bluuebunny/crossref_metadata_2025 huggingface dataset:
SOME CLINICAL IMPLICATIONS OF THE PROTEIN BINDING OF DIGOXIN
Authors: WALLACE SUSAN , WHITING B.
Published: July 2012

The binding of [3H]‐digoxiri to human plasma proteins was studied using both ultrafiltration and frontal analysis, to establish a suitable method for the measurement of digoxin‐protein interaction, and to assess the effect of variations in digoxin protein binding on its distribution.

Using ultrafiltration, [3H]‐digoxin was found to bind to plasma proteins to the extent of 30–40% over a concentration range of 0.001‐1 ng/ml. Frontal analysis was unsuccessful in the measurement of digoxin protein binding.

Dilution experiments using plasma and human serum albumin suggested that variations in digoxin protein binding would be unlikely to cause significant alterations in the levels of free drug in the body.

The possible clinical implications of these results are discussed.
A PHARMACOKINETIC INTERACTION IN MAN BETWEEN PHENOBARBITONE AND FENOPROFEN, A NEW ANTI‐INFLAMMATORY AGENT
Authors: HELLEBERG L. , RUBIN A. , WOLEN R.L. , RODDA B.E. , RIDOLFO A.S. , GRUBER CM.
Published: July 2012

The effect of repeated administration of phenobarbitone on the plasma disposition of fenoprofen (±‐2‐(3‐phenoxyphenyl) propionic acid) was investigated in rats and man.

The plasma elimination rate constants increased significantly and the rats excreted proportionately more metabolized fenoprofen in the urine. These findings are consistent with an increase in the rate of metabolism of fenoprofen.

This interaction between phenobarbitone (and presumably other inducers of drug metabolizing enzymes) and fenoprofen should be considered when evaluating the clinical usefulness of fenoprofen.
BIOLOGICAL AVAILABILITY AND IN VITRO DISSOLUTION OF OXYTETRACYCLINE DIHYDRATE TABLETS
Authors: BARBER H.E. , CALVEY T.N. , MUIR K. , HART A.
Published: July 2012

The concentration of oxytetracycline in plasma was studied by microbiological assay after oral administration of four different preparations of oxytetracycline dihydrate tablets.

There were statistically significant differences in biological availability between the four preparations, as assessed by the peak plasma level, the area under the plasma concentration‐time curve, or the cumulative fraction of the dose excreted in urine at 405 minutes. In contrast, differences between the subjects were not statistically significant.

The differences in biological availability were not predictably related to the in vitro dissolution of the tablets.
THE RELATIONSHIP OF PLASMA CHLORPROMAZINE TO ITS 7‐HYDROXY AND SULPHOXIDE METABOLITES IN A LARGE POPULATION OF CHRONIC SCHIZOPHRENICS
Authors: MACKAY A.V.P. , HEALEY A.F. , BAKER J.
Published: July 2012

Blood samples were obtained from eighty‐six chronic schizophrenics receiving a wide range of oral doses of chlorpromazine. Plasma concentrations of chlorpromazine, 7‐hydroxychlorpromazine and chlorpromazine sulphoxide were estimated using a sensitive gas‐liquid chromatographic method and their relationships to oral dose and to global clinical control were investigated.

Wide variability was observed in the plasma concentrations of unchanged drug and metabolites between patients receiving similar daily doses.

In general the plasma concentrations of the 7‐hydroxy and sulphoxide metabolites were of similar magnitude to the concentrations of chlorpromazine.

Global symptom control was unrelated to the plasma concentration of unchanged chlorpromazine. However, patients judged to be under good control had relatively higher concentrations of the biologically active 7‐hydroxy metabolite in their plasma than patients who were poorly controlled and in whom the biologically inactive sulphoxide metabolite predominated. When the ratio of 7‐hydroxychlorpromazine to chlorpromazine sulphoxide was derived for each patient, a highly significant difference was found to exist between the metabolite ratios of patients grouped according to clinical control.

It is suggested that a prediction of therapeutic response to chlorpromazine may be provided in the form of the ratio of the plasma concentration of biologically active metabolite to the concentration of either the unchanged drug or its inactive metabolite
INTRINSIC HEART RATE ON EXERCISE AND THE MEASUREMENT OF β‐ADRENOCEPTOR BLOCKADE
Authors: CARRUTHERS S.G. , SHANKS R.G. , McDEVITT D.G.
Published: July 2012

Methods of expressing the effects of β‐adrenoceptor blocking drugs on exercise heart rate have been evaluated using a standardised exercise test.

In six normal subjects given atropine (0.04 mg/kg) on two separate occasions, the mean ± s.e. mean exercise heart rate rose by 10.3± 1.8 beats/min and by 11.0± 1.6 beats/min respectively. This increase was designated the ‘vagal effect and was not significantly different in the two studies.

After atropinsation, propranolol (0.2 mg/kg) reduced mean ± s.e. mean exercise heart rate by 45.3 ± 2.6 beats/min and 0.4 mg/kg by 50.8 ±4.5 beats/min. This mean sympathetic blockade was not altered significantly by increasing the dose of propranolol but, in four of the six subjects, the larger dose produced an increased effect of 4, 6, 12 and 16 beats/min, suggesting that maximum sympathetic blockade may not have been produced by 0.2 mg/kg.

Knowledge of the vagal effect in each subject with standardised exercise enabled prediction to be made of the exercise heart rate after propranolol (0.4 mg/kg) without previous atropinisation. Propranolol (0.4 mg/kg) was then given intravenously to each subject and the actual exercise heart rate measured. There was no significant difference between the predicted and observed exercise heart rates.

Propranolol (0.6 mg/kg) without atropine was then given to the four subjects who had shown increased effect with (0.4 mg/kg) and the sympathetic blockade was measured. In one subject, a further increase in sympathetic blockade of 10 beats/min was found.

The intrinsic heart rate at rest and on exercise was measured for propranolol (0.2 and 0.4 mg/kg) and, for propranolol (0.6 mg/kg), the intrinsic heart rate on exercise was calculated. At rest, although no significant difference was found between the two dose levels, three subjects did not appear to have maximum autonomic blockade at 0.2 mg/kg. Similarly, several subjects had lower intrinsic heart rates on exercise after 0.4 or 0.6 mg/kg than after 0.2 mg/kg. The intrinsic heart rate on exercise was significantly greater than that obtained at rest.

Using the maximum sympathetic blockade obtained in each subject as the sympathetic component of exercise, the effects of increasing oral doses of practolol on exercise heart were measured as percentage blockade of sympathetic effect and this was compared with other conventional methods of measuring β‐adrenoceptor blockade. It was found that percentage blockade of sympathetic effect correlated most closely with both percentage and absolute reduction of exercise heart rate. Correlations with exercise heart rate after drug and percentage inhibition of tachycardia, whilst also significant, did not appear as good.

When the effects of practolol were expressed in terms of the potential blockade, a plateau occurred between 70 and 80% of ‘maximum’ sympathetic blockade. The failure to achieve higher levels with practolol may be the result of its partial agonist or intrinsic sympathomimetic activity.
DRUG INTERACTIONS AND LONG‐TERM ANTIDIABETIC THERAPY
Authors: LOGIE A.W. , GALLOWAY D.B. , PETRIE J.C.
Published: July 2012

A study has been carried out on a representative sample (709 patients) of the Aberdeen Diabetic Clinic. The aims were to measure the occurrence and attempt to assess the clinical significance of drug interactions involving antidiabetic agents.

In the month before interview, 63% of the patients were taking between one and nine additional prescribed medicines. Fifty‐one per cent of the patients had been exposed to one to five drugs with a potential to interact with their anti‐diabetic therapy. Only 22% of the patients had taken no drugs other than their anti‐diabetic medication.

The degree of control of diabetes, based on arbitrary criteria on data from seven consecutive out‐patient visits, was significantly worse for sulphonylurea‐treated patients exposed to drugs with the potential to interact compared to patients not taking such drugs. In particular, control was adversely affected in older patients taking concurrent barbiturate or diuretic therapy. No such influence of interacting drugs on control was evident in patients on insulin or biguanide therapy.

A system designed to prevent the unintentional initiation of drug interactions in patients on hypoglycaemic agents is described.
DIGOXIN CONCENTRATIONS IN SERUM AND SALIVA: RELATIONSHIP TO ECG CHANGES AND DOSAGE IN HEALTHY VOLUNTEERS
Authors: JOUBERT P.H. , AUCAMP B.N. , MÜLLER F.O.
Published: July 2012

After 1 week of baseline observations increasing oral doses of digoxin were administered to four healthy volunteers over a 6–7 week period.

A dose‐response relationship exists with regards to PTQ‐changes (a quantitative measure of ECG‐changes).

PTQ‐changes were related linearly to both serum and salivary digoxin levels.

PTQ‐changes appear to be useful as a non‐invasive measure for studying various aspects of digoxin pharmacodynamics.

Serial salivary digoxin levels might be a better index of the effect of cardiac glycosides than individual or serial serum levels.
AN ELECTROENCEPHALOGRAPHIC INVESTIGATION OF SHORT‐TERM EFFECTS OF THREE HYPOTHALAMIC HORMONES (TRH, LH/FSH‐RH, GH‐RIH) IN NORMAL SUBJECTS
Authors: ASHTON HEATHER , MILLMAN J. E. , TELFORD ROSEMARY , THOMPSON J. W. , DAVIES T. F. , HALL R.
Published: July 2012

Three hypothalamic regulatory hormones, thyrotrophin‐releasing hormone (TRH), luteinizing hormone/follicle‐stimulating hormone‐releasing hormone (LH/FSH—RH) and growth hormone‐release inhibiting hormone (GH—RIH) given intravenously had no effect on the electroencephalographic response known as the contingent negative variation (CNV) in normal subjects.

TRH was given as a 10 ml infusion of 600 μg over 8 min to six subjects. This produced subjective sensations and a rise in heart rate but no significant alteration of CNV magnitude.

LH/FSH—RH was given in a dose of 200 μg in 10 ml over 2 min to six subjects. This had no effect on CNV magnitude or heart rate and produced no subjective effects.

GH—RIH was given as a 10 ml infusion of 250 μg over 10 min to six subjects. Again there was no alteration in the magnitude of the CNV; the heart rate was slowed.
THE CARDIOVASCULAR EFFECTS OF BROMOCRIPTINE IN PARKINSONISM
Authors: GREENACRE J.K. , TEYCHENNE P.F. , PETRIE A. , CALNE D.B. , LEIGH P.N. , REID J.L.
Published: July 2012

The cardiovascular effects of bromocriptine, a dopamine receptor agonist, were investigated in twenty‐eight Parkinsonian patients.

Bromocriptine caused a significant impairment of postural compensation with a fall in systolic pressure and an absence of the rise in diastolic pressure after standing for 1 min when patients taking active drug were compared to the same patients on placebo. The hypotensive effect persisted for at least 6 weeks of treatment. There was also a significant reduction in supine heart rate.

One patient had marked falls in supine and erect blood pressure after a single oral dose of bromocriptine (2.5 mg) and a further patient developed paroxysmal atrial tachyarrhythmias. Both blood pressure and heart rate changes reversed spontaneously after stopping bromocriptine.

It is proposed that dopaminergic mechanisms either in the central nervous system or the periphery contribute to cardiovascular regulation in man.
EFFECTS OF ORAL SALBUTAMOL AND PIRBUTEROL ON FEV1, HEART RATE AND BLOOD PRESSURE IN ASTHMATICS
Authors: WILLEY R.F. , GRANT I.W.B. , POCOCK S.J.
Published: July 2012

In a double‐blind trial the effects on ventilatory function (FEV1), heart rate and blood pressure of oral pirbuterol and oral salbutamol in various single doses were studied in ten patients with chronic asthma.

Pirbuterol (15 mg) and salbutamol (4 mg) produced equal peak levels of bronchodilatation.

There was no significant difference in the mean rise in heart rates caused by the two drugs, and no other significant side‐effects were noted.
DIGOXIN THERAPY: TEXTBOOKS, THEORY AND PRACTICE
Authors: ARONSON J.K. , GRAHAME‐SMITH D.G.
Published: July 2012

Recommendations for correct therapy with digoxin from twenty‐five sources are reviewed.

Some recommendations may be unsuitable for use with high bioavailability tablets; some are accompanied by insufficient data relating to factors affecting both the response to digoxin and its handling by the body.

Guidelines based on pharmacokinetic and pharmacodynamic principles are suggested to help decide optimal digoxin treatment schedules in the presence and absence of non‐cardiac disease.
BRONCHODILATOR EFFECTS OF DRY SALBUTAMOL POWDER ADMINISTERED BY ROTAHALER
Authors: HARTLEY J.P.R. , NOGRADY S.G. , GIBBY O.M. , SEATON A.
Published: July 2012

The bronchodilator effects of inhaled dry salbutamol powder (50, 100, 200 and 400 μg) have been compared in ten asthmatic patients with those of aerosolized salbutamol (200 μg) delivered from a standard pressurized inhaler.

A dose of salbutamol powder (400 μg) produced greater bronchodilatation than 50, 100 or 200 μg of powder, but there was no significant difference between 400 μg of powder and 200 μg of aerosolized salbutamol.

Powder administered by Rotahaler is well tolerated and offers several advantages over the pressurized aerosol canister.
Effect of nomifensine on brain amines and epilepsy in photosensitive baboons.
Authors: Trimble MR , Meldrum BS , Anlezark G.
Published: July 2012

1. The literature, both clinical and experimental, suggests that tricyclic antidepressants are potentially epileptogenic. Using the experimental model of epilepsy provided by the photosensitive baboon, Papio papio, the epileptic potential of four antidepressant drugs, two of which are tricyclic, has been assessed. The drugs used were imipramine 1, 10 and 20 mg/kg, chlorimipramine 1, 10 and 20 mg/kg, maprotiline 1 and 10 mg/kg and nomifensine 10 and 20 mg/kg. In a second series of experiments the 5‐hydroxytryptamine (5‐HT) precursor 5‐ hydroxytryptophan (5‐HTP) 10 and 25 mg/kg has been administered before administration of imipramine 10 mg/kg and chlorimipramine 10 mg/kg. 2. The results of the experiments indicate that at 10 mg/kg imipramine, chlorimipramine and maprotiline all induce seizures and lower the seizure threshold. In contrast nomifensine at this dose did not alter the seizure threshold. 5‐HTP 25 mg/kg administered before the antidepressants, abolished seizures. These results are discussed in the light of other experiments which have attempted to explain the pathophysiology of epileptic seizures following antidepressants, and it is concluded that dopaminergic mechanisms are probably responsible for the differing effect noted with nomifensine.
Influence of nomifensine and desipramine on tyramine pressor responses in healthy volunteers.
Authors: McEwen J.
Published: July 2012

1. Pressor responses following a series of bolus intravenous injections of tyramine were used to assess the influence of single oral doses of nomifensine 75 mg on peripheral sympathetic neuronal uptake mechanisms in healthy volunteers. Desipramine 50 mg served as a positive control. 2. Following each treatment the effect of tyramine was diminished, with a shift to the right in the tyramine dose‐response curve. In addition, there was a suggestion that in these experimental conditions nomifensine was less potent than desipramine.
Nomifensine in parkinsonism.
Authors: Park DM , Findley LJ , Teychenne PF
Published: July 2012

1. The effect of nomifensine was compared with that of placebo in a double‐blind crossover study in patients with parkinsonism. 2. Of the 29 patients who entered the study, three were previously untreated and 26 continued their L‐DOPA or other antiparkinsonian therapy, or both, during the trial. 3. Clinical assessments were made at fortnightly intervals throughout the study. 4. The most noticeable improvement during active treatment‐namely, tremor, facial expression and finger flexion were moderate in extent. 5. When placebo was substituted for active drug a significant deterioration of physical signs and functional disability occurred (P less than 0.001). 6. Elderly patients fared less well than younger patients, and the most common adverse effect was involuntary movements.
Effects of nomifensine, an inhibitor of endogenous catecholamine re‐ uptake, in acromegaly, in hyperprolactinaemia, and against stimulated prolactin release in man.
Authors: Scanlon MF , Gomez‐Pan A. , Mora B. , Cook DB , Dewar JH , Hildyard A. , Weightman DR , Evered DC , Hall R.
Published: July 2012

1. Nomifensine, an inhibitor of endogenous catecholamine re‐uptake, did not affect the growth hormone (GH) or prolactin levels in patients with acromegaly or hyperprolactinaemia. It does not, therefore, have any therapeutic role in these conditions at the dosage used in this study. 2. It had no effect on thyrotrophin‐releasing hormone (TRH)‐induced thyrotrophin (TSH) or prolactin release in males, yet caused marked suppression of monoiodotyrosine (MIT)‐induced prolactin release in males but not in females. 3. The significant suppression of MIT‐induced prolactin release in males is likely to reflect the dopamine (DA) agonist activity of the drug and its lack of effect in the other situations tested could be dose related. 4. It is proposed that the difference in male and female patterns of prolactin response to MIT after nomifensine, could be due to a “damping” effect of oestrogen on the hypothalamic dopaminergic system.
Plasma protein binding of valproic acid in healthy subjects and in patients with renal disease.
Authors: Gugler R , Mueller G
Published: July 2012

1 Based on the Scatchard plot of the binding data of valproic acid (VPA) it is concluded that the drug is bound by two groups of binding sites with the association constants K1=40.0 X 10(‐3) and K2=0.39 X 10(3), and the number of binding sites n1=1.5 and n2=6.8. 2 The binding is dependent on dialysis time, on temperature, on the drug concentration, and on the protein concentration in plasma. 3 At therapeutic plasma concentrations unbound VPA is 8.4 +/− 2.5%, but is increased to 20.3 +/− 4.7% in patients with significant impairment of renal function (P less than 0.001). 4 In patients with renal disease a good correlation is found between unbound VPA and serum creatinine, creatinine clearance, blood nitrogen and uric acid, respectively. A poor correlation is seen between unbound VPA and total protein or albumin concentration in plasma.
The influence of digoxin particle size on absorption of digoxin and the effect of propantheline and metoclopramide.
Authors: Johnson BF , O'Grady J , Bye C
Published: July 2012

1 The influence of particle size on absorption of digoxin was studied in ten healthy volunteers who received 0.5 mg digoxin as two standard Lanoxin tablets, or tablets containing micronized digoxin or large particle size digoxin. Tablets were given 30 min after 15 mg propantheline, 10 mg metoclopramine or a placebo tablet, and following an overnight fast. 2 The overall mean cumulative 4 day urinary excretion of digoxin was significantly lower (P less than 0.01) after large particle size digoxin than after standard or micronized digoxin. Mean cumulative urinary excretion following large particle size digoxin was reduced when administered after metoclopramide and increased after propantheline, the difference between these two treatments being significant (P less than 0.05). There was a significantly lower (P less than 0.05) overall mean cumulative excretion following standard by comparison with micronized digoxin. However, by comparison with placebo, neither metoclopramide nor propantheline significantly altered mean cumulative excretion after standard or micronized digoxin. Propantheline and metoclopramide affect absorption of digoxin from formulations of large particle size and slow dissolution rate only.
THE EFFECTS OF TWO ANTIDEPRESSANT AGENTS ON PERFORMANCE ON THE STROOP COLOUR‐WORD TEST IN NORMAL MALE VOLUNTEER SUBJECTS
Authors: HARVEY P.G. , CLAYTON A.B. , BETTS T.A.
Published: July 2012

Healthy male volunteers were given either imipramine (25 mgs three times a day), viloxazine hydrochloride (Vivalan) (50 mgs three times a day), placebo or no tablets on a double‐blind basis.

Subjects took the tablets for 7 days, and were tested before treatment and then after 1, 7 and 21 doses.

The Stroop Colour‐Word test was used to assess performance.

While no significant drug effects were found it is suggested that some of the trends shown are indicative of a slight worsening of performance with imipramine and a slight improvement with viloxazine hydrochloride after seven doses.
PERFORMANCE STUDIES WITH DIAZEPAM AND ITS HYDROXYLATED METABOLITES
Authors: NICHOLSON A.N.
Published: July 2012

Visuo‐motor coordination has been used to study the immediate and residual effects of benzodiazepines on performance in man. The technique provides dose and time response data related to the decrement and the persistence of impaired performance.

With the overnight ingestion of flurazepam hydrochloride 30 mg and nitrazepam 10 mg, performance was impaired to 16 h and, at least, 19 h, respectively. Performance was not impaired after the overnight ingestion of diazepam, 5 and 10 mg, temazepam 10, 20 and 30 mg or oxazepam 15 and 30 mg. However, with temazepam 30 mg there was a trend toward impaired performance, and with oxazepam 45 mg, performance was impaired 10 h after ingestion. With morning ingestion, coordination was impaired 0.5 and 2.5 h after diazepam 10 mg, at 0.5 h after temazepam 20 mg, and after oxazepam 30 mg at 2.5 and 4.5 hours.

The studies suggest that diazepam 5–10 mg, temazepam 10–20 mg and oxazepam 15–30 mg may be of use in the management of sleep disturbance when impaired performance the next day is to be avoided.
HYPNOTIC EFFICACY OF TEMAZEPAM: A LONG‐TERM SLEEP LABORATORY EVALUATION
Authors: MITLER M.M. , CARSKADON MARY A. , PHILLIPS R.L , STERLING W.R. , ZARCONE V.P. , SPIEGEL R. , GUILLEMINAULT C. , DEMENT W.C.
Published: July 2012

Temazepam was evaluated in a strictly defined insomniac patient population under sleep laboratory conditions. Two protocols were used: a short‐term (26‐night) and a long‐term (54‐night) protocol evaluated the efficacy of the drug administered at night at 15 mg (short‐term study) and 30 mg (long‐term study), respectively.

Temazepam seemed to be both safe and effective at doses of 15 and 30 mg with up to 5 weeks of ingestion.

Suppression of slow wave sleep was observed at the high dose, but no suppression of REM sleep, found in studies with other benzodiazepines, was noted.

No evidence was found for development of tolerance or rebound effects.
Clobazam: chemical aspects of the 1,4 and 1,5‐benzodiazepines.
Authors: Kuch H
Published: July 2012

1 The structures and chemistry of the 1,4‐ and 1,5‐benzodiazepines are compared. These two groups of drugs differ in respect to basicity, lipophilicity and electronic charge distribution. 2 The 1,4‐ benzodiazepine diazepam has a weakly basic imine group in contrast to the acid methylene protons of clobazam. 3 The imine function of diazepam is more lipophilic than the carboxamide group of clobazam with its rather hydrophilic character. 4 Diazepam and clobazam differ in electronic charge distribution and hence in the location of the chemically reactive centres, the imine partial structure in diazepam and the malonic acid portion of clobazam.
In vitro studies on GABA release.
Authors: Schacht U , Backer G
Published: July 2012

1 Recent studies have demonstrated growing evidence for a primary action of the benzodiazepines on gabaminergic neurones which induces a facilitation of gamma‐aminobutyric acid (GABA)‐mediated neurotransmission. As enhancement of GABA release has been suggested to account for their activation of GABA mechanisms, the effect of diazepam and clobazam, and of several other psychotropic drugs, on stimulated GABA release have been studied. 2 Using rat brain cortex slices saturated with [3H]‐GABA, the electrically stimulated overflow of GABA is reduced in a concentration‐dependent manner in the presence of both diazepam and clobazam. 3 The benzodiazepine‐induced reduction in GABA overflow during electrical stimulation is antagonized by the GABA receptor blocker bicuculline, whereas bicuculline alone at 10(‐6) M concentration does not change the overflow. 4 Among some other centrally active drugs tested, hexobarbitone and the 'second messenger; cyclic GMP also induce a significant but less marked reduction in GABA release. 5 A schematic model of a central gabaminergic synapse is proposed, which may explain the benzodiazepine effects on stimulated GABA release by suggesting an inhibitory feedback control of transmitter release mediated by presynaptic GABA receptors ('autoreceptors').
Some aspects of the effects of clobazam on human psychomotor performance.
Authors: Hindmarch I
Published: July 2012

1 Three studies are described, the first being a comparison of the effects of acute night‐time doses of clobazam 20 mg, amylobarbitone sodium 100 mg, nitrazepam 5 mg and placebo, on choice reaction time, critical flicker fusion (CFF) and stabilometer performance. Clobazam improved early morning performance on a choice reaction test, in contrast to the other two active drugs. 2 Repeated doses of clobazam 10 mg three times daily, chlordiazepoxide 10 mg three times daily and diazepam 5 mg three times daily were given for 5 days. Again clobazam did not produce any impairment of psychomotor performance, and noticeably increased CFF thresholds. 3 The effects of an acute night‐ time dose of clobazam 20 mg on psychomotor performance the morning after night‐time medication were correlated with the neuroticism scores (on the EPI) of the subjects. Clobazam exerts a differential effect on psychomotor performance dependent on the basic personality trait. 4 Clobazam seems to differ significantly from the 1,4‐benzodiazepines in that, although it reduces anxiety, it does so without any apparent impairment of psychomotor performance.
Evaluation of the effects of clobazam, A 1,5 benzodiazepine, on mood and psychomotor performance in clinically anxious patients in general practice.
Authors: Salkind MR , Hanks GW , Silverstone JT
Published: July 2012

1 The methodology of clinical trails of anxiolytic drugs carried out in general practice conditions is discussed. Particular problems include: the selection of suitable patients; placebo effects; the influence of non‐specific variables such as life‐events; and patient compliance. 2 Clobazam, a novel 1,5 benzodiazepine, and diazepam were compared with placebo in a double‐blind group comparative trial in general practice, which was designed to avoid as many confounding variables as possible. Anxiety‐reducing effects were evaluated and at the same time the effects of the drugs on psychomotor performance were examined. 3 Both clobazam and diazepam produced significant improvements in anxiety ratings on the Hamilton Anxiety Scale and the Morbid Anxiety Inventory, whereas placebo did not. 4 The placebo group demonstrated a significant improvement in performance on a pursuit rotor and digit symbol substitution test (DSST), whereas the diazepam group's performance did not change. The clobazam group showed improvement in both tests, significantly so in the DSST. This suggests that diazepam produces impairment in performance, which had negated the practice effects seen in the placebo group, whereas clobazam did not seem to produce similar impairment.
Possible significance of the pharmacological differentiation of beta‐ blockers for therapy of hypertension.
Authors: Leenen FH
Published: July 2012

1 Cardioselective and non‐selective beta‐blockers affect to a different degree several aspects of the circulatory homeostasis. The evidence available in this regard has been evaluated and the possible clinical importance of these differences has been discussed. 2 Venous return in partly regulated by beta‐receptors (possibly of the beta 2 type) in the venous resistance vessels. Differences in blockade of venous return by the two classes of beta‐blockers may, therefore, influence the degree of increase in left ventricular size, left ventricular end diastolic BPs and stroke volume during beta‐blockade. 3 At the first part of the dose‐reponse curve, non‐selective beta‐blockers seem to block more effectively renin release than cardioselective beta‐blockers. 4 The direction and the extent to which beta‐blockers 'directly' affect total peripheral resistance (TPR), is determined by the resultant of the degree of decrease in TPR by blockade of renin release and the extent of the increase in TPR by blockade of the beta 2‐receptors in the arteriolar wall. 5 The clinical relevance of these differences could be that–especially in the low doses range–non‐selective beta‐blockers may be more 'safe' in patients with compromised cardiac function and may be more appropriate for the therapy of high renin hypertension than cardioselective blockers, whereas the latter may be more appropriate for the majority of hypertensive patients who have low to normal renin hypertension.
Elimination of nadolol by patients with renal impairment.
Authors: Herrera J , Vukovich RA , Griffith DL
Published: July 2012

1 Nadolol excretion was studied in 24 patients with chronic renal failure. 2 The amount of nadolol excreted during the 120‐h period after receiving the drug ranged from less than 1% in functionally anephric, patients up to 11.5% in patients with average creatinine clearance of 57.9 +/‐ 3.6 ml/min/1.73 m2. 3 Renal clearance of nadolol was found to correlate with creatinine clearance; nadolol elimination is retarded in patients with renal failure. 4 Nadolol serum half‐life is prolonged in proportion to the remaining renal function. Therefore, dosage intervals in renal patients receiving nadolol should be adjusted to creatinine clearance. 5 Haemodialysis effectively reduced serum concentration of the drug; it may therefore be a useful therapy for drug intoxication.
Inhibitors of the renin‐angiotensin system in experimental hypertension, with a note on the measurement of angiotensin I, II and III during infusion of converting‐enzyme inhibitor.
Authors: Morton JJ , Casals‐Stenzel J , Lever AF , Millar JA , Riegger AJ , Tree M
Published: July 2012

1 Prolonged infusion (11 h) of both saralasin and angiotensin‐ converting enzyme inhibitor (SQ20881) gradually lowered BP in two‐ kidney hypertensive rats to levels similar to that in normotensive rats infused with dextrose. 2 Saralasin did not lower BP in DOCA‐salt hypertensive rats. 3 These observations support the notion that in chronic renal hypertension, angiotensin II may maintain hypertension by a slowly developing action. 4 Plasma angiotensin II in rats infused with SQ20881 was suppressed relative to renin, but was not eliminated. 5 Chromatography of angiotensin II extracts from dogs infused with converting enzyme inhibitor (SQ14,225) showed that the very high levels of angiotensin I achieved after treatment with SQ14,225 can lead to falsely high estimated angiotensin II levels as a result of angiotensin I cross‐reacting with the angiotensin II assay.
Regression of left ventricular hypertrophy during treatment with antihypertensive agents.
Authors: Hill LS , Monaghan M , Richardson PJ
Published: July 2012

1 Echocardiography showed 14 of 24 patients with essential hypertension to have hypertrophy of their left ventricular walls. In eight of these 14 patients the left ventricular configuration initially fulfilled the criteria for asymmetric septal hypertrophy (ASH) and six were symmetrically hypertrophied, the remaining ten being normal. 2 Following 12 weeks' treatment of hypertension with the object of reducing the supine BP to 150/90 mmHg or below, there was a reduction of wall thickness so that only two of the eight continued to show ASH. 3 The six patients with symmetrical left ventricular hypertrophy also showed a significant reduction in the thickness of the septum and the posterior wall. Those with normal echocardiograms did not change. 4 This reduction of wall thickness produced by antihypertensive therapy may represent regression of left ventricular hypertrophy.
Mixed agonist‐antagonist opiates and physical dependence.
Authors: Jacob JJ , Michaud GM , Tremblay EC
Published: July 2012

1 General methods (chronic, subacute and acute) for assessing physical dependence potential, abstinence precipitating capacity and abstinence preventing activity are briefly presented. 2 Direct dependence experiments indicate that, in general, mixed agonist‐antagonist analgesics have relatively lower physical dependence potentials than pure agonist analgesics. That of buprenorphine seems to be particularly low in various animal species. 3 When substitution techniques are used, the dependence potential of buprenorphine seems to be somewhat more developed than with direct dependence techniques. 4 Among various agonists (morphine, methadone and etorphine), antagonists (naloxone, naltrexone and diprenorphine) and mixed agonist‐antagonists (pentazocine, butorphanol and buprenorphine), buprenorphine is the most potent and the longest acting drug in preventing precipitated abstinence in mice, rats and dogs. 5 The low physical dependence potential of buprenorphine may result in part from the very slow dissociation of the complex it forms with opiate receptors. This potential might be underestimated when precipitated abstinence methods are used, as naloxone would displace buprenorphine from its receptors only to a very limited extent. New means of evaluating dependence by more direct means need to be developed. 6 Overall, the properties of mixed agonists in general justify their use as analgesics with lower physical dependence potential than the pure opiates and further, those of buprenorphine seem to indicate its possible utility for the treatment of opiate addiction.
Drug recovery following buccal absorption of propranolol.
Authors: Henry JA , Ohashi K , Wadsworth J , Turner P
Published: July 2012

1 Buccal absorption of propranolol in two volunteers was followed by repeated rinsing of the mouth with buffer solutions for twelve 2 min periods. Values for absorption, recovery and asymptotic recovery were calculated. 2 Large amounts of propranolol were recoverable from the buccal mucosa; recovery was biexponential and the amount recovered depended on the time allowed for absorption and on the pH of buffers used for recovery. 3 In the case of the drug studied, the buccal absorption test was not an adequate model of passive drug transfer through lipid membranes, and more clearly reflected partitioning into the buccal mucosa. 4 It does not follow from disappearance of drug from the buccal cavity that it has entered the circulation. Unabsorbed drug clearly cannot enter the circulation, but other conclusions about systemic absorption cannot be drawn with certainty from the buccal absorption model. 5 Partitioning back into the saliva after absorption also needs to be taken into account for a true model of systemic absorption of orally administered drugs, and a revised schematic representation of the kinetics of oral drug absorption is presented.
Long‐term effect of lithium on the uptake of 5‐hydroxytryptamine by human platelets.
Authors: Born GV , Grignani G , Martin K
Published: July 2012

1 The content, uptake and storage of 5‐hydroxytryptamine (5‐HT) in platelets were determined in eight manic‐depressive patients not on lithium (Li); in ten manic‐depressive patients on Li; and in ten apparently normal persons as controls. 2 Platelets from the patients, whether or not on Li, contained less 5‐HT than platelets from normal people. 3 5‐HT uptake and storage by platelets from untreated patients were significantly lower than those of control subjects. 4 When patients had been on Li for 3 months or longer the diminished uptake and storage of 5‐HT by their platelets were more than fully reversed. 5 Li added to platelet‐rich plasma in vitro had no effect on the uptake of 5‐HT by platelets.
Combination of aminophylline (Phyllocontin Continus tablets) and salbutamol in the management of chronic obstructive airways disease.
Authors: Clark CJ , Boyd G
Published: July 2012

1 The effect of a controlled release theophylline derivative (Phyllocontin Continus tablets) and an adrenoceptor agonist (salbutamol) was compared when taken singly and concomitantly in twenty patients with chronic bronchitis and additional reversible airways obstruction using a double‐blind crossover technique. 2 The pulmonary function data showed a significant improvement in airways obstruction with an associated reduction in hyperinflation on combination therapy, as compared with either drug taken alone. 3 No significant improvement in patient symptoms occurred on combination therapy as compared with either drug taken alone. 4 A high incidence of side‐effects was noted with both Phyllocontin Continus and salbutamol. Combination therapy, however, did not increase the frequency or severity of side‐effects seen on either drug alone. 5 Although a proportion of patients showed evidence of intercurrent infection during the nine‐week trial period, this did not appear to influence the results for the group as a whole.
Drug resistance, inappropriate dosing and non‐compliance in hypertensive patients.
Authors: Silas JH , Tucker GT , Smith AJ
Published: July 2012

1 From an understanding of the biological fate and hypotensive effect of debrisoquine (D) we have assessed the relative importance of true drug resistance, inappropriately low dosage and non‐compliance as causes of apparent resistance to treatment with this drug. 2 Among 37 hypertensive patients prescribed D, eleven (30%) were non‐compliant on the day of testing. 3 Non‐compliance was found in 64% of patients with poor blood pressure control but only 15% of patients with intermediate and good blood pressure control (P less than 0.02). 4 Five patients received doses which were too low for pharmacological effect while in a further five an increase in dose may have improved blood pressure control. 5 Resistance to D was uncommon indicating that non‐compliance and inadequate dosing are the major causes of apparent resistance to treatment with this compound.
Activity of a new high efficiency diuretic in man: piretanide (HOE 118).
Authors: Pozet N , Hadj‐Aissa A , Pellet M , Traeger J
Published: July 2012

1 The pharmacological actions of piretanide, a new high efficiency diuretic, were studied in sixteen patients with GFR (inulin clearance) varying from 0.1–2.5 ml/s. 2 After hydration and following two control periods, a single dose of 6 mg piretanide was ingested. Thereafter, urine was collected every 30 min for 2 h and every hour for the next 4 h. Fluid losses were replaced. 3 The following measurements were made: urine flow rate, clearances of inulin, PAH, urea, creatinine, uric acid, osmolar and free water clearances, excretion rates of sodium, chloride, potassium, calcium, phosphate, bicarbonate, ammonium, titratable acidity and urine pH. 4 Main results showed piretanide was efficient in the group with normal GFR (inulin clearance greater than 1.5 ml/s) and in the group with slightly decreased GFR (1.0 less than inulin clearance less than 1.4 ml/s), in terms of diuresis, natriuresis, kaliuresis and calciuresis. It was inefficient in the group with severe renal insufficiency (inulin clearance less than 0.3 ml/s). 5 Free water clearance showed preservation of diluting ability to a large extent. 6 In the three groups, no significant change in inulin clearance and PAH clearance occurred.
Loading dose of digoxin in renal failure.
Authors: Gault MH , Churchill DN , Kalra J
Published: July 2012

1 Twenty‐two dialysis dependent patients received an intravenous loading dose of digoxin of 10 microgram/kg and the mean +/‐ s.d. serum digoxin concentration 24 h later was 1.5 ng/ml +/‐ 0.4 (range 0.8–2.1 ng/ml). No evidence of toxicity was observed. 2 The average apparent volume of distribution of digoxin in dialysis dependent patients was found to be reduced by about one third compared with that reported for individuals with normal renal function, but there was great variation. 3 An appropriate intravenous loading dose of digoxin in most patients with advanced renal failure is 10 microgram/kg.
Effect of therapeutic dosage of lithium on the heart.
Authors: Dumovic P , Burrows GD , Chamberlain K , Vohra J , Fuller J , Sloman JG
Published: July 2012

1 The cardiac effects of therapeutic levels of lithium were investigated in six healthy male volunteers. Subjects were studied: (1) before lithium ingestion, and (2) when steady‐state plasma lithium levels were attained (at least 2 weeks after beginning daily lithium ingestion). 2 A 12‐lead electrocardiogram (ECG) and high‐speed high‐ fidelity ECG were used to record electrical activity of the heart. Fractional shortening of the left ventricle using echocardiography, and systolic time intervals (at rest and during exercise), were used as measures of myocardial performance. 3 In this group of healthy volunteers administration of lithium carbonate was associated with a reduction in T wave amplitude in standard electrocardiograms but no statistically significant impairment of myocardial performance.
Oral sustained‐release aminophylline in medical inpatients: factors related to toxicity and plasma theophylline concentrations.
Authors: Ramsay LE , Mackay A , Eppel ML , Oliver JS
Published: July 2012

1 Consecutive medical inpatients expected to benefit from a theophyllinate were treated with sustained‐release aminophylline in a protocol conforming with ordinary practice. Of 16 patients, five had toxicity with aminophylline 450 mg daily, and a further three with 900 mg daily. Toxicity was serious in three patients. 2 Toxicity was significantly less common in cigarette smokers, and was related to higher plasma theophylline concentrations. However, there was a large overlap between concentrations associated with toxicity (as low as 9 micrograms/ml) and the accepted therapeutic range (5‐20 micrograms/ml). Most patients with toxicity had theophylline levels within the therapeutic range. 3 For the same dose of aminophylline there was sevenfold variation between patients in plasma theophylline, with higher concentrations in non‐smokers, infrequent alcohol users, older patients, those with left ventricular failure and those with lower serum transaminases. There variables could not be separated completely because of the small number of observations. 4 A nomogram for aminophylline dosage or monitoring of serum theophylline levels would have prevented little of the toxicity observed in these patients, although these measures would ensure that therapeutic concentrations were attained, and might prevent life‐threatening toxicity.
The erythrocyte sodium and potassium in patients treated with digoxin.
Authors: Morgan DB , Cumberbatch M , Cohn S , Scott D , Gunasuntharam T , Davidson C , Chapman C
Published: July 2012

1 Four healthy persons and ten patients with heart failure were studied for 5 to 20 days after they started taking digoxin. The sodium content of their erythrocytes increased and there was an equimolar decrease in potassium content. 2 The increase in erythrocyte sodium for a given increase in plasma digoxin during this acute digitalization was less on average and varied more in the patients than in the healthy persons, that is the patients' erythrocytes were less responsive to digoxin. 3 The average erythrocyte sodium was greater in 183 patients who had been taking digoxin for at least 2 months than in 100 healthy persons not taking digoxin but there was no significant correlation between the plasma digoxin concentrations and erythrocyte sodium concentration in the patients. Indeed, there was no apparent change in the erythrocyte sodium in many of the patients taking digoxin. 4 If the erythrocyte sodium concentration is a reliable guide to the tissue effects of digoxin then the results suggest that there is a wide variation in the response to digoxin between patients both during acute digitalization and during chronic treatment with digoxin.
Disopyramide and lignocaine. A comparison of cardiac effects using echocardiography.
Authors: Martin MA , Bax ND , Tucker GT , Ward JW
Published: July 2012

1 The cardiac effects of disopyramide (D) and lignocaine (L) were measured and compared in normal volunteers (D n=4; L n=3) following the establishment of a series of three steady‐state drug plasma concentrations spanning the therapeutic range (1.5‐5 micrograms base ml‐ 1). 2 During control and steady‐state periods multiple measurements were made of heart rate, blood pressure, drug concentrations and echocardiographic measurement of cardiac dimensions and estimated left ventricular function. 3 No change in heart size or estimated function occurred with L except for a small increase in estimated cardiac output (+0.5 1 min‐1) secondary to a small rise in heart rate (maximum +7 beats min‐1). Blood pressure rose slightly (maximum +11 mmHg). 4 D caused an increase in heart size, marked at end systole (+0.63 cm), and a decrease in echo indices of ventricular function (25‐33%). These changes were related to plasma drug concentration but were not reflected in cardiac output estimation since heart rate rose (+15 beats min‐1). Blood pressure also rose (+10 mmHg). 5 Significant differences were shown between D and L at similar plasma drug concentrations. The negative inotropic effect of D may be greater than previously suggested and clinically important.
Pharmacokinetics of oral disopyramide phosphate in patients with renal impairment.
Authors: Johnston A , Henry JA , Warrington SJ , Hamer NA
Published: July 2012

1 The pharmacokinetics of disopyramide were studied after the oral administration of a 300 mg dose to 11 patients with stable chronic renal impairment (creatinine clearance 2‐53 ml min‐1). 2 Absorption half‐life and volume of distribution were similar to those seen in normal subjects. 3 Mean plasma elimination half‐life in these patients was 12.7 h, which is substantially greater than that reported for normal subjects. Elimination half‐life tended to increase as creatinine clearance fell, and renal clearance of disopyramide correlated significantly (r=0.814; P < 0.001) with creatinine clearance. 4 From these results, we have calculated that patients with renal impairment should be started on a dose of disopyramide 1.5 mg kg‐1 thrice daily and the regimen subsequently altered according to plasma concentrations of the drug. However, further studies are needed to define the handling of the metabolites of disopyramide.
Effect of colchicine on polymorphonuclear leucocyte chemotaxis in human volunteers.
Authors: Ehrenfeld M , Levy M , Bar Eli M , Gallily R , Eliakim M
Published: July 2012

1 The effect of colchicine on polymorphonuclear leucocyte chemotaxis was assessed in eight healthy volunteers. Four of them received 1.0 mg colchicine and the other four received placebo daily for 8 successive days. 2 Chemotaxis decreased significantly within 24 h of the ingestion of colchicine; the values remained low throughout the 8 days of treatment and returned to normal within 48 h of cessation of medication. 3 There were no significant changes in the placebo treated subjects.
Efficacy of some benzodiazepines for day‐time sleep.
Authors: Nicholson AN , Stone BM , Pascoe PA
Published: July 2012

1 Effects of flunitrazepam (0.25‐0.50 mg) and the 1,4‐ triazolodiazepines, triazolam (0.25‐0.50 mg) and brotizolam (0.3‐0.6 mg), on day time sleep were studied by electroencephalography. 2 Flunitrazepam (0.25‐0.50 mg) and triazolam (0.25‐0.50 mg) reduced awake activity (P < 0.05) and improved the sleep efficiency index (P < 0.05). The higher dose of each drug increased total sleep time (P < 0.05 and < 0.01 respectively) and duration of stage 2 sleep (P < 0.01), and also delayed the first REM period (P < 0.05 and < 0.01 respectively). 3 Brotizolam (0.6 mg) markedly increased total sleep time (P < 0.001) and the sleep efficiency index (P < 0.01), and prolonged stages 2 (P < 0.01 and slow wave (P < 0.01) sleep. Over the dose range 0.3‐0.6 mg, the latency to stage 3 sleep was shortened (P < 0.05), and that to the first REM period lengthened (P < 0.05). 4 All three drugs improved day time sleep. However the present observations and data from previous studies suggest that flunitrazepam (0.25‐0.50 mg) may be particularly appropriate for sleep at unusual times.