted for Vmax. 3 For fluvoxamine, significant negative relationships were established between the Vmax of platelet 5‐HT uptake and plasma levels. 4 The trial had to be discontinued prematurely for some patients due to apparent lack of efficacy, unwanted effects or a combination of both in the fluvoxamine‐ treated patients. Low plasma levels of fluvoxamine may have contributed to the apparent lack of prophylactic efficacy of the drug. 5 Reference is made to the activity of receptor systems in patients receiving lithium and the consequent changes occurring after the administration of a potent 5‐HT re‐uptake inhibitor.
A dose ranging study of atenolol in hypertension: fall in blood pressure and plasma renin activity, beta‐blockade and steady‐state pharmacokinetics.
Authors: Ishizaki T , Oyama Y , Suganuma T , Sasaki T , Nakaya H , Shibuya T , Sato T
Published: July 2012

The relationship between the oral dosage and plasma concentration of the long‐acting cardioselective beta‐adrenoceptor blocker atenolol and the antihypertensive response to the the degree of beta‐adrenoceptor blockade and change in plasma renin activity (PRA) was evaluated in patients with mild‐to‐moderate essential hypertension in a double‐ blind, randomized, between‐patient, dose‐ranging (25, 50 or 100 mg once daily for 4 weeks) study. The optimum, or minimum, daily dose of atenolol to treat patients with mild‐to‐moderate hypertension was not clearly identified in this study. A between‐treatment comparison did not demonstrate that all blood pressure falls were always less in the 25 mg group than in the other two groups. Calculation of beta‐error or the power for the negative results between doses suggested that a large sample size is required to draw a conclusion that no dose‐ antihypertensive relationship of atenolol exists in the treatment of mild‐to‐moderate hypertension. A relatively flat plasma concentration‐ antihypertensive response relationship was observed. Steady‐state plasma concentrations of atenolol were dose‐related and renal drug clearance was well correlated with individual creatinine clearance. beta‐adrenoceptor blockade was better correlated with plasma atenolol concentration. Correlations which were less strong were between plasma drug concentration and change in various blood pressures and between blood pressure falls and beta‐adrenoceptor blockade. There was no relationship between the fall in blood pressure and change in PRA. Atenolol appeared to suppress PRA in an all‐or‐none fashion.
Pharmacokinetics of cyclophosphamide in Kenyan Africans.
Authors: Juma F , Ogada T
Published: July 2012

The pharmacokinetics of cyclophosphamide was studied in 10 Kenyan Africans with Hodgkins lymphoma. The mean +/‐ s.d. elimination half‐ life (t1/2) was 7.5 +/‐ 1.38 h. The mean +/‐ s.d. volume of the central compartment (V1) was 0.35 +/‐ 0.12 l/kg and the apparent volume of distribution (V) was 0.64 +/‐ 0.06 l/kg. The microconstants k21, k12 and k10 were 1.81 +/‐ 0.84 h‐1, 1.90 +/‐ 1.080 h‐1 and 2.05 +/‐ 0.86 h‐ 1 respectively (mean +/‐ s.d.).
Absorption of orally administered amphotericin B lozenges.
Authors: Ching MS , Raymond K , Bury RW , Mashford ML , Morgan DJ
Published: July 2012

The systemic absorption of amphotericin B, administered as a 10 mg lozenge, was investigated in 14 patients with malignancies, who received three or four doses daily during chronic administration. The mean plasma amphotericin B concentration, measured 3 h after the morning dose on from 1‐20 occasions over a 1‐80 day period, ranged among subjects from 46 +/‐ 13 ng/ml (s.d., n = 20) to 136 +/‐ 25 ng/ml (n = 19). Using the previously reported intravenous clearance of the drug, the fraction of the dose absorbed was estimated at 8.3‐9.9%. This is considerably greater than that estimated from earlier reports (0.2‐ 0.9%), which used much higher oral doses (2‐10 g/day).
Dopaminergic control of gastric acid and gastrin secretion in man: lack of effects after acute oral administration of ibopamine, an analogue of dopamine.
Authors: Caldara R , Masci E , Barbieri C , Cambielli M , Ferrari C , Tittobello A
Published: July 2012

The effect of oral administration of the dopaminergic drug, ibopamine, at the dose of 200 mg and 400 mg, on basal and submaximal pentagastrin (0.25 microgram kg‐1 h‐1) stimulated gastric acid secretion as well as basal serum gastrin concentration has been evaluated in 24 healthy individuals. In comparison with placebo no significant changes were observed in all the variables studied. The lack of effects on gastric acid secretion might be due to a selective stimulation of dopaminergic receptors not active in the regulation of gastric acidity or not present in gastric mucosa, while unchanged serum gastrin secretion is possibly due to a poor crossing of blood‐brain barrier by ibopamine.