bluuebunny/crossref_metadata_2025 huggingface dataset:
Audit of a monitoring service for free phenytoin.
Authors: Peterson GM , McLean S , von Witt RJ , Millingen KS
Published: July 2012

This study assessed the value of introducing the measurement of free phenytoin levels in a public hospital. After publicising the availability and purpose of the assay, free phenytoin levels were determined either (a) on the doctor's request or (b) when the total level was requested and the patient's record showed evidence of factors predisposing to an elevated unbound fraction. Total phenytoin was measured by EMIT, and the unbound fraction by ultrafiltration at 37 degrees C using [14C]‐phenytoin as a tracer. During a 9 month period, 70 free level determinations were performed on 46 patients. These comprised 20% of all phenytoin assays. The median free phenytoin fraction was 13.6% (range 9.3‐28.6%). While total phenytoin levels were below the normal optimum range in 61% cases, free levels were probably therapeutic or above in 70% cases. Dosage adjustments were recommended on the basis of the free level, and were followed more often when the doctor had requested the free level assay (P less than 0.05). The results suggest that a free phenytoin level assay can improve the usefulness of therapeutic drug monitoring, particularly when the doctor understands the purpose of the assay.
Effects of verapamil on calcium‐induced rigidity and on filterability of red blood cells from healthy volunteers and patients with progressive systemic sclerosis.
Authors: Sowemimo‐Coker SO , Kovacs IB , Kirby JD , Turner P
Published: July 2012

The effects of verapamil on calcium‐induced decrease deformability of red blood cells (RBCs) and on the filterability of RBCs from healthy volunteers and patients with progressive systemic sclerosis (PSS) were investigated in vitro using a gravity driven filtration technique. The filterability of RBCs was increased by verapamil 1 microgram/ml (P less than 0.01) in healthy volunteers (P less than 0.05) and in patients with PSS (P less than 0.05). A high concentration of verapamil (200 micrograms/ml) caused an 80% reduction (P less than 0.05) in the filterability of RBCs from healthy volunteers. The filterability of RBCs stored at 4 degrees C for 24 h was increased by 1 microgram/ml verapamil (P less than 0.05). Verapamil (1 microgram/ml) prevented the decrease in deformability of RBCs due to an increase in either extracellular or intracellular calcium concentrations (P less than 0.05). By increasing red cell filterability verapamil may be useful in the treatment of PSS and other peripheral vascular diseases where decreased red cell deformability may play an important role in the pathogenesis.
The pharmacokinetics of high dose metoclopramide in patients with neoplastic disease.
Authors: Bryson SM , McGovern EM , Kelman AW , White K , Addis GJ , Whiting B
Published: July 2012

High dose metoclopramide infusions (10 mg/kg) were administered to nineteen patients with bronchial carcinoma who were receiving intravenous cyclophosphamide as single agent chemotherapy. Considerable interindividual variability in metoclopramide disposition was observed. Mean clearance was 0.33 +/‐ 0.13 (s.d.) l h‐1 kg‐1, mean volume of distribution at steady state was 3.8 +/‐ 1.2 (s.d.) l/kg and mean elimination half‐life was 8.3 +/‐ 4.4 (s.d.) h. These results were significantly different from mean values previously reported for young healthy volunteers given conventional doses (0.70 l h‐1 kg‐1, 2.2 l/kg and 2.6 h respectively). Significant correlations were found between serum urea, serum creatinine and metoclopramide clearance. The metoclopramide regimens were well tolerated and, with the exception of two patients, were completely effective in the prevention of nausea and vomiting. To achieve and maintain target serum metoclopramide concentrations of 1 microgram/ml, we now administer a loading infusion of 3.61 mg/kg over 30 min followed by a maintenance infusion of 0.36 mg kg‐1 h‐1 for 10 h. Cyclophosphamide is normally administered concurrently with the second infusion. For patients with evidence of mild renal impairment, the maintenance infusion rate of metoclopramide hydrochloride should be adjusted according to the predicted individual clearance value; CL (l h‐1 kg‐1) = 0.57 ‐ [0.036 X urea (mmol/l)].
A comparative study of a new selective beta 2‐adrenoceptor agonist, procaterol and salbutamol in asthma.
Authors: Crowe MJ , Counihan HE , O'Malley K
Published: July 2012

The effects of single oral doses of a new selective beta 2‐adrenoceptor agonist procaterol (0.05 mg and 0.1 mg) and salbutamol (4 mg) on ventilatory function, were compared in 24 asthmatic patients. A bronchodilator effect of similar duration and magnitude followed all three treatments with no evidence of a dose‐related response in the case of procaterol. There was no significant difference in blood pressure or heart rate responses or pattern of unwanted effects. We conclude that procaterol and salbutamol are clinically similar with oral dosing and that the maximum effective dose of procaterol is not greater than 0.05 mg.
Chlorpromazine‐a specific effect on breathlessness?
Authors: O'Neill PA , Morton PB , Stark RD
Published: July 2012

Previous work has left unresolved questions on whether promethazine reduces the sensation of breathlessness. This study was designed to provide a definitive answer and to determine the contributions from promethazine's major pharmacological actions. Twelve healthy subjects participated in a double‐blind, within‐subject comparison of promethazine and placebo each given acutely by mouth. Breathlessness was assessed with visual analogue scales during a progressive exercise test and was related to minute ventilation. Promethazine had no significant effect on breathlessness nor on the relationship between breathlessness and ventilation. The role of histamine‐antagonism was investigated in a subgroup of the subjects by administration of mebhydrolin. No effect on breathlessness was detected. In contrast, the standard phenothiazine, chlorpromazine, caused a marked and statistically significant reduction in breathlessness without affecting ventilation and without causing detectable sedation. This unexpected finding merits further study in patients and is discussed with reference to the role of chlorpromazine as a constituent of Brompton's Mixture.
Plasma melatonin during desmethylimipramine treatment: evidence for changes in noradrenergic transmission.
Authors: Cowen PJ , Green AR , Grahame‐Smith DG , Braddock LE
Published: July 2012

Plasma melatonin was used to determine overall beta‐adrenergic transmission through pineal neuro‐effector junctions during desmethylimipramine (DMI) treatment in 10 normal subjects. Changes in plasma melatonin indicated that an initial increase in noradrenaline (NA) transmission produced by DMI was counteracted by adaptive changes which restored transmission to normal by the third week of treatment. A 'rebound' increase in NA transmission was seen on DMI withdrawal. The results suggest that the adaptive changes which occur in NA synapses during DMI treatment do not, as has been proposed, decrease NA transmission below normal levels, but instead restore homeostasis in the presence of the drug.
The ex vivo plasma protein binding of theophylline in renal disease.
Authors: Leopold D , Webb D , Buss DC , Fifield RA , Smith AP , Routledge PA
Published: July 2012

The plasma protein binding of theophylline was measured in 21 patients with renal disease and 21 healthy age and sex matched controls. The percentage of theophylline unbound to plasma was greater in patients with nephrotic syndrome and in chronic renal failure than in controls. In nephrotic syndrome the impairment of drug binding mirrored the marked degree of hypoalbuminaemia seen in this condition but in chronic renal failure the impairment of protein binding was greater than would be expected from the plasma albumin concentration changes. The percentage of theophylline free in plasma in renal disease may be increased (by as much as 50%). Such changes should be taken into account in interpreting the relationship between total plasma theophylline concentration and drug effect in renal disease.
Measuring side‐effects of beta‐adrenoceptor antagonists: a comparison of two methods.
Authors: Lewis RV , Jackson PR , Ramsay LE
Published: July 2012

The prevalence of side‐effects of beta‐adrenoceptor antagonists among hypertensive patients was assessed by two methods. Using visual analogue scales, scores for tired legs, cold digits and vivid dreaming were significantly higher in patients taking beta‐adrenoceptor blockers than in patients not taking beta‐adrenoceptor blockers. When measured by numerical scales, from 1 to 10, these symptoms showed no relation to beta‐adrenoceptor blocker treatment. The visual analogue scales were more sensitive than the numerical scales because the scores were distributed more evenly over the analogue scales.
Chronopharmacokinetics of paracetamol in normal subjects.
Authors: Malan J , Moncrieff J , Bosch E
Published: July 2012

The chronopharmacokinetics of paracetamol was studied in six male volunteers. Serum concentrations of paracetamol were determined after a single oral dose of 1 g, on three occasions, spaced at least 1 week apart. Plasma drug concentration vs time curves were obtained after dosage at 08.00 h (Day 1), 14.00 h (Day 2) and 20.00 h (Day 3), under standardized conditions. Pharmacokinetic parameters compared were t1/2,alpha, t1/2,Z, tmax, Cmax and AUCpo. No statistically significant differences were found.
Neurotic illness: conserving a threatened concept.
Authors: Sims AC
Published: July 2012

With the advent of the American Psychiatric Association's Classification DSM III, the usefulness of the term neurosis as a unitary concept has been questioned. This is largely because of the psychodynamic connotations that invest the term in the USA. However there has been pragmatic development, since the word was introduced into the English language in 1784, that carries epidemiological, behavioural and phenomenological implications. This is demonstrated in the definition contained in ICD 9. Disturbance of self‐experience and problems with interpersonal relationships are common to all neurotic disorders, and bodily symptoms of non‐organic cause are usual. Neurotic disorders are extremely frequent in the general population, amongst those who consult general practitioners and in psychiatric out‐ patients; they necessarily concern doctors. It is concluded that what different neurotic disorders have in common is more important for classification than the differences between them. An important practical consideration is that there are general aspects of treatment appropriate for all neuroses which are of less relevance in the treatment of other psychiatric disorders. Also the provision of treatment services require different emphases for the neuroses.
Antidepressant properties of the triazolobenzodiazepines alprazolam and adinazolam: studies on the olfactory bulbectomized rat model of depression.
Authors: O'Connor WT , Earley B , Leonard BE
Published: July 2012

Chronically administered alprazolam and adinazolam attenuated the hyperactivity of bilaterally bulbectomized rats when placed in a stressful, novel environment (‘open field’ apparatus). These drugs had no effect on the activities of sham operated animals under the same experimental conditions. In other studies in these laboratories, clinically effective antidepressant drugs have been shown to have a qualitatively similar effect to alprazolam and adinazolam. Chronically administered diazepam and phenobarbitone did not affect the hyperactivity of bulbectomized rats in the ‘open field’ apparatus. No difference could be found between the behaviour of bulbectomized rats and the sham operated controls when the animals were placed in a novel, non‐stressful environment (‘hole board’ apparatus and Y‐maze). Chronic treatment of either the lesioned or non‐lesioned animals with alprazolam or adinazolam did not cause any change in the behaviour of the animals in these situations. This suggests that the behaviour of the rat on the ‘hole board’ is not a reliable indication of anti‐ anxiety activity for chronically administered benzodiazepines. When unstarved lesioned and non‐lesioned animals were given a choice of five palatable foods for a period of 1 h, slight differences in preference for the type of food chosen could be detected. Thus unsweetened biscuit (‘cream crackers’) was the most preferred choice of the sham operated rats while cheese and chocolate were the least preferred. Bulbectomized rats showed a more varied food choice, with processed meat (‘corned beef’) and raisins being preferred to biscuit in two out of four groups. Chronic treatment with either alprazolam or adinazolam did not appear to affect the food preference.(ABSTRACT TRUNCATED AT 250 WORDS)
Evaluation of oxprenolol and metoprolol Oros systems in the dog: comparison of in vivo and in vitro drug release, and of drug absorption from duodenal and colonic infusion sites.
Authors: Fara JW , Myrback RE , Swanson DR
Published: July 2012

The performance of oxprenolol and metoprolol Oros systems has been evaluated in the dog. One study compared in vivo and in vitro release from both systems over 2‐14 h. The other compared the systemic availabilities of both drugs after 3 h infusion at a constant rate into the cephalic and hepatic portal veins, and into the lumen of the duodenum and colon. In the in vivo release studies, Oros systems were recovered throughout the gut from the stomach to the colon. The amounts of drug remaining in the systems corresponded closely to those measured in a parallel in vitro release experiment. In vitro testing is thus a reliable indicator of in vivo system performance. In the absorption studies, both metoprolol and oxprenolol were shown to be subject to substantial first‐pass metabolism. Additionally, for metoprolol the data indicated a significant loss during transport from the gut lumen into the portal circulation. For both drugs the availability from the colon was equal to that from the duodenum. These results provide some justification for the development of oral dosage forms with extended durations of release even for drugs which undergo significant first‐ pass metabolism.
Investigation of drug absorption from the gastrointestinal tract of man. III. Metoprolol in the colon.
Authors: Godbillon J , Evard D , Vidon N , Duval M , Schoeller JP , Bernier JJ , Hirtz J
Published: July 2012

The colonic absorption of metoprolol was indirectly evaluated by measuring drug appearance in plasma following intravenous, jejunal or colonic infusion in six healthy volunteers. Plasma concentrations of alpha‐hydroxymetoprolol and urinary excretion of the main metabolites were also measured. Plasma profiles of metoprolol after colonic and jejunal perfusion were similar, and the relative bioavailabilities of the drug from these two regions of the gut were not significantly different. The concentrations of alpha‐hydroxymetoprolol, the major metabolite in plasma, were similar after jejunal and colonic perfusion, but higher than those observed after intravenous administration. The percentage of the dose recovered in urine over 24 h as two metabolites was not significantly influenced by the route of administration.
Oxprenolol absorption in man after single bolus dosing into two segments of the colon compared with that after oral dosing.
Authors: Antonin KH , Bieck P , Scheurlen M , Jedrychowski M , Malchow H
Published: July 2012

The systemic availability of oxprenolol after colonic and oral administration has been compared in a crossover study involving six healthy male volunteers. Drug administration into two regions of the colon (caecum and left flexure) was achieved by means of a colonoscopic technique. There were no obvious differences in plasma concentrations after drug administration to the caecum and left flexure, although in one subject it was necessary to repeat colonic administration because of unexpectedly high plasma drug levels on the first occasion. The possible reasons for this abnormal response are discussed. The mean systemic availability of oxprenolol was 82% after colonic compared with oral dosing, although marked differences were observed in individual plasma levels following drug administration by the two routes. The results of this study support the concept of extending the duration of oxprenolol release from a rate‐controlled dosage form to permit once‐ daily administration with this short elimination half‐life drug.
Gastrointestinal transit of Oros drug delivery systems in healthy volunteers: a short report.
Authors: John VA , Shotton PA , Moppert J , Theobald W
Published: July 2012

Transit times for oxprenolol and metoprolol Oros drug delivery systems through the gastrointestinal tract have been measured in 35 individuals in six separate studies. A total of 45 systems were recovered in a median time of 27.4 h; individual transit times varied from 5.1 to 58.3 h. The residual amount of drug in recovered systems was inversely related to transit time and corresponded closely with the amount estimated from in vitro dissolution profiles.
Osmotically controlled‐delivery of metoprolol in man: in vivo performance of Oros systems with different durations of drug release.
Authors: Godbillon J , Gerardin A , Richard J , Leroy D , Moppert J
Published: July 2012

In vivo absorption from 19/190 and 19/285 metoprolol Oros drug delivery systems has been assessed by measuring plasma drug concentrations after single administration of the systems to six healthy volunteers. The initial in vitro release rate for both Oros preparations was 19 mg/h but they contained 190 or 285 mg of metoprolol fumarate. The plasma concentration‐time profiles for both Oros dosage forms were consistent with an extended duration of release and absorption from the gastrointestinal tract. Analysis of the plasma level data indicated that the rate and duration of in vivo absorption closely mirrored the in vitro release behaviour of the 19/190 and 19/285 systems, but the in vivo profiles showed a 1‐2 h initial delay. The administration of the 19/190 system on two occasions to the same six volunteers indicated that in vivo release of drug from this Oros preparation was reproducible.
Effect on postural sway of various benzodiazepine tranquillizers.
Authors: Patat A , Foulhoux P
Published: July 2012

The effects of various benzodiazepine tranquillizers (clobazam 20 mg, bromazepam 6 mg and lorazepam 2 mg) were investigated by posturography in 16 subjects in a controlled trial. Twelve received each of the three anxiolytics for 1 week in a cross‐over design, four received placebo for 1 week during the three successive treatment periods. A pharmacodynamic study was carried out after the first administration, and another assessment was done after 1 week of treatment. The first administration of lorazepam caused the most marked disturbances of body sway (increase of spectral energies, length and amplitude of the stabilogram). The first administration of bromazepam was also accompanied by an increase of the posturographic parameters, although less marked. Administration of clobazam did not produce any impairment of equilibrium, indicating that it is devoid of any sedative effect measurable by posturography. No changes of the postural sway can be detected on the measurement recorded 10 h after the last dose of 1 week's treatment.
Caffeine disposition in obesity.
Authors: Abernethy DR , Todd EL , Schwartz JB
Published: July 2012

Caffeine pharmacokinetics were studied in 16 obese (mean +/‐ s.e. mean body weight; 110 +/‐ 8 kg; % ideal body weight (IBW); 186 +/‐ 14%) and 23 normal body weight (64 +/‐ 3 kg; 103 +/‐ 3% IBW) subjects. Eight obese and four control subjects were cigarette smokers. After abstaining from caffeine for 48 h and an overnight fast, each subject ingested 162 mg caffeine orally. Concentrations of caffeine were measured in plasma samples obtained during the 24 h following the dose and pharmacokinetic variables were determined. The apparent volume of distribution was increased markedly in obese subjects (69.9 +/‐ 5.9 vs 43.6 +/‐ 2.8 l; P less than 0.001) in the absence of any change in oral clearance (135 +/‐ 14‐obese vs 112 +/‐ 12 ml/min; NS), resulting in a trend toward increased elimination half‐life (7.05 +/‐ 1.08‐obese vs 5.40 +/‐ 0.40 h; NS). Apparent volume of distribution correlated well with percent IBW (r = 0.65; P less than 0.001). Caffeine clearance, suggested as a measure of in vivo cytochrome P‐448 activity in humans, was not altered in obesity. In contrast, the extent of caffeine distribution increased in direct relation to body weight. If caffeine is used therapeutically, the loading dose should be calculated as a function of total body weight. Since clearance of caffeine is not related to body weight, these data indicate that a chronic dosing regimen to maintain a given plasma caffeine concentration should not be altered due to obesity.
Single dose pharmacokinetics and pharmacodynamics of oral loprazolam in the elderly.
Authors: Swift CG , Swift MR , Ankier SI , Pidgen A. , Robinson J.
Published: July 2012

The pharmacokinetics of the benzodiazepine hypnotic, loprazolam (1.0 mg orally), and the pharmacodynamic response to single oral doses (0.5 mg and 1.0 mg) have been compared in young and elderly healthy volunteers. No difference between the groups in peak plasma concentration (Cmax) or in the time to peak (tmax) was found, but the elimination half‐life t1/2,z and area under the plasma concentration‐time curve (AUC) were significantly greater in the elderly group. The immediate effects of loprazolam on all three performance tests used (postural sway, critical flicker fusion threshold (CFFT) and choice reaction time (CRT] and on subjective sedation tended to be more pronounced in the elderly subjects, though intersubject variability in response was high in both groups. The corresponding plasma concentrations did not differ significantly between the two groups. The higher (1.0 mg) dosage was associated with significant residual (11 h) impairment of standing steadiness in the elderly subjects. No other hangover effects were observed. The results are compatible with previous evidence of increased 'sensitivity' to benzodiazepines in the elderly and suggest that a lower (0.5 mg) starting dose of loprazolam would be appropriate for older recipients. Further investigation would be necessary to establish whether clinically relevant accumulation of loprazolam occurs in the elderly following repeated dosage.
Anticonvulsant therapy and cortisol elimination.
Authors: Evans PJ , Walker RF , Peters J.R. , Dyas J. , Riad‐Fahmy D. , Thomas JP , Rimmer E. , Tsanaclis L. , Scanlon MF
Published: July 2012

The effect of anticonvulsant therapy on early morning concentration of cortisol in saliva and plasma was assessed in a group of epileptic patients receiving regular phenytoin medication and the results compared with those obtained from a group of normal subjects not receiving drug therapy. Values of cortisol in matched samples of plasma (331 +/‐ 23 nmol l‐1, mean +/‐ s.e. mean, n = 6) and saliva (11.4 +/‐ 0.9 nmol l‐1, mean +/‐ s.e. mean, n = 9) provided by epileptics did not differ significantly from those in the plasma (334 +/‐ 41 nmol l‐1, mean +/‐ s.e. mean) and saliva (12.0 +/‐ 2.0 nmol‐1, mean +/‐ s.e. mean) of healthy volunteers (n = 12). Six anticonvulsant‐treated epileptics, together with six age and sex matched normal volunteers, each received intravenous dexamethasone (1 mg h‐1) to determine the half‐life of cortisol in plasma and saliva. In the anticonvulsant‐ treated group, the half‐life of cortisol in plasma (73 +/‐ 5 min, mean +/‐ s.e. mean) and saliva (83 +/‐ 5 min, mean +/‐ s.e. mean) was reduced significantly (P less than 0.01 plasma, P less than 0.05 saliva) from that observed in healthy volunteers. In patients, the half life of cortisol and antipyrine showed a significant correlation (r2 = 0.75, P less than 0.05 plasma, r2 = 0.71, P less than 0.05 saliva). The antipyrine half‐life in saliva was reduced significantly (P less than 0.02) and the antipyrine clearance rate, increased significantly (P less than 0.005) in the treated epileptic group, reflecting drug‐ induced microsomal enzyme production.(ABSTRACT TRUNCATED AT 250 WORDS)
Ex vivo effects of nifedipine, nisoldipine and nitrendipine on filterability of red blood cells from healthy volunteers.
Authors: Sowemimo‐Coker SO , Debbas NM , Kovacs IB , Turner P.
Published: July 2012

In a balanced, randomised and double‐blind trial, the effects of single oral dose of nifedipine, nitrendipine and nisoldipine were compared with placebo in eight healthy volunteers. Red cell filterability, measured with a gravity driven filtration technique, was not significantly altered by any of the three calcium antagonists compared with placebo, when RBCs were filtered within 2 h of venepuncture. Storage of RBCs for 24 h at 25 degrees C, however, significantly reduced RBC filterability compared with 2 h (P less than 0.05), but the reduction after nifedipine and nitrendipine was significantly (P less than 0.05) less than after placebo. The above results demonstrate an effect of calcium antagonists on filterability of stored RBCs.
Effect of short surgical procedures on salivary paracetamol elimination.
Authors: Ray K. , Adithan C. , Bapna JS , Kangle PR , Ray K. , Ramakrishnan S.
Published: July 2012

The effect of short surgical procedures on paracetamol elimination was studied in seven male patients undergoing surgery with epidural anaesthesia. Five healthy volunteers who did not undergo surgery served as a control group. Paracetamol concentration was measured in saliva at various intervals 1 day before and after surgery. Paracetamol half‐life (t1/2,z) decreased and metabolic clearance rate (CL) increased after surgery as compared to preoperative values. The results suggest that surgical stress may enhance the hepatic metabolism of paracetamol.
Intrinsic sympathomimetic activity of cardioselective beta‐adrenoceptor blockers and effects on renal function.
Authors: Mackay IG , Macnicol AM , Smith HJ , Cumming AD , Watson ML
Published: July 2012

The effects of a 21 infusion of isotonic sodium chloride on renal haemodynamics and sodium excretion were measured in nine normotensive volunteers. Changes in these responses to volume expansion induced by cardioselective beta‐adrenoceptor blockade by drugs with (epanolol) and without intrinsic sympathomimetic activity (atenolol) were examined. Renal plasma flow was significantly lower before, during and after sodium chloride infusion whilst on treatment with atenolol compared with epanolol. Urinary sodium excretion was lower on atenolol than epanolol. Glomerular filtration rate was unchanged by either drug. Basal urinary kallikrein excretion was diminished by atenolol and both epanolol and atenolol inhibited the rise in urinary kallikrein excretion after sodium chloride infusion. Although some of these findings may be due to a more potent hypotensive effect of atenolol, intrinsic sympathomimetic activity may contribute to the apparent protective effects of epanolol on renal function.
Ventilatory effects of long‐term treatment with pindolol and metoprolol in hypertensive patients with chronic obstructive lung disease.
Authors: Lammers JW , Folgering HT , van Herwaarden CL
Published: July 2012

Effects of long‐term treatment with pindolol (10 mg twice daily) and metoprolol (100 mg twice daily) on lung function and blood pressure were investigated in eight patients with chronic obstructive lung disease and hypertension. After a placebo period, both beta‐ adrenoceptor blockers were administered double‐blind and cross‐over for 4 weeks. By assessing parameters of expiratory flow an attempt was made to distinguish between large and small airways function. Diastolic blood pressure decreased significantly during both pindolol and metoprolol (P less than 0.01). Except for a decrease in forced expiratory volume in 1 s (FEV1) during metoprolol treatment, there was no other change in expiratory flow parameters after placebo or both beta‐adrenoceptor blockers. Inhalation of terbutaline induced a small improvement in large airways function after placebo and metoprolol, but not after pindolol; there was no effect of terbutaline on parameters of small airways function. If a beta‐adrenoceptor blocker is necessary in patients with chronic obstructive lung disease, a beta 1‐adrenoceptor selective blocker is preferred in combination with bronchodilator agents.
Selectivity and dose‐dependency of the inhibitory effect of propranolol on theophylline metabolism in man.
Authors: Miners JO , Wing LM , Lillywhite KJ , Robson RA
Published: July 2012

The effects of separate 5 day pretreatments of propranolol 120 mg day‐1 and 720 mg day‐1 on theophylline clearance and metabolism at steady‐ state were determined in seven healthy males. Propranolol 120 mg day‐1 decreased theophylline plasma clearance (CL) by 30%. Clearance of theophylline to each metabolite was reduced by this treatment, clearances to the two demethylated products by 42‐43% and clearance to the 8‐hydroxylation product by 27%. Propranolol 720 mg day‐1 decreased theophylline CL by 52%. Again, clearance of theophylline to each metabolite was reduced by this treatment, clearances to the two demethylation products by 73‐77% and clearance to the 8‐hydroxylation product by 44%. These data are consistent with a dose‐dependent and selective inhibitory effect of propranolol on the separate forms of cytochrome P‐450 involved in theophylline demethylation and 8‐ hydroxylation.
The influence of diflunisal on the pharmacokinetics of oxazepam.
Authors: van Hecken AM , Tjandramaga TB , Verbesselt R. , de Schepper PJ
Published: July 2012

Single dose pharmacokinetics of oxazepam, 30 mg, have been studied in six healthy male volunteers in the absence of diflunisal and during continuous treatment with diflunisal 500 mg twice daily. During diflunisal treatment, peak plasma concentration of oxazepam significantly decreased from 387 +/‐ 18 ng ml‐1 (mean +/‐ s.e. mean) to 241 +/‐ 10 ng ml‐1 and total area under the plasma concentration‐time curve (AUC) significantly decreased from 5536 +/‐ 819 ng ml‐1 h to 4643 +/‐ 562 ng ml‐1 h. The AUC of oxazepam glucuronide significantly increased from 4771 +/‐ 227 ng ml‐1 h to 8116 +/‐ 644 ng ml‐1 h and its elimination half‐life increased from 10.0 +/‐ 0.6 h to 13.0 +/‐ 1.0 h. Renal clearance for oxazepam glucuronide was significantly reduced from 74 +/‐ 2 ml min‐1 to 46 +/‐ 3 ml min‐1. In vitro, diflunisal, at concentrations of 125 to 1000 micrograms ml‐1, significantly displaced oxazepam from its plasma protein binding, the free fraction of oxazepam increasing by 28 to 56%. The free fraction of oxazepam glucuronide, ex vivo, increased by 49 +/‐ 5% (n = 3) during concomitant diflunisal treatment. These data suggest that the observed interaction between oxazepam and diflunisal results from a presystemic displacement of oxazepam from its plasma protein binding sites by diflunisal and from an inhibition of the tubular secretion of oxazepam glucuronide by the glucuronides of diflunisal.
A comparison of the pharmacokinetics of atenolol, metoprolol, oxprenolol and propranolol in elderly hypertensive and young healthy subjects.
Authors: Rigby JW , Scott AK , Hawksworth GM , Petrie JC
Published: July 2012

Six elderly patients with established hypertension and six young healthy subjects were studied after 8 days of treatment with atenolol 50 mg day‐1, metoprolol 50 mg day‐1, oxprenolol 80 mg day‐1 and propranolol 80 mg day‐1. The area under the blood concentration‐time curve was increased in the elderly group for each drug, but the difference was statistically significant only for atenolol. The lower serum albumin concentrations in the elderly group did not result in a decrease in the percentage of propranolol or oxprenolol bound to serum proteins.
Flecainide pharmacokinetics in healthy volunteers: the influence of urinary pH.
Authors: Johnston A. , Warrington S. , Turner P.
Published: July 2012

The pharmacokinetics of a single 300 mg oral dose of flecainide were studied in eight healthy volunteers on four separate occasions under different conditions of urinary pH. The urinary pH of the volunteers was manipulated chemically to produce four distinct groups spanning the range of urinary pH (pH 5‐8). Neither the rate nor extent of flecainide absorption was significantly affected by changes in urinary pH. However the plasma elimination of flecainide was found to be inversely proportional to urinary pH and the volunteers' mean elimination half‐ life ranged between 10.7 +/‐ 3.2 h (s.d.) at the extreme acid pH and 17.6 +/‐ 6.3 h at the extreme alkali pH. The urinary elimination and renal clearance of flecainide decreased with increasing urinary pH. The influence of changes in urinary pH on the pharmacokinetics of flecainide will contribute to the normal variability in flecainide serum concentrations seen in patients and should be considered in patients who have adverse reactions to the drug at low dosage or who fail to respond at high doses.
Studies on the pharmacological control of gastric emptying in man.
Authors: Bateman DN
Published: July 2012

Three compounds with differing pharmacological properties have been studied with respect to their effects on gastric emptying, BP, pulse rate and sedation in comparison with placebo in three groups of normal male volunteers. BRL 20627 (10 mg i.v.), a benzamide without dopamine antagonist activity, increased gastric emptying rate (t0.5 BRL 20627 8.3 +/‐ 0.87 min, placebo 13.8 +/‐ 2.29 min, P less than 0.005). Zetidoline (20 mg orally), a dopamine D2‐receptor antagonist had no significant effect on gastric emptying parameters. BK 34/530 (50 and 100 mg orally) a compound with mixed dopamine agonist and alpha‐ adrenoceptor antagonist activity, impaired gastric adaptive relaxation as measured by the volume 5 min after the drink and at the higher dose delayed gastric emptying (placebo‐5 min volume 256 +/‐ 44.3 ml, t0.5 15.3 +/‐ 1.32 min: 50 mg BK 34/530‐5 min volume 247 +/‐ 38 ml, t0.5 14.2 +/‐ 1.94 min: 100 mg BK 34/530‐5 min volume 228 +/‐ 43.7 ml, t0.5 21.1 +/‐ 3.82 min). All three drugs resulted in small but significant falls in blood pressure, and in the case of BK 34/530 the 100 mg dose caused significant tachycardia. These studies suggest that dopamine antagonist activity is not a prerequisite for 'gastrokinetic' effects in man, and that there is no inhibitory dopaminergic tone on gastric emptying in normal subjects.
Characteristics of prostaglandin induced cough in man.
Authors: Costello JF , Dunlop LS , Gardiner PJ
Published: July 2012

Inhaled PGF2 alpha and PGE2 were evaluated for relative tussive activity to non‐prostanoid tussive agents. In addition a comparison was sought between the present observations and those in the cat, the only laboratory animal which consistently coughs to prostanoids. Five healthy volunteers were repeatedly challenged at 90 min intervals with aerosols of PGE2 (100‐500 micrograms ml‐1) and tussive activity was monitored. In a second separate study again monitoring tussive activity 10 healthy volunteers inhaled aerosols of either PGF2 alpha (0.1‐100 micrograms ml‐1), PGE2 (0.1‐100 micrograms ml‐1), acetylcholine (0.1‐50 mg ml‐1) or citric acid (5‐20% w/v) in a randomised procedure. Objective measurement of tussive activity was achieved using a throat microphone linked via a discriminator to a pen recorder. All four compounds produced two distinct phases of tussive activity, an early phase during challenge and a late phase 1‐15 min post‐challenge. Repeated challenges with PGE2, produced significant (P less than 0.01) tachyphylaxis to the late phase responses only. Both PGF2 alpha and PGE2 were approximately 1000 and 10,000 times more potent than acetylcholine and citric acid respectively for both phases of tussive activity. Tussive activity was accompanied with retrosternal soreness and tightness of the chest for PGE2, increased sputum for PGF2 alpha, and sore throats with citric acid. Although a correlation exists for man and cat with regards to the tussive potency and the early and late phases of PGF2 alpha activity no such correlation seems to exist for PGE2. The high tussive potency of the prostaglandins in man suggest that their local release in various respiratory pathophysiological conditions may be responsible for the accompanying coughs/irritancy.
The effect of repeated doses of temazepam and nitrazepam on human psychomotor performance.
Authors: Tedeschi G. , Griffiths AN , Smith AT , Richens A.
Published: July 2012

The effects of six nightly doses of temazepam (20 mg), nitrazepam (10 mg) and placebo on saccadic eye movements, critical flicker fusion, choice reaction time and on subjective feelings were studied in a double blind cross‐over study in eight volunteers. Testing was performed on nights 1 and 6 of treatment. Nitrazepam, a benzodiazepine with a long elimination half‐life produced a residual performance impairment on night 1 that had disappeared by night 6, despite higher serum concentrations of the drug on the sixth night of treatment. Temazepam, with a shorter elimination half‐life produced no significant performance impairment on night 1, but by night 6 a significant impairment of saccadic eye movements (P less than 0.05), was seen 1 h after drug intake. We conclude that tolerance developed to the sedative action of nitrazepam over the 6 night period of the study. No evidence of tolerance was seen with temazepam.
The tremorolytic action of beta‐adrenoceptor blockers in essential, physiological and isoprenaline‐induced tremor is mediated by beta‐ adrenoceptors located in a deep peripheral compartment.
Authors: Abila B. , Wilson JF , Marshall RW , Richens A.
Published: July 2012

The effects of intravenous propranolol 100 micrograms kg‐1, sotalol 500 micrograms kg‐1, timolol 7.8 micrograms kg‐1, atenolol 125 micrograms kg‐1 and placebo on essential, physiological and isoprenaline‐induced tremor were studied. These beta‐adrenoceptor blocker doses produced equal reduction of standing‐induced tachycardia in essential tremor patients. Atenolol produced significantly less reduction of essential and isoprenaline‐induced tremor than the non‐selective drugs, confirming the importance of beta 2‐adrenoceptor blockade in these effects. Propranolol and sotalol produced equal maximal inhibition of isoprenaline‐induced tremor but propranolol was significantly more effective in reducing essential tremor. The rate of development of the tremorolytic effect was similar in essential, physiological and isoprenaline‐induced tremors but all tremor responses developed significantly more slowly than the heart rate responses. It is proposed that these results indicate that the tremorolytic activity of beta‐ adrenoceptor blockers in essential, physiological and isoprenaline‐ induced tremor is exerted via the same beta 2‐adrenoceptors located in a deep peripheral compartment which is thought to be in the muscle spindles.
The effect of felodipine on forearm haemodynamics and the myogenic response of the forearm resistance vessels in normal man.
Authors: Mace PJ , Stallard TJ , Littler WA
Published: July 2012

The effect of felodipine 10 mg oral solution or placebo on peripheral haemodynamics and the response of the forearm resistance vessels to venous occlusion was studied in seven normotensive individuals. Felodipine produced a significant fall in diastolic blood pressure (DBP max = ‐15 mm Hg), a rise in heart rate (heart rate max = +15 beats min‐ 1) (both P less than 0.01), and an overall fall in calculated forearm vascular resistance (calculated forearm vascular resistance max = ‐19.6 units, P less than 0.001). Felodipine had no significant effect on the vasodilator response, but limited the vasoconstrictor response following venous occlusion. These observations suggest that felodipine is a potent vasodilator and interferes with the myogenic response of vascular smooth muscle of the forearm resistance vessels.
Effects of buccal nitrate on left ventricular haemodynamics and volume at rest and during exercise‐induced angina.
Authors: Silke B. , Verma SP , Frais MA , Hafizullah M. , Taylor SH
Published: July 2012

A novel approach has been employed to characterize the effects of a cardioactive drug on left ventricular haemodynamics and volume by simultaneously determining cardiac stroke volume (thermodilution) and left ventricular ejection fraction (nuclear probe). The effects of glyceryl trinitrate were evaluated in 12 patients with angiographically proven coronary artery disease at rest and 3, 7, 15 and 30 min following 10 mg buccal nitroglycerin (Suscard) administration. The impact of the drug on left ventricular haemodynamics and volume during exercise‐induced angina was determined by repeating exercise 30 min following drug administration, at the workload that reliably induced angina during control exercise. At rest buccal nitroglycerin reduced systemic arterial pressure, cardiac and stroke volume indices, and increased heart rate. The left ventricular ejection fraction (E.F.) increased; its filling pressure together with end‐diastolic and end‐ systolic volumes were significantly reduced. Compared with control supine‐bicycle exercise, the drug reduced mean systemic arterial pressure and left ventricular filling pressure without change in cardiac and stroke volume indices. There was a smaller increase in left ventricular volume during exercise, and the fall in E.F. was attenuated. These data demonstrated differential actions of glyceryl trinitrate on left ventricular function related to the physiological state in obstructive coronary artery disease. These techniques appear to hold promise in the evaluation of the effects of other therapies on left ventricular volume in coronary artery disease.
Cotrimoxazole as an inhibitor of oxidative drug metabolism: effects of trimethoprim and sulphamethoxazole separately and combined on tolbutamide disposition.
Authors: Wing LM , Miners JO
Published: July 2012

The effect of separate pretreatments with cotrimoxazole, sulphamethoxazole and trimethoprim on the disposition of tolbutamide was studied in seven healthy males. Tolbutamide 500 mg intravenously was administered on four separate occasions‐as a control without pretreatment and on the seventh day of separate twice daily administration of cotrimoxazole (sulphamethoxazole 800 mg plus trimethoprim 160 mg) (ST phase), sulphamethoxazole 1 g (S phase) and trimethoprim 150 mg (T phase). Tolbutamide total and unbound plasma clearance (CL) were reduced following each of the individual pretreatments compared to the control phase (P less than 0.001). For unbound CL the reductions were 14% in the S and T phases and 25% in ST phase. Tolbutamide elimination half‐life was prolonged following each pretreatment (P less than 0.001) by 20% in the S phase, 19% in the T phase and 30% in the ST phase. Tolbutamide total steady‐state volume of distribution (VSS) was increased by 10% in the S and ST phases (P less than 0.01), the increase being accounted for by an increase in tolbutamide unbound fraction. There was no change in tolbutamide unbound VSS following any of the pretreatments. These results are consistent with inhibition of tolbutamide oxidation by cotrimoxazole, an additive effect of the two components sulphamethoxazole and trimethoprim. Sulphamethoxazole also reduces tolbutamide plasma protein binding.
Enhanced weal and flare response to histamine in chronic idiopathic urticaria.
Authors: Krause LB , Shuster S.
Published: July 2012

Weal and flare histamine dose‐responses were measured in 30 normal subjects and 15 patients with chronic idiopathic urticaria. The log dose‐response curves were shifted to the left corresponding to an increase in histamine potency of 2.5 for weal and 3.1 for flare. An enhanced response to histamine may be important in chronic idiopathic urticaria and comparison of potency of antihistamines in different subjects may be unreliable where initial weal response is abnormal.
Tofisopam and midazolam: differences in clinical effects and in changes of CSF monoamine metabolites.
Authors: Hovi‐Viander M. , Kanto J. , Scheinin H. , Scheinin M.
Published: July 2012

The effect of two repeated oral doses of 100 mg tofisopam 15 mg midazolam and placebo on the concentrations of monoamine metabolites (MHPG, 5‐HIAA, HVA) in lumbar CSF were studied in general surgical patients operated on under spinal analgesia (n = 12 in each group). Midazolam, but not tofisopam, improved the quality of sleep the night before surgery. Both active agents reduced preoperative anxiety of the patients, but tofisopam was without subjective sedative action. In the placebo group, in contrast to the active drug groups, there was a slight positive correlation between the MHPG concentration and degree of anxiety before surgery. The only significant difference in the monoamine metabolites in lumbar CSF was found in the concentrations of HVA between tofisopam and placebo treated patients. The lower HVA concentrations suggest that the curious 3,4‐benzodiazepine derivative, tofisopam, modifies central dopaminergic activity.
Excretion of doxepin and N‐desmethyldoxepin in human milk.
Authors: Kemp J. , Ilett KF , Booth J. , Hackett LP
Published: July 2012

Doxepin and N‐desmethyldoxepin concentrations in plasma and breast milk from a lactating mother and in plasma from her infant were measured during an 8 week period using high performance liquid chromatography. Plasma concentrations ranged from 35‐68 microgram l‐1 for doxepin and 65‐131 microgram l‐1 for N‐desmethyldoxepin. Mean pre‐feed milk/plasma ratios were 1.08 and 1.02 for doxepin and N‐desmethyldoxepin respectively and increased to 1.66 and 1.53 at the post‐feed samples. Only N‐desmethyldoxepin (15 microgram l‐1) was detectable in the infant's plasma sampled after 43 days of maternal therapy.
Enoxacin decreases the clearance of theophylline in man.
Authors: Wijnands WJ , Vree TB , Van Herwaarden CL
Published: July 2012

In patients treated concurrently with theophylline and enoxacin, a new broad‐spectrum antibacterial agent of the quinolone class, unexpectedly high plasma theophylline concentrations were measured. In part I of this study, daily plasma theophylline concentrations were measured in 14 patients. The mean +/‐ s.d. theophylline concentrations increased from 8.5 +/‐ 2.8 micrograms ml‐1 prior to enoxacin to a maximum of 21.7 +/‐ 7.8 micrograms ml‐1 during coadministration. In part II, six of these patients received aminophylline intravenously at a constant infusion rate and under controlled conditions. Plasma theophylline concentrations rose from 8.4 +/‐ 2.4 micrograms ml‐1 prior to enoxacin treatment to 15.0 +/‐ 5.1 micrograms ml‐1 at day 3 of coadministration (P less than 0.005). Plasma protein‐binding and renal clearance of theophylline remained unchanged, whereas total body clearance of theophylline significantly decreased (P less than 0.005). From these observations it is concluded that the rise of plasma theophylline concentrations is caused by a reduced metabolic clearance of theophylline. If concomitant use of both drugs is necessary, monitoring of plasma theophylline concentration and adjustment of the theophylline dose is recommended.