Promethazine,scopolamine and cinnarizine: comparative time course of psychological performance effects

Single oral doses of promethazine (12.5 mg, 25 mg), scopolamine (0.6 mg), and cinnarizine (30 mg), were compared in a double-blind, placebo controlled trial. Twelve normal volunteers undertook a battery of psychological performance tests and a feeling state questionnaire, before drug administration, and at 2-h intervals after. Promethazine and cinnarizine significantly impaired psychomotor performance, information processing and feelings of alertness. With promethazine these reductions were maximal 3–4 h post-drug, with performance returning near to baseline 8–9 h post-drug. With cinnarizine these impairments were maximal 5–6 h post-drug, and performance remained depressed 8–9 h post-drug. Scopolamine significantly reduced feelings of alertness, and memory task performance; the overall performance effects were most evident 1–4 h post-drug.     

The effects of single and repeated doses of oral scopolamine,cinnarizine, and placebo upon psychological performance and physiological functioning

The present study was one in a series in the Institute of Naval Medicine's Motion Illness Project. A battery of psychological performance tests (producing 26 indices of mental and hand--eye co-ordination), together with visual near fixation point, resting heart rate and a self-rated feeling state questionnaire, were used to compare the effects of thrice-daily oral doses of scopolamine (0.6 mg), cinnarizine (30 mg) and a lactose placebo in a double-blind crossover trial on 12 healthy male volunteers. Measurements were made 1–2 and 5–6 h after the initial dose, then the next day following the last successive dose (1–2 and 5–6 h after the fourth dose; or 25–26 and 29–30 h after the initial dose). Scopolamine demonstrated clear physiological effects, with reduced heart rate from the first oral dose onwards, and visual near-point values increasingly distant over successive doeses. Cinnarizine did not produce significant physiological changes. Neither drug produced significant effects on subjective mood. Significant ANOVA drug effects or drug × time interaction effects were present with five out of the 26 performance variables: logical reasoning error, memory word-recall errors; continuous four choice reaction time; concept identification time; SERS task commission error. However only two of these (memory error, four choice reaction time) demonstrated patterns of effect which were considered to be attributable to the drugs. Both cinnarizine and scopolamine impaired memory error and four choice reaction time. Only for visual near-point with scopolamine was there evidence that repeated dosing led to increasing physiological/mental performance effects.     

The effects of transdermal scopolamine and four dose levels of oral scopolamine (0.15, 0.3, 0.6, and 1.2 mg) upon psychological performance

Four dose levels of oral scopolamine (0.15 mg, 0.3 mg, 0.6 mg, 1,2 mg), transdermal scopolamine, and placebo, were investigated for their effects upon a battery of psychological performance measures in normal subjects. Oral scopolamine produced significant linear dose-related decrements on tasks involving continuous attention, continuous performance, memory storage for new information, and on self-rated feelings of alertness and sociability. Transdermal scopolamine produced significant performance impairments on these same assessment measures. Resting heart rate levels were significantly reduced by all scopolamine conditions. Side effects (dry mouth, dizziness) were frequent following transdermal scopolamine and the higher oral dose conditions. The overall effects of the transdermal scopolamine patch were broadly equivalent to the effects of 0.8 mg oral scopolamine. This oral dose equivalence for transdermal scopolamine is higher than expected, and possible reasons for this are discussed.     

The effects of transdermal scopolamine on autonomic nervous activity during sleep

We studied the effect of transdermally applied scopolamine (scopolamine-TTS) on autonomic nervous activity during sleep. The double-blind, randomized, crossover study was carried out in six healthy male volunteers by applying 1.5 mg scopolamine-TTS or placebo patch on the retroauricular skin and by monitoring heart rate, cardiac ballistogram, respiration and body movements by using electrocardiogram and static charge sensitive bed.Scopolamine did not decrease the time the subjects desired to sleep (516 min after TTS, 511 min after placebo) or the number of body movements of 3–5 s duration the subjects spontaneously performed during sleep (47 after TTS, 58 after placebo). No adverse effects of scopolamine were reported spontaneously. Scopolamine-TTS slowed the mean heart rate during quiet sleep from 53.2 to 44.9 beats · min^–1, and increased the duration of bradycardia in response to body movements (MIB-reflex) from 12.5 to 14.7 s with a significant difference between scopolamine and placebo effects. The bradycardias were not associated with disturbances in cardiorespiratory or central nervous system functions. The cardiac vagomimetic action of scopolamine-TTS could be explained by low plasma drug concentrations (175 pg/ml) primarily blocking only neuronal inhibitory prejunctional muscarinic receptors which regulate acetylcholine release from the autonomic ganglia and parasympathetic nerve-endings.Because of the central role of acetylcholine in the physiological regulation of sleep, the effect of scopolamine-TTS on sleep merits further investigations.     

Effects of transdermal scopolamine upon psychological test performance at sea

Summary The effects of transdermal scopolamine upon objective psychological performance assessments and self reports of feeling states, were investigated with volunteer subjects at sea. Scopolamine and placebo patches were administered on consecutive days in a counterbalanced order. Psychological performance was assessed 24 h following each transdermal patch. Choice reaction time and code substitution performance levels were not significantly changed, but letter cancellation errors were significantly more frequent following transdermal scopolamine. Transdermal scopolamine caused significantly more reports of dry mouth. More subjects were also unable to undertake the performance tests following scopolamine than placebo, due to difficulties in focusing on the test materials. However despite deleterious side effects with some personnel, others responded positively to the scopolamine patch. As noted by other workers, responses to the transdermal scopolamine patch seem to be quite variable.Dr. A. C. Parrott is Senior Psychologist at the Institute of Naval Medicine.Surgeon Lt. R. Jones RN, was Medical Officer to HMS Hydra     

Effect of transdermal scopolamine on salivation

The effect of transdermal scopolamine on salivary flow and composition was analyzed in 21 healthy volunteers. The flow rate of whole saliva was significantly lowered by transdermal scopolamine. Significant positive correlations were found between the placebo rate of flow and both the quantity and percentage decreases in response to transdermal scopolamine. The magnesium concentration was significantly increased during transdermal scopolamine administration, whereas the sodium, potassium, and calcium concentrations were not consistently altered. Accordingly, the magnesium secretion rate was unaltered, whereas sodium, potassium, and calcium secretion rates were significantly lowered by transdermal scopolamine administration.     

Time-course of effects of oral cinnarizine and hyoscine on task performance

Investigations into antimotion sickness drugs fall into two main categories: efficacy ('benefits') and side-effects ('costs'). This study was of the second type. Oral cinnarizine (30 mg: normal dose; and 75 mg: 2.5 x normal dose) and placebo, were investigated using a battery of automated mental, motor, physiological and other tests in twelve young healthy male volunteers. The higher cinnarizine dose level was chosen to exaggerate effects and make it easier to track them. Oral hyoscine (1.2 mg: 2 x normal dose) was employed as a positive internal control. Side-effects were almost exclusively due to hyoscine whereas cinnarizine was almost free of significant effects even at the higher dose of 75 mg. Hyoscine impaired performance 1-3 hours postdrug, whereas the effects of cinnarizine occurred approximately 5-7 hours postdrug. This paralleled the slower time-course for the protective action of cinnarizine against motion sickness noted in earlier studies. These results, taken in conjunction with previous trials, suggest that oral cinnarizine would seem less likely than hyoscine to produce unwanted decrements in performance.     

Atropine,scopolamine and hippocampal lesion effects on alternation performance of rats

Interactions between effects of hippocampal lesions and cholinergic blocking agents were examined using two behavioral tasks, delayed spatial alternation and go-no go temporal alternation. Atrophine and scopolamine were administered to control rats and to rats with lesions in three areas of the hippocampal formation. Large hippocampal lesions disrupted performance on both tasks as did administration of atrophine or scopolamine to control rats and to rats with lesions in restricted areas of the hippocampus. However, the effects of atropine and scopolamine on performance of rats with large lesions involving all regions of the hippocampal formation depended upon the alternation task used. Atropine and scopolamine disrupted delayed spatial alternation performance of all groups tested, but atropine failed to significantly disrupt go-no go alternation performance of the group with large unrestricted hippocampal lesions. Both the size of the lesion and the behavioral task were found to be important determinants of the effects of cholinergic blockers on the performance of rats with hippocampal lesions.     

The effects of scopolamine on performance on a geometric progressive ratio schedule

Rats were trained to respond on a geometric progressive ratio schedule until performance was stable. They were then injected with the anticholinergic drug scopolamine at doses of 0.05, 0.1, 0.25, 1.0 and 2.0 mg/kg. Control animals were administered atropine methyl nitrate (1–20 mg/kg). Increasing doses of scopolamine typically produced first an increase, then a decrease in behavior compared with baseline levels, measured by total number of responses, total number of reinforcements, and final completed ratio, per session. Atropine methyl nitrate had no effect on the behaviour of the control animals.This indicates that the effects of scopolamine are due to its central action. The inverted-U dose-response curve found for scopolamine resembles that found for chlordiazepoxide, phenobarbital, and d-amphetamine on progressive schedules.Research supported by grants C70/20, 70/44, and 72/24 to N.M.B. Preparation of the paper was aided by a grant to W.J.S. from the Canterbury Branch, N.Z. Psychological Society. An early version of this paper was presented to the Annual Conference, N.Z. Ps. S., Auckland, 1973. Research reported was performed in partial fulfilment of the requirements of the M. Sc. degree by W. J. S.     

The scopolamine model of dementia: chronic transdermal administration

The transient impairments of memory produced by the muscarinic antagonist scopolamine have been adopted as a pharmacological model of Alzheimer-type dementia in normal volunteers. In this study we examined the effects of chronic (72 h) transdermal administration of scopolamine on memory, attention, sedation and visual function. The transdermal patches provided constant plasma levels of scopolamine for the duration of the study. Indices of the peripheral effects of scopolamine (visual near-point and pupil size) showed impairments that were sustained for 3 days. However, measures of sedation and memory revealed impairments that were maximal the day after patch application and which were no longer present 3 days after application. This pattern of results is discussed in relation to pharmacological modelling of Alzheimer's disease.     

Effects of transdermal scopolamine on pulmonary function, symptoms and bronchial hyperresponsiveness to methacholine

This study is a result of two consecutive double-blind, placebo-controlled, cross-over studies. In the first study, we evaluated therapeutic effects of a single transdermal scopolamine patch (Scopoderm® TTS, size 2.5 cm², Ciba Geigy) on forced expiratory volume in one second (FEV₁), reversibility, peak expiratory flow (PEF) and symptoms in ten patients with reversible airways disease (ΔFEV₁9% predicted). During the study, blood and urine samples were taken from the patients and analysed for scopolamine levels. The drug was adequately taken up from the patch into the systemic circulation. However, no significant clinical effects, nor correlations between the scopolamine levels and the outcome parameters were observed. Because of the possibility of sub-therapeutic doses in the first study, a second study with two transdermal scopolamine patches was performed in ten patients with bronchial hyperresponsiveness to methacholine. The blood and urine concentrations of free scopolamine were doubled compared to the first study. There were still no statistically significant effects on FEV₁, PEF, symptoms, and bronchial hyperresponsiveness, yet most of the patients now reported adverse side effects. We conclude that transdermal administration of scopolamine is not clinically useful in asthma and chronic obstructive pulmonary disease. Even application of two patches does not result in therapeutically effective levels at the muscarinic receptors in the lung, yet causes several side effects.     

The effects of scopolamine and atropine on the performance of an exercise-avoidance test by dogs

Summary Cholinergic blockade produced by scopolamine hydrochloride or atropine sulfate was found to disrupt the running behavior of dogs performing in exercise-avoidance test. The quaternized derivatives of these drugs were considerably less effective than the tertiary drugs and methyl atropine was effective only at a dose which was lethal to one of the animals tested.The investigation was supported by Chemical Research and Development Laboratories, Edgewood Arsenal, Maryland, on Contract No. DA 18-108-AMC-78(A). In conducting the research reported herein, the investigators adhered to the Principles of Laboratory Animal Care as established by the National Society for Medical Research.     

The effects of scopolamine on extinction and spontaneous recovery

The effects of scopolamine hydrobromide on baseline extinction levels and spontaneous recovery were assessed. Rats were trained on one of four reinforcement schedules (CRF, FR 10, FR 20, FR 40) with either food or water reinforcement. Scopolamine increased response rates in extinction and spontaneous recovery following training on all four schedules when the reinforcer was water, but had no effect on responding previously maintained by food. The results are discussed in terms of the limitations of a general theory of a cholinergic system mediating all suppressed behavior and the effects of anticholinergic drugs on central thirst mechanisms and consummatory behavior.     

The effects of scopolamine and clonidine upon the performance and learning of a motor skill

Twenty-eight subjects practised a task involving procedural knowledge in which a moving target has to be followed for two 3-min sessions. They were then randomly allocated to receive an IV injection of 0.4 mg scopolamine, 0.15 mg clonidine or saline. General impairment due to both active treatments was seen 20 min later in significantly decreased tracking performance. Subjects then had to learn a mirror-reversed version of the tracking task. This involved acquiring novel procedural knowledge. Subjects who had either saline or clonidine treatment showed rapid temporary improvements and also considerable permanent learning. Subjects treated with scopolamine, however, showed only slow temporary improvement and little permanent improvement in their performance at this task. This result suggests that a normally functioning cholinergic system is necessary not only for an efficient working memory but also for the long term acquisition of some kinds of procedural knowledge.     

The psychometric and cardiac effects of dimenhydrinate in the hyperbaric environment

STUDY OBJECTIVES: To examine the psychometric and cardiac effects of dimenhydrinate at 1 and 3 atmospheres (atm) of pressure (0 and 66 feet of sea water, respectively), and to make recommendations about the drug's safety in the diving environment. DESIGN: Double-blind, placebo-controlled, crossover study SETTING: Monoplace hyperbaric chamber of a university hospital. SUBJECTS: Thirty active divers (mean age 38 yrs). INTERVENTIONS: A bank of seven tests was used to assess cognitive function during four different dive combinations: placebo-1 atm, placebo-3 atm, dimenhydrinate-1 atm, and dimenhydrinate-3 atm. MEASUREMENTS AND MAIN RESULTS: Heart rate and cardiac rhythm were recorded during all dives. Repeated-measures multivariate analysis of variance was used to analyze the effects of dimenhydrinate, depth, and drug-depth interaction. Dimenhydrinate resulted in a significant decrease in scores of mental flexibility (trail-making, part B, p<0.05) but had no effect on scores in the six other psychometric tests (p>0.05). It had no effect on mean heart rate (p>0.05), although frequent unifocal ventricular ectopic beats occurred in two subjects after ingestion of the drug. Depth resulted in a significant decrease in verbal memory test scores (p=0.001) and mean heart rate (p<0.001). CONCLUSION: Dimenhydrinate adversely affects mental flexibility. This effect, when added to the adverse effect of depth on memory, may contribute to the dangers of diving.     

Effects of selection delays on radial maze performance: acquisition and effects of scopolamine

The effects of post-selection confinement (delays) on both the acquisition of performance and the response to the muscarinic blocker, scopolamine, were examined in an automated version of the eight arm radial maze. Long-Evans rats, exposed to post-selection delays of 0.5 sec (n = 4) or 100 sec (n = 4) during daily training trials did not differ in either the number of trials to acquire an accurate baseline of performance or in the amount of time required to obtain all eight food pellets. However, the pattern (delta-arm scores) of within-session arm selections demonstrated by the two groups of rats differed. Rats exposed to the 0.5-sec delay typically selected arms adjacent to arms from which they exited while rats exposed to the 100-sec delay were more likely to enter arms 2-removed from the exit arm. When scopolamine (0.03 to 1.0 mg/kg) was administered prior to testing, rats in the 100-sec delay group showed a greater reduction of accuracy and a larger increase in selection latency than rats in the 0.5-sec delay group. The differential effect of delay value on delta-arm scores was also eliminated in a dosage dependent manner with scopolamine. Scopolamine methylbromide (0.3 mg/kg) was found to have little effect on performance. In summary, the results indicate that the post-selection delay procedure is a sensitive and selective test for chemical-induced dysfunctioning of spatial memory in rats.     

The effects and interactions of scopolamine, physostigmine and methamphetamine on human memory.

Seventy college age subjects learned and recalled a series of word lists prior to being injected with methamphetamine (0.2 mg/kg or 0.3 mg/kg), scopolamine (8 microgram/kg), or a placebo. Following the injection subjects were tested for their free recall and recognition of the words and they completed a short-term digit recall task. Subjects who had previously received scopolamine were next injected with either methamphetamine (0.2 mg/kg or 0.3 mg/kg), physostigmine (32 microgram/kg), or placebo, while other subjects received a placebo injection. The above memory procedure was then repeated with a second series of word lists. In addition, subjective feelings were measured with a questionnaire. Scopolamine and methamphetamine did not affect recall of information learned prior to injection. Scopolamine did, however, impair performance in both the digit recall task and in the second series of memory tests. Physostigmine and methamphetamine alleviated most of the memory deficits and sedation produced by scopolamine. Methamphetamine alone produced subjective arousal and a small improvement in recall of words learned after injection and a large increase in incorrect responding.     

The effects of scopolamine on retrieval from semantic memory

The effects of two doses of scopolamine (0.6 and 1.2 mg p.o.) on retrieval from semantic memory in normal young volunteers were examined using tests of verbal fluency and categorization latency. A visual contrast sensitivity test, which has previously shown a scopolamine-induced impairment at these doses (Broks et al., 1988), was also administered. In agreement with the work of Dunne (1990) and others, no evidence for a scopolamine deficit in semantic retrieval was found; in fact scopolamine improved letter fluency. However, scopolamine did produce the expected decrease in visual contrast sensitivity. The doses of scopolamine used here have also been shown to impair learning and attention (Broks et al., 1988). It is possible that earlier studies which found a scopolamine deficit on semantic retrieval, did so because they used elderly subjects and/or large drug doses.     

The effects of verapamil, prenylamine, flunarizine and cinnarizine on coronary artery occlusion-induced arrhythmias in anaesthetized rats

In male rats, anaesthetized with pentobarbitone, ligation of the main left coronary artery causes an early phase of ventricular arrhythmias which last about 30 min. In approximately 60% of control animals, ventricular fibrillation occurs but since spontaneous reversion to sinus rhythm may occur, mortality is of the order of 30%. When administered intravenously 15 min prior to ligation, verapamil (0.01 and 0.05 mg kg-1), prenylamine (0.5 mg kg-1), flunarizine (0.1, 0.25, 0.5 and 1.0 mg kg-1) and cinnarizine (0.25, 0.5 and 1.0 mg kg-1) protected against these arrhythmias. Higher doses of verapamil (0.1 and 0.5 mg kg-1), prenylamine (5 mg kg-1) and flunarizine (2.5 mg kg-1) did not afford a similar protection and mortality was increased to or above control values. Death was due in prenylamine-treated rats to atrioventricular block leading to asystole whereas in those administered verapamil or flunarizine it was a consequence of persistent ventricular fibrillation. Prior to ligation, a sustained fall in mean arterial blood pressure was observed only following the administration of the highest doses of prenylamine, flunarizine and cinnarizine. Heart rate was reduced by administration of only the highest dose of prenylamine. These studies show that although the four calcium antagonists studied, i.e. verapamil, prenylamine, flunarizine and cinnarizine do suppress ischaemia-induced arrhythmias, this protective effect may be limited to a narrow concentration range.     

Intra-striatal haloperidol and scopolamine injections: effects on choice reaction time performance in rats

In this study the behavioral consequences of intra-striatal haloperidol and scopolamine injections were examined using a reaction time task. Haloperidol was found to increase the response time of the rats and had a modest effect on the motor components of the task. The manner in which haloperidol affected the response time distribution suggested that this drug affected attentional functions. Scopolamine did not affect the reaction time or motor performance in the reaction time task. However, a clear decrease in the number of completed trials and an increase in anticipatory responses was observed. At present no ready explanation could be given for the behavioral effects of scopolamine. The present data suggest that although dopamine and acetylcholine are intimately related in the striatal network and have been supposed to have antagonistic functions, the behavioral consequences of blockade of dopamine and acetylcholine receptors are dissimilar.