bluuebunny/crossref_metadata_2025 huggingface dataset:
ETHOSUXIMIDE: LIVER ENZYME INDUCTION AND D‐GLUCARIC ACID EXCRETION
Authors: GILBERT J.C. , SCOTT A.K. , GALLOWAY D.B. , PETRIE J.C.
Published: July 2012

A study has been carried out to determine if ethosuximide induces liver enzymes.

Ethosuximide did not affect the urinary excretion of D‐glucaric acid by healthy adult subjects nor was the mean daily D‐glucaric acid excretion of three epileptic children on long term ethosuximide therapy different from that of three matched controls.

Ethosuximide (10 mg/kg or 50 mg/kg daily) did not influence D‐glucaric acid excretion or liver microsomal protein and cytochrome P450 contents of guinea pigs but at a dose of 100 mg/kg daily in rats it increased liver microsomal protein and cytochrome P450 without altering D‐glucaric acid excretion.

These results suggest that at anticonvulsant doses ethosuximide is unlikely to induce liver enzymes. The precise relationship between D‐glucaric acid excretion and liver enzyme induction remains in doubt.
URINARY d‐GLUCARIC ACID EXCRETION AND PLASMA ANTIPYRINE KINETICS DURING ENZYME INDUCTION
Authors: DAVIS M. , SIMMONS C.J. , DORDONI BETINA , WILLIAMS R.
Published: July 2012

Changes in urinary D‐glucaric acid excretion following a 14 day course of antipyrine to produce enzyme induction have been compared in normal volunteers with changes in plasma half lives and steady state levels of antipyrine.

Urinary D‐glucaric acid excretion for the group rose significantly with induction, while there was a significant fall in the mean plasma antipyrine half life and steady state levels. The extent of the increase in urinary D‐glucaric acid excretion was inversely related to the pre‐induction level, and this also applied to the change in antipyrine half lives.

Although in individuals, urinary D‐glucaric acid excretion and plasma levels of antipyrine changed in parallel, there was no numerical correlation in the group as a whole between these two tests either before or after enzyme induction.

These findings are consistent with other recently reported evidence that plasma drug kinetics and other microsomal enzyme functions are not necessarily affected to the same degree by agents with enzyme inducing properties.
INVESTIGATION OF SALBUTAMOL TOLERANCE
Authors: SIMS B.A.
Published: July 2012

A double blind cross‐over study was carried out on patients with reversible airways disease attending an out‐patient clinic.

Twenty patients were given either salbutamol (200 μg) or propellant by aerosol for two week periods and in another study twelve patients were given identical tablets containing either salbutamol (4 mg) or placebo for four week periods. Both forms of therapy were taken four times per day but stopped the evening before attending the clinic.

The improvement in FEV1 10 min following salbutamol (200 μg) by aerosol was measured after previous treatment with either salbutamol or placebo administered by aerosol and orally and the results were compared statistically. This failed to show a significant difference and suggests that regular treatment with salbutamol does not lead to a decreased response.
BIOAVAILABILITY OF COMMERCIAL TETRACYCLINE PRODUCTS
Authors: BARNETT D.B. , SMITH R.N. , GREENWOOD N.D. , HETHERINGTON C.
Published: July 2012

Thirteen commercial tetracycline products were assessed for bioavailability by in vitro and in vivo tests. Three failed the B.P. disintegration test and three products in a dissolution test released less than 50% of their stated potency by 3 hours.

In vivo bioavailability was assessed by serum and urinary data. Six products were tested by serum data over 48 h and their bioavailability profiles varied but their ranking correlated well with in vitro dissolution in water; three were better than the others. In a further study, based on urinary excretion alone, the thirteen products showed considerable variation in bioavailability. One product gave an extremely poor result (6 mg excreted in 24 hours).

These findings of generic non‐equivalence illustrate the need for adequate standards of bioavailability testing.
BIOAVAILABILITY OF DIGOXIN FROM RAPIDLY DISSOLVING PREPARATIONS
Authors: JOHNSON B.F. , LADER SUSAN
Published: July 2012

Intestinal absorption of digoxin was assessed by determination of peak plasma concentrations, areas under plasma concentration curves over 80 h, and 10 day urinary excretion. Absorption was equal after ingestion of single doses of standard Lanoxin (Wellcome) tablets, tablets and capsules of ultra‐rapid dissolution rate material, or an oral solution of digoxin in water.

Mean plasma concentrations and dosage‐interval urinary excretion were highly similar during 14 day courses of either Lanoxin or ultra‐rapid dissolution tablets. Increased bioavailability does not result from encapsulation of solid dosage presentations, nor from increasing tablet dissolution rate beyond 75% in 15 minutes.

Fourteen day courses of tablets of slow dissolution rate produced lower and less consistent mean plasma concentrations and urinary excretion. Slow dissolution rates are associated with greater individual variability in absorption.
LITHIUM TREATMENT STRONGLY INHIBITS CHOLINE TRANSPORT IN HUMAN ERYTHROCYTES
Authors: LEE G. , LINGSCH C. , LYLE P.T. , MARTIN K.
Published: July 2012

The influx of [14C] ‐choline and the efflux of 22Na in human erythrocytes were measured in vitro using blood from patients treated with lithium, patients not on lithium and healthy individuals.

The administration of lithium to patients significantly reduces the transport of choline; during the first 6 weeks of treatment the influx of choline is about half the normal rate, later it falls to around 10%.

This inhibition of choline transport is not dependent on the presence of lithium in the incubation medium. 4 The active and passive efflux of sodium are apparently not affected by lithium treatment.
A CONTROLLED TRIAL OF PRACTOLOL IN MILD HYPERTENSION
Authors: CHAPUT D.M. , SAINTONGE DE , ROBERTS C.J.C. , STRICKLAND I.D. , VERE D.W.
Published: July 2012

Fifteen patients with diastolic blood pressures between 90 and 120 mmHg were admitted to a trial comparing placebo with practolol at doses up to 500 mg 12 hourly.

The trial was a double blind cross over study. Treatments were allocated at random and each treatment block lasted 12 weeks.

Ten patients completed the trial, and none of those who withdrew experienced serious unwanted effects. 4 Practolol caused significant falls in standing systolic and diastolic pressures and the supine diastolic pressure.
A COMPARISON OF THE EFFECTS OF PROSTAGLANDIN E2 AND SALBUTAMOL BY INTRAVENOUS INFUSION ON THE AIRWAYS OBSTRUCTION OF PATIENTS WITH ASTHMA
Authors: SMITH A.P.
Published: July 2012

The effects of intravenous infusion of prostaglandin E2 (PGE2) on forced expiratory volume in 1 second (FEV1) were studied in ten asthmatic patients and compared with the effects of intravenous salbutamol.

PGE2 at infusion rates of 5, 10 and 20 μg/min for three 15 min periods resulted in a small bronchodilator effect in four patients, bronchoconstriction in four, and had no measurable effect on FEV1 in two patients; side effects were frequent and it was concluded that PGE2 was unsuitable for use in the management of attacks of asthma.

In the same subjects bronchodilatation occurred during infusion of salbutamol at flow rates of 5, 10 and 20 μg/min (six patients), 10, 20 and 40 μg/min (two patients) and 20, 40 and 80 μg/min (two patients). Serious cardiovascular effects were not encountered at flow rates of less than 20 μg/minute.
A PRELIMINARY STUDY OF THE EFFECT OF NORFENFLURAMINE ON LIPOGENESIS BY HUMAN ADIPOSE TISSUE In vitro
Authors: ASHWELL MARGARET
Published: July 2012

Norfenfluramine is thought to be the major active metabolite of fenfluramine in man. Therefore its in vitro effect on lipogenesis in human adipose tissue from twelve patients was investigated.

Although inhibition of lipogenesis was demonstrated, the concentrations of norfenfluramine necessary (>1 mM) were much higher than normal blood levels of the drug.

There was no correlation between the degree of inhibition by norfenfluramine in vitro and fat cell size, age or relative weight of the subject. Greater degrees of inhibition were however associated with samples of tissue from patients with higher blood glycerol concentrations and lower blood triglyceride concentrations.
THE CLINICAL PHARMACOLOGY OF VILOXAZINE HYDROCHLORIDE—A NEW ANTIDEPRESSANT OF NOVEL CHEMICAL STRUCTURE
Authors: BAYLISS P.F.C. , DUNCAN S.M.
Published: July 2012

The clinical pharmacological properties of viloxazine hydrochloride (ICI 58, 834, Vivalan), a new antidepressant of novel chemical structure, have been investigated in a series of double‐blind randomized studies comparing it with placebo and imipramine. Throughout the studies, viloxazine hydrochloride was given in single doses of 100 mg (expressed as base), and imipramine hydrochloride was given in single doses of 50 mg (expressed as salt).

The effect of viloxazine upon the following parameters was measured: pulse rate, blood pressure, forced expiratory volume, reaction time, critical flicker frequency, salivary flow, pupil size and palpebral fissure size. In addition, the possible interaction between viloxazine and alcohol was investigated using measurements of reaction time.

Both viloxazine and imipramine produced a transient tachycardia, but no consistent effect on blood pressure was seen. Neither drug had any effect upon forced expiratory volume.

The differences that emerged between viloxazine and imipramine were that viloxazine depressed critical flicker frequency whereas imipramine did not, and imipramine prolonged reaction time whilst viloxazine did not. Imipramine reduced salivary flow and increased the size of the pupil and palpebral fissure. Viloxazine did neither.

Imipramine was shown to potentiate alcohol whereas, at the doses used, viloxazine did not.

It is concluded that viloxazine appears to have less anticholinergic and possibly less sympathomimetic properties than imipramine. It is also concluded that viloxazine, unlike imipramine, does not potentiate alcohol.
THE EFFECT OF FRUSEMIDE ON INDOMETHACIN PLASMA LEVELS
Authors: BROOKS P.M. , BELL M.A. , LEE P. , ROONEY P.J. , DICK W.C.
Published: July 2012

The pharmacokinetic and clinical effects of concurrent oral indomethacin and frusemide administration were determined in eight patients with rheumatoid arthritis.

Oral frusemide significantly reduces the plasma level of indomethacin following concurrent administration of the two drugs orally.

A profile of pain index, articular index and grip strength following oral indomethacin (50 mg) was determined and although the decrease in articular index was less when frusemide and indomethacin were given together it did not reach statistical significance.
THE ALIMENTARY ABSORPTION OF DIAMORPHINE AND MORPHINE IN MAN AS INDICATED BY URINARY EXCRETION STUDIES
Authors: TWYCROSS R.G. , FRY D.E. , WILLS P.D.
Published: July 2012

Urine was collected over 24 h from 40 patients with advanced malignant disease who had received a known four‐hourly oral dose of either diamorphine or morphine in an elixir or of diamorphine by injection for at least 3 days.

Samples were assayed for total urinary morphine (free and conjugated) by gas‐liquid chromatography.

The percentage of the administered dose recovered as morphine was:

diamorphine hydrochloride by injection: 70% (s.d. 25)

diamorphine hydrochloride by mouth: 77% (s.d. 27)

morphine sulphate by mouth: 56% (s.d. 21)

It is suggested that diamorphine hydrochloride is completely absorbed by the ***gastro‐intestinal tract but that morphine sulphate is only some two‐thirds absorbed.
BROMOCRIPTINE AND DOPAMINE RECEPTOR STIMULATION
Authors: DEBONO A. GALEA , MARSDEN CD. , ASSELMAN P. , PARKES J.D.
Published: July 2012

The response to different doses of bromocriptine (12.5, 25, 50 and 100 mg) has been established in six patients with Parkinson's disease.

Bromocriptine, like levodopa, causes improved mobility in patients with Parkinsonism, emesis, hallucinations, a fall in supine and erect blood pressure, increase of plasma growth hormone and suppression of prolactin concentration.

Bromocriptine (50 or 100 mg) has as great an anti‐Parkinsonian effect as average therapeutic doses of levodopa, and a longer duration of action, 6–10 hours.

In the dose range studied, bromocriptine appears to be a complete dopamine agonist, although 100 mg was less effective than 50 mg in two patients.

The different actions of bromocriptine and other dopamine agonist drugs may result from stimulation of different types of dopamine receptor.
ADRENOCEPTOR RESPONSIVENESS IN BRONCHIAL ASTHMA: EFFECT OF ISOPRENALINE INHALATION ON PLASMA CYCLIC 3′,5′‐AMP LEVELS
Authors: TREMBATH P.W. , SHAW J.
Published: July 2012

The effect of isoprenaline inhalation on plasma levels of cyclic AMP has been studied in a group of normal subjects and compared to a group of asthmatics.

The normal subjects had a prompt rise in their plasma cyclic AMP level, and when compared to the asthmatic group, had a significantly greater percentage rise in plasma cyclic AMP from the basal levels.

The markedly attenuated response to isoprenaline inhalation in the asthmatic group is consistent with the concept that asthmatics have a relative impairment of β‐adrenoceptor function.

These results support the in vitro studies demonstrating that lymphocytes from asthmatic subjects incubated with isoprenaline produce less cyclic AMP than those from normal subjects.
THE EFFECT OF METOPROLOL AND PRACTOLOL ON LUNG FUNCTION AND BLOOD PRESSURE IN HYPERTENSIVE ASTHMATICS
Authors: FORMGREN H.
Published: July 2012

The effect of metoprolol, a new β1‐adrenoceptor blocking agent, was compared to practolol in the treatment of hypertension in seventeen asthmatics during concurrent optimum bronchodilator therapy with a selectiveβ2‐adrenoceptor‐stimulant.

The two β‐adrenoceptor antagonists were given at two dose levels, practolol (200 mg and 400 mg) daily, and metoprolol (100 mg and 200 mg) daily, in a twice‐daily. dosage schedule, at 12 h intervals, for 17 days. The comparison was made double‐blind and a crossover design was used. The drugs were given in randomized order. The study started with a run‐in placebo period and there was a washout period on placebo between the treatment periods. Spirometry, blood pressures and heart rates were recorded in a standardized manner.

At the lower dose levels no influence on FEV1was noted, and no difference was found between the two active drugs. At the higher dose level FEV1was reduced by both β‐adrenoceptor‐blocking drugs. Four out of twelve patients given the higher dose experienced exacerbation of their asthma. The heart rate fell with both drugs and at both dose levels. During the placebo period a marked increase of heart rate was noted. The blood pressure fell at both dose levels compared to placebo, no difference being recorded between the two drugs.

Metoprolol and practolol are equally effective β1‐adrenoceptor blocking drugs. In this study it was found that metoprolol could be used in asthmatics who had indications for β‐adrenoceptor blockade, provided that the total daily dose did not exceed 100 mg. Optimal bronchodilator treatment with a bronchoselective β‐adrenoceptor agonist is an absolute prerequisite in order to avoid the risk of aggravation of asthma.
THE INFLUENCE OF THIETHYLPERAZINE ON THE ABSORPTION OF EFFERVESCENT ASPIRIN IN MIGRAINE
Authors: WAINSCOTT GILLIAN , KASPI TASOULLA , VOLANS G.N.
Published: July 2012

The absorption of effervescent aspirin was studied in three groups of patients during attacks of migraine. The first group received intramuscular thiethylperazine 10 min before effervescent aspirin; the second group received intramuscular metoclopramide 10 min before effervescent aspirin; and the third group received effervescent aspirin alone.

Where possible each patient was retested when headache‐free but under conditions which were otherwise as similar as possible to those during the acute attack.

Intramuscular metoclopramide corrected the impairment of drug absorption that occurred during a migraine attack, whereas thiethylperazine did not.

In the group of patients treated with thiethylperazine and aspirin, the impairment of absorption did not correlate with the duration of the symptoms, nor with the severity of the headache and nausea.

Patients treated with thiethylperazine and aspirin tended to take longer to recover than those patients treated with metoclopramide and aspirin. However, in the thiethylperazine treated group, the time to recover did not correlate with the salicylate level achieved.
ACETYLATOR PHENOTYPE AND THE CLINICAL PHARMACOLOGY OF SLOW‐RELEASE PROCAINAMIDE
Authors: CAMPBELL W. , TILSTONE W.J. , LAWSON D.H. , MUTTON I. , LAWRIE T.D.V.
Published: July 2012

Slow‐release procainamide given 8‐hourly is shown to produce plasma levels generally accepted as giving effective prophylaxis against ventricular dysrhythmias occurring after recent myocardial infarction.

Patients can be classified into ‘slow’ and ‘fast’ acetylators of procainamide.

Knowledge of acetylator status is helpful in determining the dose of procainamide necessary to attain effective steady‐state plasma levels while avoiding toxic ones.

Acetylator status cannot be assessed accurately using sulphadimidine when the patients are also taking procainamide.
EFFECT OF PHENYTOIN THERAPY ON THYROID FUNCTION
Authors: FINUCANE J.F. , GRIFFITHS R.S.
Published: July 2012

Serum total and free fraction of thyroxine and triiodothyronine and urinary losses of unconjugated hormones in normal subjects and in patients treated long‐term with therapeutic doses of phenytoin have been measured.

Decreases in serum total hormone concentrations with increased free fractions and resultant significant increase in the concentration of free thyroxine but not triiodothyronine were apparent in phenytoin‐treated subjects. However, serum free hormone concentrations remained within the euthyroid range.

These changes in serum free hormone concentration were reflected by an increased urinary loss of unconjugated thyroxine, but normal excretion of unconjugated triiodothyronine.

Phenytoin in therapeutic doses displaces thyroxine and to a lesser extent, triiodothyronine from binding proteins in serum and thus increases peripheral clearance of thyroid hormones.
THE RADIOIMMUNOASSAY OF TRICYCLIC ANTIDEPRESSANTS
Authors: AHERNE G.W. , PIALL E.M. , MARKS V.
Published: July 2012

An antiserum to nortriptyline has been produced in a sheep against a nortriptyline‐bovine serum albumin conjugate. The conjugate was prepared using the reagent N‐(4‐bromobutyl) phthalimide followed by a carbodiimide reaction to link the hapten to the carrier protein.

The antibodies produced were shown to be specific for the tricyclic group of drugs.

The sensitivity of the radioimmunoassay developed is currently limited by the lack of a high specific activity label. The possibilities of developing a radioimmunoassay for nortriptyline in plasma are discussed.
A THERAPEUTIC AUDIT AT AUTOPSY
Authors: WADE O.L. , TESH D.E.
Published: July 2012

A survey of one hundred patients submitted to autopsy has been carried out to assess the contribution of investigational procedures, surgery and drug therapy to death.

In nineteen patients drug therapy, usually appropriate and necessary therapy, was thought to have contributed to death. In five patients failure to continue therapy properly contributed to death.

The survey was not representative either of patients dying in hospital or in the community, but it suggests that a larger and more comprehensive survey should be undertaken.
α‐ADRENOCEPTOR BLOCKING DRUGS IN ASTHMA
Authors: PATEL K.R.
Published: July 2012

The effect of α‐adrenoceptor blocking drug, thymoxamine alone and in combination with isoprenaline, was studied on the specific airways conductance (SGaw) in ten patients with extrinsic asthma.

Thymoxamine when given together with isoprenaline produced significantly greater increase in SGaw as compared to improvement achieved with isoprenaline alone.

It is suggested that the potentiation of isoprenaline induced bronchodilatation by thymoxamine is mediated by increased cyclic AMP formation in the bronchial smooth muscle.
A COMPARISON OF THE EFFECT OF FRUSEMIDE AND BUMETANIDE ON THE DIURETIC RESPONSE AND FIBRINOLYTIC MECHANISM IN MAN
Authors: MACKIE P.H. , THOMSON M.R. , LEVINE D.F. , BRANCH R.A.
Published: July 2012

A double‐blind, crossover trial has compared the diuretic response of ten normal male subjects to the oral administration of frusemide (40 mg) and bumetanide (1 mg).

Both drugs gave a similar profile, with acute onset and cessation of response, and a marked peak effect.

There was no significant difference between the times taken for each drug to produce its peak diuretic effect.

The peak rate of diuretic response, and the total response for six hours after drug ingestion, were significantly greater after bumetanide, with respect to urinary volume and sodium excretion. The peak rate of magnesium excretion was greater after bumetanide. There was no difference between the drugs with respect to potassium, calcium or creatinine excretion or the urinary Na/K ratio. Following peak diuresis, potassium excretion did not show a linear return to its control value.

At the time of peak diuresis, both drugs caused a significant reduction of euglobulin lysis time; levels of available plasmin were significantly lowered after frusemide, and levels of active plasmin were significantly raised after bumetanide. The significance of these findings in relation to the fibrinolytic mechanism is discussed.

Estimations of plasma viscosity, serum total protein and magnesium concentrations showed that maximal haemoconcentration occurred several hours after diuresis.
PHENELZINE IN URINE: ASSAY AND RELATION TO ACETYLATOR STATUS
Authors: CADDY B. , TILSTONE W.J. , JOHNSTONE E.C.
Published: July 2012

Phenelzine cannot be extracted as such from biological fluids.

Formation of the acetonide derivative prior to extraction allows phenelzine to be extracted and assayed by gas chromatography at levels down to 0.5 μg/ml.

At this sensitivity the drug can be detected in urine but not in plasma, after therapeutic doses.

Persons typed as slow acetylators of sulphadimidine excreted approximately twice as much unmetabolized phenelzine in urine compared to fast acetylators.
INCREASED PLATELET AGGREGATION IN PATIENTS RECEIVING CHLORPROMAZINE: RESPONSES TO 5‐HYDROXYTRYPTAMINE, DOPAMINE AND N‐DIMETHYL DOPAMINE
Authors: BOULLIN D.J. , GRIMES R.P.J.
Published: July 2012

Platelet aggregation responses to 5‐HT, dopamine, N‐dimethyl dopamine and adenosine diphosphate were compared in normal subjects and patients treated with chlorpromazine (CPZ) for longer than 6 months.

We confirmed our previous finding that 5‐HT induced aggregation is enhanced in CPZ treated patients.

Increased aggregation responses were also observed with dopamine and N‐dimethyl dopamine.

Quantitative comparisons of aggregation rates and total changes in optical density of platelet rich plasma relative to adenosine diphosphate showed significant increases with 5‐HT, dopamine and N‐dimethyl dopamine.

Implication of dopaminergic mechanisms in the central effects of phenothiazines suggests that changes in dopamine induced aggregation responses may be useful in attempting correlations of clinical and pharmacological effects.
THE EFFECT OF FRUSEMIDE, MEXILETINE, (+)‐PROPRANOLOL AND THREE BENZODIAZEPINE DRUGS ON INTERICTAL SPIKE DISCHARGES IN THE ELECTROENCEPHALOGRAMS OF EPILEPTIC PATIENTS
Authors: AHMAD S. , PERUCCA E. , RICHENS A.
Published: July 2012

The effects of single intravenous doses of diazepam, clonazepam, lorazepam, frusemide, mexiletine and (+)‐propranolol on the frequency of electroencephalographic (EEG) interictal spike discharges were assessed in three double‐blind placebo‐controlled trials in fourteen epileptic patients.

Diazepam (5 mg) produced a significant mean decrease of spike discharges to about one third of the control frequency. The effect developed rapidly and persisted for the duration of the study (up to 25 min after injection). A larger dose (10 mg) failed to produce a further reduction in the frequency of the spike discharges.

Clonazepam (0.5 mg), frusemide (40 mg) and lorazepam (2 mg) appeared to be as effective as diazepam in reducing spike discharges, although the effect of the latter drug seemed to develop with some delay.

Mexiletine (100 mg) and (+)‐propranolol (50 mg) did not reduce paroxysmal EEG discharges, their effects being not significantly different from that of saline.

EEG spike counting after intravenous administration of single test‐doses appeared to be both a simple and promising technique for the rapid preliminary evaluation of the clinical efficacy of new anti‐epileptic drugs.
Comparative effects of aspirin and diflunisal on prostaglandin synthetase from human platelets and sheep seminal vesicles.
Authors: Majerus PW , Stanford N
Published: July 2012

1. We have compared the effects of diflunisal on prostaglandin (PG) synthetase from human platelets and sheep seminal vesicles (SSV) by measuring malonaldehyde, PG products, and rabbit aorta contraction. 2. Aspirin inhibits PG synthetase by covalently acetylating the enzyme. Inhibition is dependent on time and aspirin concentration. Aspirin is 37‐fold more potent in inhibiting enzyme in human platelets compared with enzyme from SSV. 3. Diflunisal inhibits PG synthetase from intact human platelets and SSV equally (50% inhibition at 3‐5 micronM). The drug does not covalently modify the enzyme, and inhibition is not time dependent. Diflunisal probably acts at a site similar to aspirin since the drug will inhibit acetylation of the enzyme by aspirin. 4. The results suggest that diflunisal is relatively less inhibitory to platelet function than is aspirin.
A clinical comparison of nomifensine and amitriptyline.
Authors: McClelland HA , Kerr TA , Little JC
Published: July 2012

1. The study consists of a double‐blind evaluation of nomifensine and amitriptyline in a group of 37 patients with primary depressive illness. 2. The patients were referred by their family doctors on the basis that they would ordinarily have been prescribed a tricyclic antidepressant drug. Random allocation to the treatment groups took place. Assessment took place at weekly intervals over a 4‐week period using the Visual Analogue Scale for depression and anxiety, and a side‐ effects check‐list. Patients were also assessed on the Hamilton Depression Scale before the onset and at the end of the trial. 3. No significant difference was found between the two groups as regards relief from depression and anxiety, although marginal differences were found in favour of the amitriptyline group. 4. The overall frequency of side‐effects was similar in the nomifensine and amitriptyline patients, But the development of severe side‐effects was significantly more common in the amitriptyline group.
Studies on brain metabolism of biogenic amines.
Authors: Schacht U. , Leven M. , Backer G.
Published: July 2012

1. In vitro models (synaptosones, electrically stimulated brain slices and monoamine oxidase (MAO) preparations have been used to identify the sites of action of nomifensine on brain monoamine metabolism. 2. Nomifensine potentiates neurotransmission in noradrenergic and dopaminergic synapses by blocking catecholamine uptake. 3. Nomifensine does not inhibit MAO and does not enhance the release of biogenic amines. 4. Studies on electrically stimulated brain slices suggest that nomifensine does not directly stimulate dopamine (DA) nor noradrenaline (NA) receptor sites. 5. 5‐Hydroxytryptamine (5‐HT) uptake is not inhibited at “therapeutic” concentrations of nomifensine. 6. Nomifensine differs from the tricyclic antidepressants by virtue of its effect on the dopaminergic system.
Intravenous labetalol in hypertensive patients given by fast and slow injection.
Authors: Pearson RM , Havard CW
Published: July 2012

1 Labetalol reduces blood pressure when given by fast or slow intravenous injection. 2 The extent of the reduction in arterial pressure is independent of the rate of injection but the rate of fall of blood pressure can be controlled by varying the rate of injection. There is little effect on heart rate. 3 These observations suggest that labetalol possesses important advantages over other vasodilator hypotensive drugs in current use.
Toxicity of nitrazepam in the elderly: a report from the Boston Collaborative Drug Surveillance Program.
Authors: Greenblatt DJ , Allen MD
Published: July 2012

1 To assess the potential hazards of nitrazepam therapy of insomnia in the elderly, adverse reactions to nitrazepam were studied in 2111 hospitalized medical patients who received the drug. 2 Manifestations of unwanted central nervous system (CNS) depression (such as drowsiness or 'hangover') were reported in 49 nitrazepam recipients (2.3%), and signs of unwanted CNS stimulation (such as nightmares, insomnia, agitation, etc.) in 15 (0.7%). None of the adverse reactions were considered serious. 3 Physician‐rated clinical efficacy of nitrazepam was not related to dose, but the frequency of both types of adverse reactions increased significantly at higher daily doses. CNS depression also was significantly more frequent in the elderly, being reported in 11% of those aged 80 years or older, whereas the frequency of CNS stimulation was not correlated with age. 4 The effect of age on the reported rate of unwanted CNS depression was most striking at high doses. Among patients aged 80 years or over whose daily dose averaged 10 mg or more, 55% experienced unwanted CNS depression attributed to nitrazepam. 5 Low doses of nitrazepam are safe for elderly individuals, but the elderly are readily susceptible to excessive CNS depression at high doses. The findings suggest that there is little reason to exceed 5mg doses of nitrazepam for most patients, particularly those who are elderly.
Effect of dopamine on airways conductance in normals and extrinsic asthmatics.
Authors: Thomson NC , Patel KR
Published: July 2012

1 Specific conductance was measured before and after infused and/or inhaled dopamine in nine normal subjects and twelve patients with extrinsic bronchial asthma. 2 There was no significant change in conductance in either group. 3 The alpha‐adrenergic receptor antagonist thymoxamine infused in combination with dopamine had no significant effect on conductance in three asthmatics. 4 It is concluded that dopamine has no acute effect on airways resistance and that specific dopamine receptors are unlikely to exist in human airways.
The effect of low dose carbidopa/levodopa on prolactin and growth hormone concentrations in patients with breast cancer and in benign breast tumours.
Authors: Jones MK , Ramsay ID , Jenner PG
Published: July 2012

1 Low doses of carbidopa/levodopa (12.5 mg 1‐alpha‐methyl‐ dopahydrazine, 125 mg levodopa) were administered orally to 29 patients with tumours of the breast (16 with breast cancer, 13 with benign breast disease). 2 Plasma dopa response curves were similar in all the patients studied. 3 Prolactin and growth hormone showed similar responses to carbidopa/levodopa irrespective of age or diagnosis. 4 Prolactin showed an unusual reponse in four patients which has not previously been recorded.
Enhanced elimination of warfarin during treatment with cholestyramine.
Authors: Jahnchen E , Meinertz T , Gilfrich HJ , Kersting F , Groth U
Published: July 2012

1 The elimination and anticoagulant activity of a single intravenous dose of warfarin (1.0‐1.2 mg/kg) without and with concomitant cholestyramine treatment (about 4 g three times daily) was studied in five healthy male subjects. 2 Cholestyramine treatment decreased the biological half‐life of plasma warfarin (from a mean value of 2 days − 1.3 days) and increased the total clearance of this drug (from a mean value of 37 ml kg‐1 day‐1–53 ml kg‐1 day‐1). 3 The total anticoagulant effect per dose of warfarin, as measured by the area under the effect v time curve, was also reduced by cholestyramine (average reduction of about 25%). 4 Warfarin possibly undergoes enterohepatic recycling in man which can be interrupted by cholestyramine.
A thermographic assessment of three intra‐articular prednisolone analogues given in rheumatoid synovitis.
Authors: Esselinckx W , Bacon PA , Ring EF , Crooke D , Collins AJ , Demottaz D
Published: July 2012

1 Three intra‐articular prednisolone analogues have been studied in a group of forty‐six rheumatoid arthritic subjects. Each compound was tested at 50 mg and 100 mg dose over 3 weeks. 2 The anti‐inflammatory effect was assessed by quantitative thermography. Systemic escape of the drug was monitored by plasma prednisolone and cortisol levels. 3 Both the systemic escape from the joint and the duration of effect on injected and uninjected knees were related to drug solubility. 4 Depression of plasma cortisol occurred with all three preparations and was most prolonged with the long‐acting preparation. 5 Increasing the dose from 50 mg to 100 mg increased the antiflammatory effect only with the soluble acetate preparation.
EFFECT OF URINARY pH AND NICOTINE EXCRETION RATE ON PLASMA NICOTINE DURING CIGARETTE SMOKING AND CHEWING NICOTINE GUM
Authors: FEYERABEND C. , RUSSELL M.A.H.
Published: July 2012

Plasma nicotine levels produced by chewing nicotine gum were compared with those obtained by cigarette smoking under conditions of controlled urinary pH.

Although absorption was slower, plasma levels comparable to cigarette smoking were built up on 4 mg (but not 2 mg) nicotine gum.

Urinary excretion of nicotine was influenced markedly by pH and the rate of urine flow.

Plasma nicotine was higher under alkaline compared to acidic conditions (P < 0.001) but the rate of urinary nicotine excretion appeared to have little effect on the plasma level.
DEGREE OF TOLERANCE AND THE RELATIONSHIP BETWEEN PLASMA MORPHINE CONCENTRATION AND PUPIL DIAMETER FOLLOWING INTRAVENOUS HEROIN IN MAN
Authors: TRESS KATHLEEN H. , EL‐SOBKY A.A. , AHERNE WYNNE , PIALL EVELYN
Published: July 2012

After doses of heroin to tolerant (heroin‐dependent) persons and non‐tolerant (non‐dependent) persons, pupil diameter varies with the degree of physical dependence and the plasma concentration of the drug.

The linear regression slopes of pupil diameter on plasma drug concentration correlate with daily prescription of opiates. That is, the greater the degree of physical dependence the higher the plasma drug concentration that is required for a given degree of miosis.

It is suggested that these observations might provide the basis of a test to estimate the drug requirements of drug dependent patients attending treatment clinics.
PHARMACOKINETICS OF SUSTAINED RELEASE ASPIRIN
Authors: BROOKS P.M. , ROBERTS M.S. , PATEL B.
Published: July 2012

Salivary salicylate concentrations were used to study the pharmacokinetics of a sustained release aspirin (SRA) in normal volunteers.

The effect of fasting, food and metoclopramide were studied.

Metoclopramide hastens absorption while a heavy meal delays absorption of SRA.

The mean urinary recovery of aspirin in all the trials was 608 mg and the different treatments did not significantly alter urinary recovery.
PHARMACOKINETICS AND METABOLISM OF TEMAZEPAM IN MAN AND SEVERAL ANIMAL SPECIES
Authors: SCHWARZ H.J.
Published: July 2012

Absorption, excretion and detoxification of temazepam were investigated in man, mouse, rat and dog. Considerable interspecies variation was apparent with respect to excretion and metabolite patterns in blood and urine. Animal species were exposed to equal or greater concentrations of all the metabolites occurring in man.

Pharmacokinetics of temazepam in man were investigated in a single dose study at two dose levels, and in a multiple dose study. The results of both studies were analyzed and interpreted with the help of compartmental models. Values were obtained for excretion pattern (0‐∞), half lives (1.95, 0.5, 10.0 and 1.9 h), amounts in all compartments, and for steady‐state conditions.

The bioavailability of the hard gelatin capsule dosage form was compared with that of a suspension serving as the ideal dosage form, and found to be acceptable.
EFFECTS OF TEMAZEPAM, FLURAZEPAM ANDQUINALBARBITONE ON SLEEP: PSYCHOMOTOR AND COGNITIVE FUNCTION
Authors: ROTH T. , PICCIONE P. , SALIS P. , KRAMER M. , KAFFEMAN M.
Published: July 2012

The effect of temazepam 15 and 30 mg, flurazepam 15 and 30 mg, quinalbarbitone 100 and 200 mg and placebo were studied in 14 healthy male volunteers according to a Latin‐square design. At 14‐d intervals subjects received capsules 30 min before bedtime on 2 consecutive nights and were evaluated for objective sleep characteristics, for morning estimates of sleep characteristics, and for cognitive and psychomotive performance and subjective state at 3.5, 10.0 and 22.5 h after ingestion.

Changes in sleep induction and sleep maintenance were observed with temazepam 30 mg and flurazepam 30 mg. REM sleep was suppressed by quinalbarbitone, and by flurazepam 30 mg.

Flurazepam 30 mg had the greater effect on cognitive performance, whereas quinalbarbitone 20 mg had the greater effect on psychomotive performance. Subjective assessments of alertness were most affected by flurazepam, and by quinalbarbitone 200 mg.

The results suggest that temazepam produces less residual effects and is shorter acting than quinalbarbitone and flurazepam.
DOUBLE‐BLIND EVALUATION OF THE EFFICACY AND SAFETY OF TEMAZEPAM IN OUTPATIENTS WITH INSOMNIA
Authors: FILLINGIM J.M.
Published: July 2012

The efficacy and safety of temazepam 30 mg, compared with glutethimide 500 mg and placebo, were evaluated in double‐blind conditions in a 4‐day study in 75 outpatients with a history of insomnia.

Temazepam and glutethimide were rated by the patients as effective and significantly superior to placebo for general quality of sleep, time requiredto fall asleep, frequency of nocturnal and early morning awakenings, and duration of sleep.

Residual effects reported for temazepam and glutethimide immediately after awakening and during the day were similar to or less than those reported for placebo.
CLINICAL SIGNIFICANCE OF PRESCRIBING HYPNOTICS IN GENERAL PRACTICE
Authors: WHEATLEY D.
Published: July 2012

The causes of insomnia are considered, including those amenable to improvement of the sleep environment and medical treatment.

The use of hypnotics is discussed and the investigation of new drugs in general practice reviewed.
Assay of clobazam in human serum by a radioreceptor technique.
Authors: Hunt P
Published: July 2012

1 Clobazam has been assayed in human serum using a radioreceptor technique. 2 The assay is simple and sufficiently sensitive for detecting serum levels up to 48 h after oral administration of a usual clinical dose. It has the advantage of measuring the parent compound plus active metabolites. 3 Serum clearances and elimination half‐lives have been determined for five subjects.
Psychomotor changes during initial day of benzodiazepine medication.
Authors: Wittenborn JR , Flaherty CF , McGough WE , Nash RJ
Published: July 2012

1 The detracting psychomotor effects of diazepam (5 mg three times daily) and clobazam (an investigational 1,5‐benzodiazepine) were compared with placebo effects over the course of the initial day of medication. Tests were administered at hourly intervals and the data were analyzed from the standpoint of contrasts at each session and from the standpoint of trends that accrued during the course of the day. 2 It is concluded that among normal volunteers diazepam 5 mg three times daily may be near the threshold for detracting psychomotor consequences during the initial day and that clobazam seems to be without detracting consequences and may have some enhancing effects.
Studies of clobazam and car‐driving.
Authors: Biehl B
Published: July 2012

1 The methodology used in studies to assess the effects of drugs on car‐ driving performance is reviewed. 2 Clobazam 20 mg, diazepam 10 mg or placebo were administered daily for 3 d to 24‐male students with a high neuroticism score (on the Cattell Personality Factors Questionnaire). 3 Car driving performance was assessed on the second day in real traffic conditions; tests of attention and concentration and subjective assessments were made on the third day. 4 Diazepam 10 mg significantly impaired braking reaction time in comparison with clobazam 20 mg and placebo (P less than 0.01). Subjects also reported feeling more 'depressed' and lethargic after diazepam.
Single daily dose treatment of anxiety with clobazam or dipotassium clorazepate.
Authors: Wallis TD , Valle‐Jones JC , Craven JR , Hanks GW , Stonier PD
Published: July 2012

1 Forty‐four clinically anxious patients entered a comparative double‐ blind trial of clobazam 20 mg, clobazam 30 mg and dipotassium clorazepate 15 mg, all drugs given as a single dose at night. 2 Assessment by the Hamilton Anxiety Scale, Morbid Anxiety Inventory (Salkind) and a Visual Analogue Scale showed a statistically significant improvement for all treatment groups after 2 weeks, with continued improvement after a further 2 weeks. 3 Daytime drowsiness was the commonest side‐effect in all treatment groups but there was a tendency for a lower incidence in patients on clobazam. There was no evidence of a dose‐related incidence of drowsiness in the clobazam 20 mg and 30 mg groups. Other side‐effects were few and nonspecific. 4 Clobazam is a 1,5‐benzodiazepine with an elimination half‐life of 18 hours. When given in single doses of 20‐30 mg at night it has an equivalent effect to dipotassium clorazepate 15 mg.
Clobazam: uncontrolled and standard controlled clinical trials.
Authors: Ban TA , Amin MM
Published: July 2012

1 In an uncontrolled clinical trial, carried out in 11 psychiatric patients with the clinical diagnoses of anxiety neurosis and depressive neurosis, clobazam, a new benzodiazepine preparation, in the dosage range 10‐60 mg daily produced statistically significant improvement in the total and both factor scores of the Hamilton Anxiety Scale (HAM‐A). The lowest mean total HAM‐A scores occurred with a mean clobazam dosage of 48 mg daily. 2 Results of the uncontrolled clinical trial were further substantiated in a standard‐controlled clinical study in which no statistically significant difference between the therapeutic effectiveness of clobazam and diazepam could be revealed. The lowest mean total HAM‐A scores occurred with a mean clobazam dosage of 49 mg daily. There was a lower incidence of adverse effects reported in patients receiving clobazam than in those taking the control drug (diazepam).
Review of clinical studies on clobazam.
Authors: Koeppen D
Published: July 2012

1 Clobazam was compared with placebo and diazepam in 45 double‐blind studies. 2 Clobazam dosage ranged from 5 mg daily (paediatric patients) to 120 mg daily (psychiatric in‐patients). Usual daily dosage in out‐ patient therapy ranged from 20‐30 mg clobazam. 3 Treatment duration varied from a few days up to 3.5 years. The usual duration of treatment was 2‐4 weeks. 4 Clobazam was shown to be an efficacious and well tolerated anxiolytic agent in various neurotic and psychosomatic disorders. 5 Dosages showing distinct anxiolytic effects in out‐patient therapy did not impair psychomotor performance.
Diuretics, beta‐blockers or both as treatment for essential hypertension.
Authors: Stumpe KO , Overlack O
Published: July 2012

1 Patients with borderline (group I) and sustained hypertension (group II) were treated with beta‐blocking drugs, diuretics and the combination of both. In the two groups of patients the antihypertensive effectiveness of both short‐term intravenous or chronically oral propranolol was directly related to the extent to which the drug produced an absolute reduction in plasma renin activity (PRA). No such a correlation could be obtained with pindolol. In group I following beta‐blockade, day‐night profiles of PRA were similar to those observed in group II before treatment. Thus, in this latter subgroup, low renin profiles might reflect reduced beta‐adrenergic activity. 2 When the chronically beta‐blockaded patients were changed to chronic diuretic therapy it became evident that young hypertensive patients of group II showed a more pronounced BP response than the patients of group I. In those patients of group II in whom pressure was not controlled by the diuretic alone, combination with a beta‐blocker led to pressure normalization. 3 The beta‐blocking drug induced reduction in pressure was greater in the 25‐35 yr olds, than in those older than 55. In contrast, the antihypertensive effect of the diuretic was more pronounced in the 55‐70 yr olds than in those younger than 40. 4 It is concluded that sympathetic nervous system activity mainly determined PRA as well as antihypertensive effectiveness of both the beta‐blockers and the diuretics. As to outpatient management it is proposed that with exception of young borderline hypertensives who seem to respond best to beta‐blockers, initial antihypertensive drug therapy may consist of a diuretic agent. If the antihypertensive effect of the diuretic is insufficient, combination with a beta‐blocking drug could be used to achieve the best effect.
beta‐Adrenoceptor‐blocking agents and the kidney: effect of nadolol and propranolol on the renal circulation.
Authors: Hollenberg NK , Adams DF , McKinstry DN , Williams GH , Borucki LJ , Sullivan JM
Published: July 2012

1 Nadolol was administered intravenously to five hypertensive patients and three healthy volunteers in balance on a 10 mEq sodium intake. 2 Nadolol (0.3‐10.0 micrograms/kg) induced a significant, dose‐related increase in renal blood flow, measured with radioxenon, with a maximum increase of 72 +/‐ 4 ml/100g/min (26%) at 3.0 micrograms/kg. 3 Heart rate and plasma renin activity decreased significantly over the same dose range. 4 The renal vascular response to nadolol contrasts sharply with those found with other beta‐adrenoceptor‐blocking agents. 5 The magnitude of the increase in renal blood flow, its time‐course and the parallel fall in plasma renin activity raise the possibility that the renal vasodilation reflects the reversal of angiotensin's influence on the renal arterial bed.
Pharmacological and clinical importance of narcotic antagonists and mixed antagonists‐use in cardiology.
Authors: Coltart DJ , Malcolm AD
Published: July 2012

1 The treatment of pain of cardiac origin requires a knowledge of the haemodynamic action of the analgesic agents used. 2 The haemodynamic effects of morphine, diamorphine, pavaveretum, pethidine and pentazocine are reviewed. 3 Clinical experience with the new antagonist analgesic buprenorphine is reported. 4 These studies indicate that buprenorphine may be the agent of choice for the relief of severe pain in patients with unstable circulation.
A trial of sublingual buprenorphine in cancer pain.
Authors: Robbie DS
Published: July 2012

1 Buprenorphine is a new antagonist analgesic which was offered sublingually to 141 patients with moderate cancer pain as an alternative to their current analgesic. These patients were not on regular strong morphine‐like analgesics. 2 Forty‐seven patients used the drug on demand in unit doses ranging from 0.15‐0.8 mg for an average of 12 weeks. A full‐time nurse‐observer was used throughout the studies. 3 Good analgesic results were obtained. Certain difficult chronic dull aching pains in the head and neck were especially helped by the drug. There was no indication of dependence or tolerance in this study. 4 The main side‐effect was drowsiness which lessened with usage of the drug. A major advantage of the drug was the absence of constipation as a side‐effect. 5 This sublingual preparation seems worthy of addition to the commercially available range of analgesics in clinical practice.