bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recent advances in the clinical pharmacology of benzodiazepines part I: Pharmacokinetics
Authors: Saletu B. , Pakesch G. 
Published: December 2004

AbstractTranquillizers, and specifically benzodiazepines (BZD), have become one of the most widely used group of drugs in the world; some have suggested too widely used. Interest in these drugs is still extremely high, both from the scientific and sociological point of view. This is best documented by the fact that the present review is based on more than 700 articles published between 1981 and 1984 covering various aspects of clinical pharmacology. Pharmacokinetic studies dealing with absorption, metabolism and elimination after acute and chronic administration demonstrate that the onset and duration of action of BZD after single oral doses depend largely on absorption rate and the rate and extent of distribution. The rate and extent of accumulation during multiple dosage depend on the elimination half‐life and clearance. A framework is proposed for classification of BZD according to the elimination half‐life. Various factors — such as age, sex, disease state and drug interaction — influence the pharmacokinetic properties of BZD. Pharmacodynamic studies are mostly concerned with effects of the drug on the central nervous system (CNS), as well as on behaviour and neuroendocrine functions. The former include computer‐assisted quantitative analyses of the scalp‐recorded wake electroencephalogram (EEG), based on which it seems possible to determine if, how, when and at what dose a newly developed compound affects the human brain. Sleep investigations are now concerned not only with the effect of the drug on the all‐night sleep, but also on the quality of awakening and early morning behaviour as well as with residual effects during daytime, affecting mnestic and cognitive functions, psychomotor performance (specifically in regard to driving ability), as well as mood and affectivity. Finally, for almost a decade increasing concern has been expressed about the widespread use of tranquillizers in society. Scientific evidence concerning this issue will be reviewed so that an appropriate medical decision may be reached for the treatment of the individual patients after consideration of the beneficial effects as well as undesirable side‐effects.
Tardive dyskinesia in schizophrenia and other disorders: Associations with ageing, cognitive dysfunction and structural brain pathology in relation to neuroleptic exposure
Authors: Waddington J. L. 
Published: December 2004

AbstractLittle is known of the processes which confer vulnerability to the emergence of involuntary movements (tardive dyskinesia) in only a proportion of patients receiving long‐term treatment with neuroleptic drugs. There is no consistent evidence that patients with involuntary movements have received either longer or more vigorous pharmacotherapy, and it has proved difficult to demonstrate any general relationship between increasing neuroleptic exposure and the emergence of the syndrome. Advancing age may be associated more with deleterious changes in the central nervous system within individual patients that can raise vulnerability to the emergence of involuntary movements, than with particular predisposing patterns of neuroleptic exposure. The literature in schizophrenic patients reveals that two indirect and putative indices of ‘organicity’, namely cognitive dysfunction and negative schizophrenic symptoms, together with several CT indices of structural brain pathology, show similar and robust associations with the presence of involuntary movements. In schizophrenia, predisposition to the emergence of involuntary movements during long‐term neuroleptic therapy appears intimately related with particular features of the illness, especially those associated with clinical deterioration. It is argued from clinical and animal studies that neuroleptics may hasten the appearance of dyskinetic movements in individuals with the greatest likelihood of ultimately having such movements spontaneously as cerebral deterioration proceeds.
Temazepam as a hypnotic in osteoarthritic patients
Authors: Leigh T. J. , Hindmarch I. , Bird H. A. , Wright V. 
Published: December 2004

AbstractThe effects of nocturnal temazepam elixir on 14 male osteoarthritic patients and 16 age‐ and sex‐matched healthy controls were investigated in a double‐blind parallel groups study. Temazepam produced a number of significant changes in objective sleep. In the osteoarthritic patients temazepam reduced the duration of awakenings, percentage stage 0, percentage stage 1, percentage stages (0+1) and increased percentage stage 2 and REM latency. In the controls temazepam reduced the duration of awakenings, percentage stage 0, percentage stages (0+1) and increased percentage stage 2, sleep efficiency and REM latency. During the drug period, seven out of 15 subjects receiving temazepam reported improved sleep, compared with one out of 15 placebo subjects. There was no evidence to suggest that temazepam caused any unwanted side‐effects or affected the duration of morning stiffness in osteoarthritic patients. Temazepam produced no significant impairment of early morning psychomotor performance or significant withdrawal effects in either patients or controls.
The effects of practice on measures of performance
Authors: McClelland G. R. 
Published: December 2004

AbstractThe effects of practice on a range of performance measures often used in studies of psychoactive drugs have been assessed in 50 normal healthy adult volunteers, during 10 practice sessions over an 8‐day period. There was no dramatic effect of practice on any of the parameters measured, only one of the mean values at the tenth session exceeded one standard deviation of the mean of the first session (manipulative motor task). Practice did not materially affect performance on elapsing time estimation, tapping rate, body sway measured by a ultrasonic method or rapid visual information processing task variables. There tended to be a non‐significant, exponential learning curve for choice reaction response and movement times to visual stimuli, flash fusion threshold and the manipulative motor task, with a statistically significant practice effect on all 16 visual analogue scales used; a plateau was apparently achieved by the fifth practice session for all these parameters. There was a statistically significant straight‐line improvement in digit span across the 10 sessions. It is concluded that for most simple measures of performance used in psychopharmacology including visual analogue scales, four pre‐study training sessions are necessary, and that direct methods of recording body sway are preferred to indirect methods such as the balance platform.
Antipsychotic properties of neuroleptic‐like neuropeptides in schizophrenia: A clinical review
Authors: Verhoeven W. M. A. , Van Ree J. M. 
Published: December 2004

AbstractRecently much interest has been shown in the antipsychotic efficacy of neuroleptic‐like neuropeptides in schizophenia. In this article the clinical effects of the non‐opioid fragments of γ‐endorphin, the so‐called γ‐type endorphins DTγE and DEγE, are reviewed. In addition, preliminary clinical studies of peptides related to cholecystokinin are considered. It is concluded that γ‐type endorphins possess antipsychotic properties in a subgroup of patients who may belong to Type I schizophrenia. With cholecystokinin‐related peptides, in particular ceruletide, antipsychotic effects have been reported which seem to be more or less comparable to those observed with γ‐type endorphins.
Beyond the benzodiazepines: The search for new anxiolytics. A summary of pre‐clinical approaches
Authors: File Sandra E. 
Published: December 2004

AbstractThe clinical efficacy of the benzodiazepines in reducing anxiety is widely accepted. However, the search for novel anxiolytics continues, motivated by the hope of finding a non‐sedative anxiolytic. This article reviews the pre‐clinical evidence for new compounds as it relates both to their anxiolytic actions in animal tests and to their sedative potential. Drugs acting at sites on the GABA‐benzodiazepine receptor complex are discussed, as well as the potential importance of aminergic and peptidergic pathways.
A double‐blind placebo‐controlled trial of tanakan in the treatment of idiopathic cognitive impairment in the elderly
Authors: Wesnes K. , Simmons D. , Rook M. , Simpson P. 
Published: December 2004

AbstractFifty‐four elderly patients, living at home, completed a 3‐month, double‐blind, randomized, placebo‐controlled trial of the effects of Tanakan on both cognitive efficiency and the quality of life. Patients were included in the study if they showed mild signs of impairment in everyday function on the Crichton Geriatric Rating Scale. Cognitive efficiency was measured before and at monthly intervals during the trial using a battery of tests of mental ability comprising both computerized and pencil‐and‐paper tasks. The quality of life was assessed using a behavioural questionnaire which was administered before and after the study. Individual analyses of the cognitive tests showed some advantage of Tanakan over placebo, but when the accuracy scores from all eight tests were combined using two different techniques, although both groups improved over time, the improvement with Tanakan at week 12 was significantly greater than with placebo. No signs of improvement were detected with placebo when the reaction time measures were combined using these techniques, whereas by week 4 the Tanakan group were significantly faster than at baseline, and were superior to placebo throughout the study. These improvements in mental efficiency were accompanied by a significant increase in the interest taken in everyday activities, and suggest that the drug might be helpful in treating the early stages of primary degenerative dementia.
Three antidepressants (amitriptyline, dothiepin, fluoxetine), with and without alcohol, compared with placebo on tests of psychomotor ability related to car driving
Authors: Hindmarch Ian 
Published: December 2004

AbstractEight female volunteers received acute doses of amitriptyline 50 mg (AMI), dothiepin 50 mg (DOT), fluoxetine 40 mg (FLU) or placebo both with and without a ‘social’ dose of alcohol (ALC) equivalent to 0·5 g/kg body weight absolute alcohol. Performance on a variety of tests of psychomotor ability and cognitive function (critical flicker fusion, choice reaction time, tracking, Maddox Wing and simulated car steering) were performed at 1·5 and 4 hours following treatment. AMI and DOT both with and without ALC impaired performance on a range of tests at either or both 1·5 and 4 hours, although the effects of AMI and AMI + ALC were more widespread and severe than those found with either DOT or DOT + ALC. FLU and FLU + ALC showed no evidence of impairment on any test at either the 1·5 or the 4 hours assessments. The results suggest that there are differences between the experimental substances, at the doses used, in their intrinsic potential for impairing aspects of psychomotor performance and cognitive function.
A ‘levels of processing’ study of the effects of benzodiazepines on human memory
Authors: Curran H. V. , Schiwy W. , Eves F. , Shine P. , Lader M. 
Published: December 2004

AbstractA study was designed to test whether anterograde impairments of memory caused by benzodiazepines are dependent on the depth at which information is processed. The effects of two dose levels of two benzodiazepines (lorazepam 1, 2 mg; oxazepam 15, 30 mg) and a placebo were compared using a double‐blind, independent group design with 45 healthy, human volunteers. Subjects given benzodiazepines were slower in processing semantic information than subjects given placebo. The two benzodiazepines caused dose‐related impairments in retention in recognition testing, but these impairments did not depend on the level at which information had been initially processed. It was concluded that the levels of processing framework is inappropriate for conceptualizing the amnesic properties of benzodiazepines.
An investigation of the range of cognitive impairments induced by scopolamine 0·6 mg s.c
Authors: Wesnes K. , Simpson P. , Kidd A. 
Published: December 2004

AbstractThe present study was conducted to determine the degree to which impairments in attention accompany the memory deficits produced by scopolamine. Eighteen healthy young volunteers received scopolamine 0·6 mg subcutaneously on three experimental sessions and placebo on three others. On each session, prior to, and 60 min after injection, the subjects underwent an automated computerized battery of 11 cognitive tasks. The study was run double‐blind and the order of treatment conditions over successive visits was counterbalanced between subjects. Scopolamine produced marked and significant decrements on all major aspects of performance from the battery. The drug lowered the efficiency of the detection and processing of information in tests of visual vigilance, rapid information processing, choice reaction, letter cancellation and logical reasoning. These effects were accompanied by a lowering of critical flicker‐fusion frequency and subjective alertness. Memory was also impaired on tests of immediate recall, delayed recall, recognition and memory scanning. These findings confirm and extend previous work, demonstrating that scopolamine impairs the selection and evaluation of environmental information, as well as reducing the likelihood of information being subsequently recalled or recognized. Whether the former effects contribute to the latter is not known, but this must be considered a possibility. This potential role of processing deficits in memory loss associated with cholinergic blockade is briefly considered in relation to the cholinergic hypothesis of geriatric memory loss.
The effect of clonidine and bright light on plasma melatonin
Authors: Grasby P. M. , Cowen P. J. 
Published: December 2004

AbstractWe studied the effect of the α2‐adrenoceptor agonist, clonidine, and bright artificial light (>2500 lux) on the nocturnal increase in plasma melatonin in normal subjects. Clonidine (1.5 μg/kg, intravenously) was without effect on plasma melatonin concentration. In contrast, bright light treatment abolished the increase in night‐time melatonin. Bright light is a simple and effective means of altering melatonin secretion in humans.
Hypotension and bradycardia induced by amitriptyline in healthy volunteers
Authors: Curry Stephen H. , Devane C. Lindsay , Wolfe M. Michael 
Published: December 2004

AbstractSeventeen healthy volunters in three groups received no treatment, or 25 or 50 mg doses of amitriptyline. Maximal measured concentrations of amitriptyline occurred at 4 h post‐dosage. There was a dose‐dependent change in performance of a digit symbol substitution test. Visual analogue scales measuring drowsiness, speed of thinking, and lethargy were sensitive to the drug. The low dose induced no blood pressure changes, but tachycardia occurred. The higher dose induced hypotension with bradycardia, a hitherto undocumented reaction to the drug.
A double‐blind trial of evening primrose oil in the premenstrual syndrome: Nervous symptom subgroup
Authors: Callender Kay , McGregor Molly , Kirk Peter , Thomas Christopher S. 
Published: December 2004

AbstractForty‐five women were referred to the premenstrual syndrome (PMS) clinic by their general practitioners over a 2‐year period; 24 were included in the study. For 2 months they attended the clinic weekly, where they completed a menstrual distress questionnaire and self‐rating scales relating to depression and anxiety. They also kept a daily record of their symptoms. After this observation period the presence of ‘nervous symptoms’ limited to the premenstrual phase of the menstrual cycle was found in only 12 subjects. These women were randomly allocated to receive either Efamol in combination with Efavit or placebo for 2 months. The following 2‐month washout period was succeeded by a crossover to the other treatment regimen. Ten women completed the trial. The results showed that the depression and anxiety scores improved during the medication months, but that there was no difference between active therapy and placebo.
The benefits and risks of antidepressant drugs
Authors: Pinder R. M. 
Published: December 2004

AbstractAntidepressant drugs have unequivocally altered the short‐term outcome of depressive illness and reduced considerably the risk of morbidity. Their influence upon the chronic course of depression or upon the excess mortality associated with depressive illness is less easy to quantify. Nevertheless, the benefits of effectively treating depression far outweigh the considerable risks of leaving depressed patients inadequately, inappropriately or untreated. Most antidepressants currently available have broadly equal efficacy, although some drugs may be more appropriate in certain types of patient, when particular symptoms are prominent or when a particular side‐effect is undesirable.Antidepressants vary in their side‐effect profiles, and the newer non‐tricyclic drugs appear to offer a reduced risk of anticholinergic and cardiovascular effects. All of the newer drugs carry additional adverse effects, however, leading in the cases of zimeldine and nomifensin to withdrawal from the market and with mianserin to controls on prescription. Analysis of overdosage data indicates that the greatest risk of any antidepressant is fatality upon overdosage, the numbers of which far exceed fatalities from adverse effects. It is suggested that any assessment of the overall benefitsand risks of antidepressant drugs should include not only risks at therapeutic dosage but also the dangers of overdosage.
The effects of quazepam, triazolam, flunitrazepam and placebo, alone and in combination with ethanol, on day‐time sleep, memory, mood and performance
Authors: Wickstrøm Egil , Godtlibsen Ole Birger 
Published: December 2004

AbstractDay‐time sleep and residual effects of quazepam 15 mg, triazolam 0·25 mg, flunitrazepam 1 mg, and placebo, alone and in combination with ethanol, were studied using a randomized, double‐blind, crossover, single‐dose design. Eight healthy volunteers, four male and four female, aged 19–24 years, received each medication in the morning after a ‘normal’ sleep at home the preceding night.Quazepam and triazolam decreased the sleep onset when compared to placebo. The combination with ethanol did not change these findings. Quazepam and placebo showed less residual effects than triazolam and flunitrazepam at 4 hours after drug intake: in combination with ethanol at 4 and 6 hours. No significant differences in mood were found between the different ‘treatments’, except with regard to alertness for quazepam and placebo compared to flunitrazepam, alone and in combination with ethanol, all at 4 hours.The combination drug/ethanol showed an increase in Cmax of the former and a delay in Tmax when compared to drug alone. The study indicated few clinically useful correlations between clinical effect and plasma concentration.
Pharmacodynamic and pharmacokinetic comparison of two formulations of lorazepam and placebo
Authors: Abrams S. M. L. , Harry T. V. A. , Hedges A. , Murray G. A. , Turner P. 
Published: December 2004

AbstractNine healthy male volunteers took part in a comparison of the pharmacokinetic profiles and effects on psychomotor performance and memory following single dosing with an experimental sustained release (SR) and a conventional release (CR) formulation of lorazepam. There was evidence of a sustained release profile for the SR formulation which had a later tmax (median 8 h) and significantly lower peak serum concentration (mean 12·1 ng ml−1) compared with CR lorazepam (2 h and 21.8 ng ml−1 respectively). The effect of SR lorazepam on pharmacodynamic variables occurred later and was less intense than with CR lorazepam. Good correlations were obtained between most of the pharmacodynamic parameters measured and the logarithm of the serum concentration for both formulations, with the exception of the choice reaction time test for SR lorazepam. However, both formulations produced a similar degree of impairment of 24h recall.
Convulsant actions of the anxiolytic buspirone in combination with antidepressants
Authors: File Sandra E. 
Published: December 2004

AbstractThe anxiolytic, buspirone, was given to rats in combination with four antidepressants: clomipramine (3–30 mg/g), desipramine (5–10 mg/kg), maprotiline (5–15 mg/kg) and mianserin (10–15 mg/kg). Even 2 mg/kg buspirone caused a significant incidence of myoclonic seizures, when combined with clomipramine (30 mg/kg), desipramine (5–10 mg/kg) and mianserin (15 mg/kg). Higher doses of buspirone caused seizures when combined with all doses of the four antidepressants tested. The only antidepressant to cause myoclonus on its own was maprotiline (10 and 15 mg/kg). The university of the incidence of myoclonus precluded any conclusions about the underlying mechnaism. However, whilst it is difficult to draw cross‐species conclusions, our results would caution against the clinical use of buspirone in combination with antidepressants.
Neuropsychiatric aspects of sedative drug withdrawal
Authors: Duncan John 
Published: December 2004

AbstractThe withdrawal syndromes after discontinuance of alcohol, barbiturates, benzodiazepines and other sedative drugs, such as chloral and paraldehyde, are all similar. The severity of a withdrawal reaction is largely determined by the daily dose, the duration of administration and the rate of fall of the drug levels after withdrawal, as well as the propensity of the individual patient. The time course of a withdrawal reaction is determined by the drug's clearance. Alcohol has a half‐life of a few hours; withdrawal symptoms may develop within 6–8 hours of abstinence and convulsions in 12–48 hours. After discontinuance of short‐ or medium‐acting barbiturates (half‐life 8–40 hours) symptoms may develop in 1–3 days, followed by convulsions and delirium after 3–8 days. Symptoms and seizures may develop in the 1–10 days after withdrawal of benezodiazepines.In patients with no prior history of epilepsy the types of seizures most commonly induced by drug withdrawal are generalized convulsions, but partial seizures are not uncommon if there is a focal cerebral lesion, or a previous history of partial seizures. Paroxysmal activity and photosensitivity may occur after barbiturate withdrawal in non‐epileptics, more commonly in severe withdrawal reactions. Similar EEG changes may be seen after alcohol and benzodiazepine withdrawal, but photosensitivity does not appear to have been shown to be a feature of the benzodiazepine withdrawal syndrome.
Heart rate response to standing as an index of adaptation to imipramine during treatment of panic disorder
Authors: Middleton H. C. , Nutt D. J. 
Published: December 2004

AbstractThe heart rate and blood pressure response to standing in eight patients receiving imipramine treatment for panic disorder were compared with the same measures in eight normal subjects after a single large dose. Despite higher plasma drug levels, patients on long‐term medication had a less abnormal orthostatic response than volunteers. This suggests that the heart rate response to standing could be a useful index of the neuropharmacological adaptation known to occur during administration of therapeutic doses of tricyclic antidepressant.
Absence of acute stimulant effects after intravenous thyrotropin‐releasing hormone (TRH) in man: Comparison to d‐amphetamine
Authors: Little Karley Y. , Garbutt James C. , Mayo James P. 
Published: December 2004

AbstractThyrotropin‐releasing hormone (TRH) has been reported to have behavioural effects in man. The current study compared TRH to d‐amphetamine and placebo in normal humans. While a number of d‐Amp effects were noted, TRH was not significantly different from placebo.