bluuebunny/crossref_metadata_2025 huggingface dataset:
EFFECTS ON THE HUMAN CENTRAL NERVOUS SYSTEM OF TWO ISOMERS OF EPHEDRINE AND TRIPROLIDINE, AND THEIR INTERACTION
Authors: BYE C. , DEWSBURY D. , PECK A.W.
Published: July 2012

D(‐)ephedrine is four times as potent as L(+)pseudoephedrine in producing both tachycardia and a rise in systolic blood pressure. No changes in diastolic blood pressure occurred in 12 subjects with doses of up to D(‐)ephedrine (50 mg) and L(+)pseudoephedrine (180mg).

Significant evidence of stimulation of the central nervous system occurred only after D(‐)ephedrine in that tapping rates were increased and subjects could reliably detect that they had received an active drug. While mean performance rates in an auditory vigilance test were higher following both ephedrine isomers these changes were not significant.

Impairment of both tapping rates and auditory vigilance occurred following triprolidine in another group of 12 subjects. The effect was generally related to dose of antihistamine given and lasted up to 7.25 hours. Subjective effects were reliably recognized by subjects following all treatments containing triprolidine (2.5 mg or more) for up to 4.75 hours. Using analogue lines for self rating the subjective effects following triprolidine indicated both mental and physical impairment differing significantly from scores after lactose and L(+)pseudoephedrine (60 mg).

Combination of triprolidine (2.5 mg) and L(+)pseudoephedrine (60 mg) produced effects similar to triprolidine alone on both subjective measures and the auditory vigilance test. It is suggested that these objective tests and subjective scales could be used to measure effects on the central nervous system produced by antihistamines together with similar drugs, and their interaction with other compounds administered concurrently.
THE ASSESSMENT OF β‐ADRENOCEPTOR BLOCKING DRUGS IN HYPERTHYROIDISM
Authors: CARRUTHERS S.G. , GHOSAL A. , McDEVITT D.G. , NELSON J.K. , SHANKS R.G.
Published: July 2012

Intravenous propranolol and practolol both reduced resting supine heart rate in patients with hyperthyroidism. Propranolol produced a significantly greater reduction than practolol, which did not have a dose‐dependent effect.

The effect of these drugs on resting heart rate was much less than their effect on the tachycardias produced both by severe exercise and by standing upright in hyperthyroid patients. Propranolol again produced a significantly greater reduction than practolol in each situation, but practolol did have a dose dependent effect on exercise heart rate.

The percentage reduction of standing tachycardia produced by the two drugs appeared to parallel closely the reduction in exercise tachycardia.

It is concluded that a simple and convenient way of assessing the activity of β‐adrenoceptor blocking drugs in hyperthyroid patients would be to measure their effect on the tachycardia induced by standing. Their effect on resting heart rate should not be used.

Practolol may be useful in the management of hyperthyroidism in patients in whom propranolol and similar non‐selective β‐adrenoceptor blocking drugs are contraindicated.
THE ASSESSMENT OF POTENTIAL DRUG INTERACTIONS WITH A NEW TRICYCLIC ANTIDEPRESSANT DRUG
Authors: BRIANT R.H. , GEORGE C.F.
Published: July 2012

Methods for the investigation of possible interactions with tricyclic antidepressant drugs are described. These methods have been applied to a new compound, Ciba 34276‐Ba, which has been shown to have antidepressant activity.

In five normal volunteers tested before and during treatment with Ciba 34276‐Ba, no abnormalities of resting or post‐exercise electrocardiographs occurred. A three‐fold reduction in tyramine‐responsiveness was seen in three normal subjects studied, but no potentiation of the noradrenaline pressor effect occurred. One of six patients given Ciba 34276‐Ba whilst on long‐term treatment with bethanidine showed loss of blood pressure control.

The metabolic clearance of antipyrine was unaltered in two subjects studied, showing no evidence of induction or inhibition of hepatic microsomal oxidizing enzymes by Ciba 34276‐Ba.
METABOLISM OF TERBUTALINE IN MAN AND DOG
Authors: DAVIES D.S. , GEORGE C.F. , BLACKWELL ELAINE , CONOLLY M.E. , DOLLERY C.T.
Published: July 2012

The metabolism of terbutaline (1‐(3,5‐dmydroxyphenyl)‐2‐tertiarybutylamino‐ethanol), a drug which acts selectively on β2 ‐adrenoceptors has been studied in man and dog.

The sulphate conjugate of terbutaline was the only metabolite identified in plasma or urine from humans or dogs given the drug either orally or intravenously. We have confirmed that terbutaline, a resorcinol derivative, is not a substrate for catechol‐0‐methyl transferase in man or dog.

Metabolism of terbutaline was dependent upon the route of administration in man, but not in dog. In man, oral terbutaline was largely conjugated whereas drug administered intravenously appeared largely unchanged in urine.

Conjugation of oral terbutaline, which probably occurred during the ‘first‐pass’ through the gut wall or liver, was less than oral isoprenaline. This may explain why the poorly absorbed terbutaline is a more effective oral bronchodilator than isoprenaline, even though the latter drug is completely absorbed following oral dosing.
THE EFFECTS OF DRUGS ON ERYTHROCYTES in vitro: HEINZ BODY FORMATION, GLUTATHIONE PEROXIDASE INHIBITION AND CHANGES IN MECHANICAL FRAGILITY
Authors: HOPKINS J. , TUDHOPE G.R.
Published: July 2012

The relationship between mechanical fragility, glutathione peroxidase inhibition and Heinz body formation, in erythrocytes exposed to oxidant drugs in vitro, has been investigated. All drugs tested caused Heinz body formation, and with the exception of acetyl salicylic acid and salicylic acid, also caused increased erythrocyte mechanical fragility.

There was a direct relationship between mechanical fragility and drug concentration. Mechanical fragility increased in parallel with Heinz body formation, with primaquine, gentisic acid, ascorbic acid and potassium chlorate. In contrast Heinz body formation occurred at drug concentrations which did not cause a marked increase in mechanical fragility in the case of menadione, acetyl phenylhydrazine and phenylhydrazine.

The degree of inhibition of glutathione peroxidase was directly related to increased mechanical fragility with menadione, gentisic acid and potassium chlorate. However other substances causing increased mechanical fragility resulted in little or no loss of glutathione peroxidase activity.

The results show that there is no constant relationship between mechanical fragility caused by drugs, the formation of Heinz bodies and the inhibition of glutathione peroxidase. The factors contributing to oxidant drug‐induced haemolysis appear to be variable and depend upon the drug concerned.
EFFECT OF THE IMIDAZOLINE‐DERIVATIVE ST‐91 ON HEART RATE AND BLOOD PRESSURE IN HEALTHY MAN
Authors: SAUNAMÄKI K.I.
Published: July 2012

ST‐91, 2‐(2, 6‐diethylphenylamino)‐2‐imidazoline hydrochloride produces in animal experiments bradycardia, and in larger doses, also hypertension, due to α‐sympathomimetic activity and probable central sympathetic inhibition.

The effects of ST‐91, after oral administration, were studied in 10 healthy volunteers. A dose‐dependent, significant decrease of the heart rate was observed. On average the resting heart rate was reduced by 11–19 beats/min (15–29%). During exercise the decrease of the heart rate was less pronounced. After the largest dose there was a fall of the systolic blood pressure during exercise averaging at 14–15 mmHg (11–12%). Otherwise the blood pressure remained unchanged.

Eight out of the 10 test‐subjects complained of hair‐raising and goose‐flesh after all doses, due to the α‐sympathomimetic effect of the drug. No toxic effects were observed.
HUMAN PERFORMANCE AFTER A BARBITURATE (HEPTABARBITONE)
Authors: BORLAND R.G. , NICHOLSON A.N.
Published: July 2012

The residual effects of heptabarbitone given overnight were studied by an adaptive tracking technique. Decrements in performance were observed at the 10 h interval after 200 mg, at the 10 h and 13 h intervals after 300 mg and at the 10 h, 13 h, 16 h and 19 h intervals after 400 mg of the drug. Decrements in performance at each interval and the persistence of the effects were dose related.

Subjective assessments of performance correlated with measured performance, but the subjects, as a group, over‐estimated their performance after placebo and heptabarbitone. With heptabarbitone (400 mg) highly significant decrements in performance persisted to the 19 h interval after ingestion, but subjective assessments of performance to the 19 h interval did not differ significantly from subjective assessments of control activity of the day before.

Individual blood concentrations of heptabarbitone did not give a significant correlation with individual performance decrements, though the blood concentrations and performance decrements at each dose were related.
PRELIMINARY ASSESSMENT OF RX 72601, A NEW ANTICHOLINESTERASE IN MAN: REVERSAL OF COMPETITIVE NEUROMUSCULAR BLOCKADE
Authors: DETTMAR P.W. , METCALF G. , SMITH M.H. , GILLETT G.B. , HEDGES ANNMARIE , RICHENS A.
Published: July 2012

The effect of RX 72601, neostigmine plus atropine, or saline on neuromuscular blockade with (+)‐tubocurarine was studied in a double blind trial in four healthy male volunteers.

The methods used to assess neuromuscular function were voluntary grip strength and indirectly evoked muscle twitches. The muscarinic action was assessed by measuring intestinal motility with a pressure sensitive radio pill, and auscultation of the abdomen. Blood pressure and pulse rate were also recorded. The degree of acetylcholinesterase inhibition achieved in whole blood was determined before and at intervals after the administration of the anticholinesterases.

Both RX 72601 (0.66‐0.83 mg) and neostigmine (2.5 mg) completely reversed the neuromuscular blockade produced by tubocurarine, but the time course of reversal differed. RX 72601 (0.66‐0.83 mg) produced similar inhibition of acetylcholinesterase in whole blood to neostigmine (2.5 mg). The doses of RX 72601 used caused minimal stimulation at muscarinic sites as evidenced by the limited effect on pulse rate and intestinal activity.

It was concluded that RX 72601 could be safely used to reverse the effects of neuromuscular blockade without the need for premedication with atropine.
AN ASSESSMENT OF GASTRIC EMPTYING BY BREATHALYSER
Authors: FINCH J.E. , KENDALL M.J. , MITCHARD M.
Published: July 2012

A breathalyser has been used to measure blood alcohol levels at short intervals to produce an absorption curve which we have shown is reproducible.

Changes in the rate of absorption which reflect changes in gastric emptying times produced by metoclopromide and propantheline have been demonstrated.

The breathalyser technique described appears to offer a simple method of studying the effects of drugs on the rate of gastric emptying.
THE INFLUENCE OF DIPHENHYDRAMINE ON THE ABSORPTION OF METHAQUALONE IN MAN
Authors: WILLIAMS M.E. , DAVIS S.S. , POXON R. , KENDALL M.J. , MITCHARD M.
Published: July 2012

The effects of diphenhydramine on the buccal absorption, in vivo absorption and the in vitro dissolution of methaqualone have been studied.

Diphenhydramine significantly reduced the buccal absorption of methaqualone and the effect was dose and pH dependent. In vivo, diphenhydramine did not alter the rate of absorption or the distribution of methaqualone in blood. In vitro, the presence of diphenhydramine increased the rate of dissolution of methaqualone and the effect was more marked when the particle size was small.

The reasons for and the implications of these apparently contradictory results are discussed and it is concluded that any increased efficacy resulting from combining diphenhydramine with methaqualone cannot be due to increased plasma drug levels.
THE CLINICAL SIGNIFICANCE OF INDOMETHACIN‐PROBENECID INTERACTION
Authors: BROOKS P.M. , BELL M.A. , STURROCK R.D. , FAMAEY J.P. , DICK W.C.
Published: July 2012

The effect of the addition of probenecid to oral and rectal regimes of indomethacin was studied in three groups of rheumatoid arthritic patients.

The addition of probenecid increases plasma levels of indomethacin given both orally and rectally and significantly reduces the clinical parameters of joint inflammation.

The use of probenecid with indomethacin at night may be useful in reducing morning stiffness and pain. 4 Though indomethacin plasma levels are markedly raised during concurrent probenecid therapy remarkably few side effects were observed.
THE EFFECT OF DIFFERENT NEBULIZERS WITH AND WITHOUT INTERMITTENT POSITIVE PRESSURE BREATHING ON THE ABSORPTION AND METABOLISM OF SALBUTAMOL
Authors: SHENFIELD GILLIAN M. , EVANS MARION E. , PATERSON J.W.
Published: July 2012

The absorption and metabolism of [3H]‐salbutamol have been studied to assess whether intermittent positive pressure breathing (IPPB) or a particular nebulizer have any advantages in delivering bronchodilator drugs to asthmatic patients.

[3H]‐salbutamol (10 mg) was given to asthmatic patients from either the Bird Mark 7 ventilator without intermittent positive pressure, the Bird micronebulizer attached to an electric air compressor, or the Wright's nebulizer attached to the same compressor.

All patients showed a high early plasma level of radioactivity due mainly to free salbutamol. This pattern suggests absorption from the lung and is similar to that seen after giving the drug from the Bird nebulizer using IPPB.

In all cases less than 20% of the original dose was absorbed by the patient.

Improvement in forced expiratory volume in one second (FEV1) was seen with all three treatments.
A PILOT STUDY OF ORALLY ADMINISTERED Δ1‐TRANS‐TETRAHYDROCANNABINOL IN THE MANAGEMENT OF PATIENTS UNDERGOING RADIOTHERAPY FOR CARCINOMA OF THE BRONCHUS
Authors: DAVIES B.H. , WEATHERSTONE R.M. , GRAHAM J.D.P. , GRIFFITHS R.D.
Published: July 2012

Δ1 ‐trans‐tetrahydrocannabinol (Δ1‐THC; 10 mg) or a placebo was given orally on 7 days to two groups of six patients on a cross‐over pattern with 7 days rest between.

The patients were hospitalized, suffering from inoperable bronchogenic carcinoma, subjected to radiation therapy, and anxious.

Self‐rating mood scales were filled in before, and 2 and 6 h after ingestion on the first and seventh day of medication.

Records of sleep, pain, general well‐being, temperature, cardiovascular and gastrointestinal parameters were kept.

Δ1‐THC caused drowsiness and improved night sleep, reduced pain, increased fatigue and confusion and reduced elation and vigour; it caused slight tachycardia and hypotension as also did placebo.

The effects of Δ1‐THC were stronger after 2 h than 6 h and no tolerance had developed at 7 days.

The management of stressful patients was considered to have been improved by the drug.
THE EFFECT OF β‐ADRENOCEPTOR BLOCKADE ON BODY TEMPERATURE AND PLASMA RENIN ACTIVITY IN HEAT‐EXPOSED MAN
Authors: BERLYNE G.M. , FINBERG J.P.M. , YORAN C.
Published: July 2012

1 The effect of propranolol (5 mg i.v.) on rectal and skin temperatures, heart rate, blood pressure, plasma renin activity (PRA) and plasma renin substrate concentration (PRS) was investigated in twelve men exercising in the heat. The effect of practolol (10 mg i.v.) on PRA was investigated in five men. 2 Body temperatures were insignificantly affected by propranolol, while heart rate elevation in response to exercise in the heat was 21% lower than in the same subjects receiving saline. Diastolic blood pressure during exercise was elevated by propranolol. 3 The normal increase in PRA seen in heat exposure was suppressed by propranolol to levels seen when the same exercise was carried out at 25° C. Practolol did not affect the renin response to heat exposure. 4 PRS was not altered significantly by exercise or heat. 5 The results indicate that the increase in PRA seen in the heat is largely a result of increased sympathetic activity.
PHYSIOLOGICAL AND PSYCHOLOGICAL EFFECTS OF ±‐PROPRANOLOL, +‐PROPRANOLOL AND DIAZEPAM IN INDUCED ANXIETY
Authors: TYRER P.J. , LADER M.H.
Published: July 2012

Four equal‐sexed groups of eight normal subjects were given single doses of either (±)‐propranolol (120 mg), (+)‐propranolol (120 mg), diazepam (6 mg) or placebo using double‐blind procedure and their effects studied under three types of experimental stress and at rest.

Finger tremor, EEG, averaged auditory evoked response, skin conductance, heart rate and respiratory rate were measured at each time of testing, and subjects also completed performance tests (reaction time, tapping speed and symbol copying) and subjective mood scales.

Neither (+)‐ nor (±)‐propranolol had any beneficial effects on mood and physiological tests showed that, although adequate β‐adrenoceptor blockade was achieved, there was no evidence of sedation.

Diazepam reduced subjective anxiety, significantly lessened the main amplitude of the auditory evoked response and also reduced the proportion of slower rhythms in the EEG.

The results suggest that (+)‐ and (±)‐propranolol have no psychotropic effects on induced anxiety and that their modes of action are fundamentally different from that of diazepam.
PHYSIOLOGICAL RESPONSE TO PROPRANOLOL AND DIAZEPAM IN CHRONIC ANXIETY
Authors: TYRER P.J. , LADER M.H.
Published: July 2012

Twelve chronically anxious psychiatric out‐patients, comprising six with somatic anxiety and six with psychic anxiety, were treated with (±)‐propranolol, diazepam and placebo for one week each in flexible dosage using a balanced cross‐over experimental design.

After each treatment, in addition to ratings completed by patient and psychiatrist, finger tremor, EEG, averaged auditory evoked response, skin conductance, heart and respiratory rate were measured.

Diazepam significantly increased the amount of fast activity (13.5–26 Hz) in the EEG but produced few peripheral effects apart from a reduction in finger tremor.

Propranolol had no central physiological effects but reduced both pulse rate and finger tremor.

The physiological effects of propranolol in chronic anxiety are different from those of diazepam and therapeutic benefit appears to be due to a direct effect on certain somatic symptoms.
THE CLINICAL PHARMACOLOGY OF SALMEFAMOL
Authors: EVANS MARION E. , SHENFIELD GILLIAN M. , PATERSON J.W.
Published: July 2012

The absorption, excretion and metabolism of [3H]‐salmefamol, a new sympathomimetic bronchodilator drug, have been studied in asthmatic patients.

Following oral administration of 1 or 2 mg to four patients the drug was well absorbed, peak plasma levels occurring from 0.6‐2.0 h after administration. An improvement in forced expiratory volume in 1 s (FEV1) (ranging from 12–50% above baseline) was seen.

Following aerosol administration of 0.22‐0.34 mg to four patients a rapid rise in FEV1 was seen (range 26–117%). The plasma and urinary pictures following this route were similar to those seen after oral administration, suggesting that the majority of the dose was swallowed.

Very little free salmefamol was found in plasma or urine, the majority being present as metabolites. Urinary radioactivity was mainly present in the form of sulphate conjugates of at least two compounds, one of which was salmefamol. The other compound has not been identified but it is suggested that it may be an active metabolite.
THE INFLUENCE OF ELEVATED PLASMA HYDROCORTISONE CONCENTRATIONS ON ANTIPYRINE METABOLISM IN MAN
Authors: FLANAGAN R.J. , RICHENS A.
Published: July 2012

The plasma half‐life of antipyrine was estimated overnight in four healthy volunteers on two separate occasions, one during i.v. infusion of hydrocortisone (3 mg/h) and the second during an infusion of normal saline.

The plasma fluorogenic corticosteroid concentration averaged 12.5 μg/100 ml during saline infusion, increasing to 20.1 μg/100 ml during hydrocortisone infusion.

The mean antipyrine half‐life increased from 9.7 h during saline infusion to 12.6 h during hydrocortisone infusion.

No consistent change was found in the apparent volume of distribution or urinary excretion of antipyrine, or of the urinary excretion of D‐glucaric acid.

The stimulation by hydrocortisone of antipyrine metabolism demonstrated by other workers has not been found.
THE ABSORPTION AND METABOLISM OF A STANDARD ORAL DOSE OF LEVODOPA IN PATIENTS WITH PARKINSONISM
Authors: BERGMANN S. , CURZON G. , FRIEDEL J. , GODWIN‐AUSTEN R.B. , MARSDEN C.D. , PARKES J.D.
Published: July 2012

The metabolism of a standard oral dose of levodopa was studied in forty‐two patients with Parkinsonism. Plasma levodopa and 3‐o‐methyldopa concentrations were estimated at intervals for 8 h after ingestion and the concentration of homovanillic acid (HVA) in the lumbar cerebrospinal fluid (CSF) was measured at 8 hours. Clinical responses 3 months after the test were compared with these findings.

Although therapeutic benefit correlated significantly with calculated estimates of both plasma levodopa concentration and CSF HVA at optimal levodopa dose, individual values were widely scattered. There was no significant correlation between toxic effects and plasma levodopa or CSF HVA; and 3‐o‐methyldopa concentrations similarly did not show a significant correlation with either toxic or therapeutic effects.

Blood and CSF levels of levodopa or the metabolites measured in this study were not significantly altered by concurrent treatment with either anticholinergic drugs or amantadine nor by previous treatment with levodopa.
ACETYLATION OF PROCAINE AMIDE IN MAN STUDIED WITH A NEW GAS CHROMATOGRAPHIC METHOD
Authors: KARLSSON E. , MOLIN LILIAN , NORLANDER B. , SJÖQVIST F.
Published: July 2012

A specific gas‐chromatographic method was developed for determination of N‐acetylprocaine amide in plasma and urine, using 4‐amino‐N‐(2‐piperidinoethyl)benzamide as an internal standard. The investigation was performed in 50 cardiac patients who had reached steady‐state plasma concentrations of procaine amide.

The plasma concentrations of the acetylated metabolite varied between 1.0 and 15.0 μg/ml and were thus of the same order of magnitude as those of the parent drug. Especially high plasma levels of the metabolite were seen in patients with poor kidney function.

The urinary excretion of the metabolite varied markedly between individuals and ranged between 6 and 52% of the administered daily dose. There was a clear tendency towards higher rates of acetylation of procaine amide in patients with short plasma half‐lives of isoniazid, i.e. the phenotype rapid acetylators. Because of coexisting therapy with other drugs and impaired renal function in some patients studies are required in healthy human volunteers to ascertain whether the acetylation of procaine amide and isoniazid are mediated by the same enzyme system.
THE EFFECTS OF ORAL AH 5158, A COMBINED α AND β‐ADRENOCEPTOR ANTAGONIST, IN HEALTHY VOLUNTEERS
Authors: RICHARDS D.A. , WOODINGS E.P. , STEPHENS M.D.B. , MACONOCHIE J.G.
Published: July 2012

In healthy male volunteers after single oral doses, AH 5158 produced inhibition of exercise induced tachycardia, falls in systolic and diastolic pressure at rest and in response to exercise, which are probably related to combined β‐ and α‐adrenoceptor antagonism.

At increasing doses from 100 mg to 400 mg there exists a dose related antagonistic effect, though the dominant effect of β‐adrenoceptor antagonism is more easily demonstrable than is α antagonism.

As indicated by the pattern of pharmacological effects, absorption of the oral drug is good and the duration of action of a 400 mg dose is approximately 8 hours.

Despite being administered in β‐adrenoceptor blocking doses, AH 5158 had no adverse effects upon peak expiratory flow at rest or in response to exercise.

It is concluded that the pharmacological profile of this combined α‐ and β‐adrenoceptor antagonism suggests a potential therapeutic role as an antihypertensive drug.
PLASMA DOPA CONCENTRATIONS AFTER DIFFERENT PREPARATIONS OF LEVODOPA IN NORMAL SUBJECTS
Authors: MORRIS J.G.L. , PARSONS R.L. , TROUNCE J.R. , GROVES M.J.
Published: July 2012

The concurrent administration of levodopa with a decarboxylase inhibitor produced a plasma concentration/time curve comparable with 1/4 to 1/5 of the dose of levodopa given alone.

There was no evidence to suggest that the decarboxylase inhibitor slowed the rate of elimination of levodopa from plasma.

Metoclopramide (Maxolon) increased the rate of levodopa absorption. Higher plasma concentrations of levodopa during the first 2 h after dosing were followed by lower plasma concentrations during the third and fourth hours. The amount of levodopa absorbed after Larodopa as indicated by the AUC was not altered by adding metoclopramide.

None of the current preparations of levodopa produced sustained plasma concentrations.

In vitro testing confirmed that Brocadopa Temtabs tablets disintegrate and dissolve slowly. In vivo, Brocadopa Temtabs behaved as a slow release preparation but it did not produce sustained plasma concentrations of levodopa.
BIOTRANSFORMATION AND EXCRETION OF LORAZEPAM IN PATIENTS WITH CHRONIC RENAL FAILURE
Authors: VERBEECK R. , TJANDRAMAGA T.B. , VERBERCKMOES R. , DE SCHEPPER P.J.
Published: July 2012

To evaluate the effect of end‐stage renal insufficiency and haemodialysis on the elimination of lorazepam, single oral doses of the drug (2.5 mg) were administered to normal subjects and patients with chronic renal failure (Ccr: less than 2 ml/min) in the interdialysis period and during haemodialysis.

The concentration of lorazepam and its major metabolite, lorazepam‐glucuronide, were assayed using electron capture g.1.c.

Plasma half‐life (T1/2) of unchanged lorazepam in the patient group (11.3 ± 0.6 h) was not different from that obtained in normals (11.1 ± 0.9 h).

Only minor quantities of the unchanged drug could be recovered in the 24 h urine in both groups: 0.3% of the ingested dose in normals and trace amounts in the patient group.

No unchanged lorazepam could be detected in the ultrafiltrate from the coil kidney. Since the lower sensitivity of the method is about 5 ng/ml, this would indicate the in vivo binding of the active drug to plasma proteins to be at least 70%.

The effect of haemodialysis on lorazepam plasma T1/2 was also insignificant (9.4 ±1.0 h).

Urinary excretion of lorazepam‐glucuronide was found to be considerably decreased in chronic renal failure associated with accumulation of high concentrations of this conjugate in plasma during days after a single oral dose. The plasma T1/2 of this conjugate in normals was 20.7 ± 2.1 h.

Roughly 35% of this main metabolite's concentration in plasma was detected in the ultrafiltrate from the coil kidney indicating the dialyzability of this conjugate and that the extent of plasma protein binding of lorazepam‐glucuronide in vivo was approximately 65%.

The above results indicate that after a single oral dose (2.5 mg) the biotransformation of lorazepam to its glucuronide conjugate remains unaltered and that high concentrations of this metabolite accumulate in plasma in the presence of severe renal function impairment.
Assessment of drugs in schizophrenia. Asessment of drug‐induced extrapyramidal reactions and of drugs given for their control.
Authors: Mindham RHS
Published: July 2012

I have tried to bring out some of the important methodological problems found in examining the effectiveness of drugs used in the control of druginduced parkinsonism by referring mainly to studies in which I have taken part. I hope I have shown that the whole topic is far less well understood than is often assumed. The main points may be summarized as follows: there is doubt as to whether many of the drugs used in controlling drug‐induced parkinsonism are really effective; the results of many studies are conflicting; many studies contain serious flaws in design; methods for assessing extrapyramidal signs are not well developed; we are ignorant of the way in which drug‐induced extrapyramidal signs change spontaneously. There is a clear need for further research in this area to improve techniques of assessment, to provide basic information on drug‐induced syndromes, and to rigorously examine the efficacy of the drugs used in controlling them.
EFFECT OF DIAZEPAM AND FOSAZEPAM (A SOLUBLE DERIVATIVE OF DIAZEPAM) ON SLEEP IN MAN
Authors: NICHOLSON A.N. , STONE BARBARA M. , CLARKE CORAL H.
Published: July 2012

The effect of diazepam (5 mg and 10 mg), and fosazepam (60 mg and 80 mg), a soluble derivative of diazepam, on sleep was studied in six healthy adult males using electroencephalography for sleep measures, and analogue scales for subjective assessments of well‐being and sleep quality. The effect of diazepam was limited to the night of ingestion, but the effect of fosazepam was carried over to the next night and so modified sleep for about 30 h after ingestion.

Effects on total sleep time were limited to the night of ingestion. There were increases with diazepam (10 mg) (P=0.05), and with fosazepam (60 mg and 80 mg) (P = 0.001). For the night of ingestion sleep onset latencies were shortened, and awakenings were reduced by both drugs. The latency to stage 3 was shortened by fosazepam (60 mg and 80 mg) (P = 0.05).

The low and high dose of each drug reduced the duration (min) of stage 0 sleep (P = 0.01), but fosazepam also reduced the duration (min) of stage 1 sleep (P = 0.001), and there was an increase in stage 2 sleep (P = 0.01). With fosazepam there were carry over effects to the next night with reduction of stage 1 sleep (P = 0.05). There were no effects on the duration of stage 3, but there was evidence that stage 4 activity was reduced during the recovery night after ingestion of fosazepam (80 mg). No effects were observed on REM sleep.

Subjects reported an improved sense of well‐being during the day after ingestion of diazepam and fosazepam, and with fosazepam they reported improved sleep. Correlations were calculated for sleep measures and subjective assessments.
EFFECT OF A METABOLITE OF DIAZEPAM, 3‐HYDROXYDIAZEPAM (TEMAZEPAM), ON SLEEP IN MAN
Authors: NICHOLSON A.N. , STONE BARBARA M.
Published: July 2012

The effect of 3‐hydroxydiazepam (temazepam, 10 mg and 20 mg) on sleep was studied in six healthy adult males using electroencephalography for sleep measures, and analogue scales for subjective assessments of well‐being and sleep quality. The effects were compared with diazepam (5 mg and 10 mg).

Effect on total sleep time was restricted to the night of ingestion. There was no change in total sleep time after temazepam (10 mg), but with 20 mg total sleep time was increased (P = 0.01). Sleep onset latencies and awakenings were markedly reduced.

Temazepam reduced the duration (min) of stage 0 (P = 0.05) and stage 1 (P = 0.01) sleep, and the effect on stage 1 was seen during each two hourly interval of sleep (P= 0.05). No effects were observed with stage 3, 3+4 and REM sleep, except that the appearance of the first REM period was delayed with temazepam (20 mg) (P = 0.001).

The subjects, as a group, reported improved sleep, but subjective assessments of well‐being were not altered. Correlations were calculated for sleep measures and subjective assessments.
A COMPARISON OF SOME PHYSIOLOGICAL AND PSYCHOLOGICAL EFFECTS OF PROPRANOLOL AND DIAZEPAM IN NORMAL SUBJECTS
Authors: ASHTON HEATHER , MILLMAN J.E. , TELFORD ROSEMARY , THOMPSON J.W.
Published: July 2012

Some central and peripheral effects of orally administered propranolol (60 mg), diazepam (5 mg) and placebo were compared in normal subjects.

The central effects measured were changes in magnitude of the contingent negative variation (CNV) and subjective anxiety ratings; the peripheral effects were changes in heart rate, blood pressure, galvanic skin response and hand steadiness.

After diazepam there was a decrease in CNV magnitude and in the level of subjective anxiety; there was a slight fall in blood pressure but little change in heart rate.

After propranolol, on the other hand, there was no significant change in CNV magnitude or anxiety rating, but a significant fall in heart rate and systolic blood pressure.

It is concluded that, at the dosage used, propranolol, unlike diazepam, does not affect the central mechanisms determining CNV magnitude or subjective anxiety. The relationship of this finding to the use of β‐adrenergic receptor blockers in clinical anxiety states is discussed.
CSF CONCENTRATIONS AND SERUM PROTEIN BINDING OF CARBAMAZEPINE AND CARBAMAZEPINE‐10, 11‐EPOXIDE IN EPILEPTIC PATIENTS
Authors: JOHANNESSEN S.I. , GERNA M. , BAKKE J. , STRANDJORD R.E. , MORSELLI P.L.
Published: July 2012

Serum and CSF samples of patients receiving chronic carbamazepine treatment were analysed.

Daily fluctuations in serum levels of carbamazepine and carbamazepine‐10, 11‐epoxide did not appear to be related to the dosage schedule, but some patients tended to have lower fluctuations when the carbamazepine was given more frequently.

The epoxide/carbamazepine serum ratios varied greatly from patient to patient, and also fluctuated during the day for the same patient.

Carbamazepine and carbamazepine‐10, 11‐epoxide were present in CSF in concentrations ranging from 19 to 34% and 26 to 71% of the serum concentrations, respectively.

There was a significant relationship between the free fraction of both drugs evaluated in vivo and the CSF/serum ratios.

The need for a careful evaluation of the possible clinical effect of the epoxide is stressed.
COMPARISON OF ORAL THEOPHYLLINE AND SALBUTAMOL BY INHALATION IN ASTHMATIC PATIENTS
Authors: HARTNETT B.J.S. , MARLIN G.E.
Published: July 2012

The bronchodilator effects of 375 mg theophylline orally and 200 μg salbutamol by pressurized aerosol were compared in a randomized, cross‐over, double‐blind trial in fourteen asthmatic patients.

The mean peak percentage FEV1 increase from control was 43.7% at 60 min after salbutamol and 30.3% at 180 min after theophylline.

Salbutamol produced significantly greater bronchodilatation than theophylline for the initial 30 min (P<0.01).

Theophylline demonstrated a longer duration of action than salbutamol, with a significantly greater FEV1 response at 360 min (P < 0.02).

There was no significant difference between the total effect of each drug for the 360 min period, as calculated by the areas under the respective FEV1 response curves.
CANRENONE—THE PRINCIPAL ACTIVE METABOLITE OF SPIRONOLACTONE?
Authors: RAMSAY L.E. , SHELTON J.R. , WILKINSON D. , TIDD M.J.
Published: July 2012

The properties of the aldosterone antagonists spironolactone and potassium canrenoate in tablet formulations were examined in two studies in healthy subjects, the first study comparing levels of their common major metabolite, canrenone, in plasma and the second study comparing the pharmacological activity of the two drugs in reversing the renal effects of the synthetic mineralocorticoid fludrocortisone.

At equal dosage by weight potassium canrenoate yielded peak levels and areas under the curve for canrenone in plasma which were significantly lower than those for spironolactone, and the peak level of canrenone was reached significantly later. Comparison with published work suggests that the experimental formulation of potassium canrenoate had low bioavailability.

Spironolactone produced statistically valid log dose‐response curves against fludrocortisone as regards sodium excretion, potassium retention and increased urine sodium to potassium ratio. There was no significant log dose‐reponse after potassium canrenoate, and a statistically valid estimate of relative potency could not be obtained.

The results of the two studies seem inconsistent with the view that canrenone alone is responsible for the pharmacological activity of both drugs, and suggest that a significant part of the activity of spironolactone may be attributable to metabolites other than canrenone.
FACTORS INFLUENCING THE ABSORPTION AND DISPOSITION OF MECILLINAM AND PIVMECILLINAM IN MAN
Authors: ANDREWS J. , KENDALL M.J. , MITCHARD M.
Published: July 2012

In a pharmacokinetic study in six volunteers peak serum mecillinam concentrations were proportional to the oral dose of pivmecillinam at two dose levels of 200 and 400 mg.

Effects of bed rest, probenecid and a 6 day course of treatment with pivmecillinam on serum mecillinam concentrations after an oral dose of pivmecillinam (two 200 mg capsules) have been investigated.

Resting subjects had lower peak serum levels and a decreased rate of clearance than moderately active subjects, changes which are similar to those previously reported for benzylpenicillin.

Pretreatment with probenecid produced significantly higher serum mecillinam levels, a longer serum antibiotic half‐life and a decreased rate of drug clearance which suggests that mecillinam is actively excreted by kidney tubules.

Plasma mecillinam level profiles obtained after the first dose of a 6 day treatment period were not significantly different from corresponding values after the first dose on the seventh day which indicates that each dose of mecillinam is eliminated in healthy young adults before succeeding doses are taken.
INTERACTION BETWEEN CHOLINEA THEOPHYLLINATE AND SALMEFAMOL IN PATIENTS WITH REVERSIBLE AIRWAYS OBSTRUCTION: Study by the British Thoracic and Tuberculosis Association
Authors: DYSON A.J. , CAMPBELL I.A.
Published: July 2012

In 54 patients with reversible airways obstruction, a study of the interaction between oral choline theophyllinate (a methyl xanthine derivative) and oral salmefamol (a β2‐adrenergic receptor stimulant) showed that on peak flow their effect was additive, but failed to demonstrate synergy. The only example of statistically significant synergy was their combined effect on the patients' tremor of the hands.
Diflunisal: efficacy in postoperative pain.
Authors: Van Winzum C , Rodda B
Published: July 2012

1. Seven hundred and forty patients complaining of pain after oral or orthopaedic surgery or episiotomy were studied in five single dose or short‐term double‐blind, controlled, randomized studies comparing efficacy and safety of diflunisal with that of acetylsalicylic acid, glafenin or placebo. 2. Diflunisal was found to be effective in relieving postoperative pain in 75‐85% of patients. A twice day dosage schedule seems to be clinically adequate, 375 mg twice daily proving to be equally effective as glafenin 200 mg three times daily. No serious drug‐related clinical or laboratory adverse experiences were encountered in any of the five studies.
Experience of the use of beclomethasone dipropionate aerosol in general practice.
Authors: Gregg I
Published: July 2012

1. The findings of an open trial of beclomethasone dipropionate aerosol (BDA), carried out in 1972 in the author's general practice, are discussed in the light of subsequent, more extensive experience of its use of BDA. 2. An important reason why BDA may be unsuccessful in controlling asthma, and may give rise to various problems, is that patients are often given an inadequate explanation of the purpose and proper use of this treatment.
Effects of beclomethasone dipropionate aerosol on nasal mucosa.
Authors: Mygind N
Published: July 2012

Rhinoscopic examination and histological studies of the nasal mucosa in patients with perennial allergic rhinitis and nasal polyposis treated with beclomethasone dipropionate aerosol provided no evidence that this form of treatment, given for one year, produced any harmful effects, such as atrophic rhinitis.
Determination of nomifensine by a sensitive radioimmunoassay.
Authors: Heptner W. , Badian MJ , Baudner S. , Christ OE , Fraser HM , Rupp W. , Weimer KE , Wissmann H.
Published: July 2012

1. A radioimmunoassay (RIA) has been developed for determination of both nomifensine and total nomifensine (nomifensine + conjugated nomifensine) in serum, plasma, and urine. 2. Antibodies were prepared in rabbits by immunization with N‐(8‐Nomifensine) succinamic acid‐ bovine serum albumin. 3H‐labelled drug was used as tracer. Separation of free from antibody‐bound nomifensine was carried out using dextran‐ coated charcoal. For determination of total nomifensine, the acid‐ labile conjugate was split by acidification. 3. The limit of detection for nomifensine is 300 pg/ml plasma and the cross‐reactivity of the metabolites is less that 1%. The influence of conjugated nomifensine on the results of nomifensine can be corrected. 4. Pharmacokinetics of nomifensine were determined in healthy volunteers after oral administration of 100 mg 14C‐labelled drug. Peak levels of 14C radioactivity (2,150 ng/ml), total nomifensine (1,252 ng/ml) and nomifensine (53 ng/ml) appeared within 1.5‐2 h; the half‐life of elimination from plasma was 1.5‐2 hours. The advantages of this routine method are high sensitivity, the requirement of small amounts of plasma, and simple handling.
Pharmacokinetics of nomifensine in impaired renal function.
Authors: Ringoir S. , Lameire N. , Munche M. , Heptner W. , Taeuber K.
Published: July 2012

1. In uremia, an increased frequency of adverse drug reactions is observed at elevated plasma levels of active drug. This is a consequence of decreased renal elimination of unchanged drug or pharmacologically active metabolites. 2. To study the pharmacokinetics of nomifensine in uremia, a single dose of nomifensine maleate 50 mg was given to 10 patients with a glomerular filtration rate between 0 and 61 ml/min. In three additional patients on maintenance haemodialysis, the influence of dialysis on the elimination of nomifensine after single oral doses of 50 mg was studied. 3. Blood samples were obtained before and at regular half‐hourly or hourly intervals after administration. Plasma levels of nomifensine were examined using a radioimmunological determination method and pharmacokinetic parameters were calculated by computer program. 4. Whereas in healthy subjects the half‐life of nomifensine was found to be 1.8 h, this parameter was found to be prolonged in renal patients. In a patient with a creatinine clearance of 0 ml/min the elimination half‐life was 46 hours. Nomifensine is not eliminated by haemodialysis. 5. Our findings suggest that nomifensine should not be administered to renal patients with a glomerular filtration rate below 25 ml/minute.
Laboratory investigation of effect of acute doses of nomifensine on a simulated aspect of night‐time car driving performance.
Authors: Hindmarch I.
Published: July 2012

1. Six healthy volunteers received single doses of either nomifensine 100 mg, nomifensine 50 mg or placebo at weekly intervals in a randomized double‐blind crossover study. 2. Subjects were subjected to a simulated test of car driving at night. 3. Testing lasted about 1.5 h and consisted of measuring responses to light stimuli, a modification of a test designed by Baker & Theologus (1972). 4. Nomifensine 100 mg reduced the latency of response significantly when compared with placebo (P less than 0.05). Nomifensine 50 mg had no significant effect. 5. It was concluded that nomifensine was unlikely to impair night driving performance.
Controlled study comparing nomifensine and clomipramine in unipolar depression, using the probenecid technique.
Authors: Van Scheyen JD , Van Praag HM , Korf J.
Published: July 2012

1. Central dopamine turnover may be lowered in patients with unipolar endogenous depression particularly when associated with retardation. 2. Nomifensine selectively activates the central dopaminergic system and may be of special therapeutic value in patients with motor inhibition. 3. A double‐blind comparison of clomipramine and nomifensine was carried out in patients with recurrent unipolar depression. Biochemical and clinical assessments were carried out weekly for 4 weeks. 4. The mean homovanillic acid level in cisternal liquor of those patients who responded to nomifensine, was significantly lower than the mean level of the total group. 5. The factor “retardation” on the Hamilton Depression Scale was improved more with nomifensine than with clomipramine.
Comparison of nomifensine and placebo.
Authors: Taeuber K.
Published: July 2012

1. Methodological reasons are discussed which make placebo‐controlled trials on antidepressant drugs necessary. 2. The ethical problem of treating a sick patient with an inactive compound are shown to have an impact on the methodology of such trials. 3. Three double‐blind placebo‐ controlled trials with nomifensine are reviewed; one in neurotic depression, one in psychotic depression and one in geriatric patients showing depressive symptoms. 4. In all three trials the effect of nomifensine has been shown to be superior to that of placebo.
A review of controlled studies with nomifensine, performed outside the UK.
Authors: Habermann W.
Published: July 2012

1. Double‐blind controlled comparisons of nomifensine with placebo, imipramine, desipramine, viloxazine, nortriptyline, a combination of amitriptyline and chlordiazepoxide, and diazepam have been carried out in various parts of the world. 2. Dosage ranged from 50‐225 mg daily, and treatment lasted from 2‐26 weeks. 3. Nomifensine was shown to possess useful antidepressive activity, to counteract inhibition, to restore drive and to relieve anxiety. 4. Adverse reactions were uncommon, particularly anticholinergic effects, and nomifensine was not shown to cause sedation or to interact with alcohol. No withdrawal phenomena were observed after 6 months' treatment. 5. Nomifensine is not suitable for severely agitated patients.
A comparative review of the pharmacology of nomifensine.
Authors: Hoffmann I.
Published: July 2012

1. Nomifensine is a new substance which showed, in tests for antidepressant activity, a pronounced effect which is quantitatively better than that of the reference substances. 2. With regard to thymoleptic effects in animal studies the effect of nomifensine is similar to that of tricyclic antidepressants, but nomifensine has no pronounced anticholinergic activity. 3. Nomifensine influences the cardiovascular system very slightly. 4. The mechanism of action of nomifensine differs from that of tricyclic antidepressants and must be clearly differentiated from phenylalkyl amines with sympathomimetric activity. 5. Nomifensine is a compound with a special, new profile of action, and thus cannot be calssified in known categories.
(+)‐Propranolol clearance, an estimation of hepatic blood flow in man.
Authors: Weiss YA , Safar ME , Lehner JP , Levenson JA , Simon A , Alexandre JM
Published: July 2012

1 Hepatic blood flow was determined before and during (+)‐ and (+/‐)‐ propranolol plasma concentration plateaus in 19 patients with suspected renal hypertension and normal liver function. 2 Hepatic blood flow significantly decreased (P less than 0.001) during (+/‐)‐propranolol administration and remained unchanged during (+)‐propranolol administration. 3 Hepatic extraction ratio was 74 +/− 1% (+/‐)‐ propranolol and 79 +/− 2% for (+)‐propranolol. 4 Total propranolol clearances were determined during the steady‐state achieved by a constant infusion. A highly significant positive relationship was observed (r = +0.86; P less than 0.01) between hepatic blood flow and (+)‐propranolol clearance. The slope of the curve was 1.05 +/− 0.27. 5 The result implies that the total clearance of (+)‐propranolol constitutes an accurate estimation of basal hepatic blood flow in subjects with normal liver function.
Influence of soft gelatin on digoxin absorption.
Authors: O'Grady J , Johnson BF , Bye C , Sabey GA
Published: July 2012

1 The influence of encapsulation in soft gelatin on the absorption of digoxin from a solvent mixture of polyethylene glycol 400 90% W/W, ethanol 6% W/W, propylene glycol 3% W/W and water 1% W/W was studied in eight healthy volunteers. 2 Each volunteer received 0.6 mg digoxin as solution alone, as three intact capsules containing digoxin solution, as three capsules containing digoxin solution sectioned in half and as three capsules containing digoxin solution dissolved in water prior to administration. 3 There was no significant difference between the four treatments in terms of area under the plasma concentration‐time curves for 7 h, peak plasma concentrations, time to peak or in the cumulative urinary excretion for 6 days. 4 It is suggested that a constituent of the solvent rather than the presence of or encapsulation within soft gelatin may be the determining factor in enhanced absorption of digoxin from soft gelatin capsules as compared to aqueous solution or tablets of rapid dissolution rate.