Effects Of Sedative Drugs Research Articles

Postoperative analgesia and sedation in the adult intensive care unit: a guide to drug selection.

An essential goal of all critical care physicians should be to maintain an optimal level of pain control and sedation for their patients. This has become increasingly important because of evidence showing that the combined use of sedatives and analgesics may ameliorate the detrimental stress response in critically ill patients. Unfortunately, both pain and anxiety are subjective and difficult to measure, thereby limiting our ability to analyse these states and making management more challenging. Although there is still a lack of high quality, randomised, prospective, controlled trials comparing agents, monitoring techniques and scoring scales, several societies have come together to publish some clinical practice guidelines for sedation and analgesia. Recommended opioids are fentanyl or hydromorphone for short-term use, and morphine or hydromorphone for longer-term therapy. Midazolam or diazepam are recommended for sedation of the acutely agitated patient, while lorazepam is recommended for longer infusions. Propofol is preferred when rapid awakening is desired. The challenge for critical care physicians is to use these medications to provide comfort and safety without increasing morbidity or mortality. Most studies support the use of protocols in order to help achieve these goals. The bottom line is that most protocols end up stressing some common issues. These include daily cessation of drugs to evaluate the patient and frequent reassessment of the level of sedation required by each specific patient. Much is still unknown about the long-term effects of sedative and analgesic drugs used as infusions that may last from days to weeks to months. Hopefully, as more studies are performed, we will have more defined clinical end-points, newer drugs with rapid onset and offset and no active metabolites, and decreased morbidity and mortality for our patients.

Cortical Deactivation Induced by Visual Stimulation in Human Slow-Wave Sleep

It has previously been demonstrated that sleeping and sedated young children respond with a paradoxical decrease in the blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signal in the rostro-medial occipital visual cortex during visual stimulation. It is unresolved whether this negative BOLD response pattern is of developmental neurobiological origin particular to a given age or to a general effect of sleep or sedative drugs. To further elucidate this issue, we used fMRI and positron emission tomography (PET) to study the brain activation pattern during visual stimulation in spontaneously sleeping adult volunteers. In five sleeping volunteers fMRI studies confirmed a robust signal decrease during stimulation in the rostro-medial occipital cortex. A similar relative decrease at the same location was found during visual stimulation and polysomnographically verified slow-wave sleep in a separate group of six subjects using H 2 15O PET measures of the regional cerebral blood flow (rCBF). This decrease was more rostro-dorsal compared to the relative rCBF increase along the calcarine sulcus found during visual stimulation in the awake state. This study reconfirms the previously described paradoxical stimulation-correlated negative BOLD signal change in the rostro-medial occipital cortex, expanding this response mode to an age spectrum ranging from the newborn to the adult. Further, the use of complementary brain mapping techniques suggests that this decrease was secondary to a relative rCBF decrease. Possible mechanisms for the paradoxical response pattern during sleep include an active inhibition of the visual cortex or a disruption of an energy-consuming process.

A New Computerized Test Battery to Evaluate Drug Effects on Psychomotor Performance. Lorazepam-induced Impaired Performance in Healthy Volunteers.

Objective: This study was performed to evaluate the sensitivity of a new computerized test battery which we developed for the detection of drug-induced impaired psychomotor performance.Methods: Twelve healthy male volunteers participated in this study. Lorazepam (0.5 or 1.0 mg oral), an antianxiety drug, or placebo was administered in a double-blind fashion with a Latin square design, with an interval of more than one week. The psychomotor performance tests were done before, and at 1 and 3 hours after drug administration. The test battery consisted of four different tasks ; a simple number copying test (SNCT), a continuous number addition test (CNAT), a number comparison test (NCT) and two types of reaction time tests (RTT). In SNCT, CNAT and NCT, percent changes in the number of keyed-in figures and the number of correctly keyed-in figures were automatically measured, and in RTT, the latency to respond was automatically recorded. To measurelorazepam-induced subjective sedative actions, visual analogue scales (VAS) were used.Results: The performance was impaired in SNCT and CNAT 1 hour after administration of 1.0 mg lorazepam, and in NCT 1 hour after administration of 0.5 and 1.0 mg lorazepam. There was no significant difference between lorazepam and placebo in RTT. The impaired psychomotor performance was observed irrespective of the absence of lorazepam-induced subjective sedative effects.Conclusion: The lorazepam-induced impaired psychomotor performance was objectively and sensitively detected in healthy volunteers by a new computerized test battery which we developed. This new objective method can be applied to sensitively detect minimal sedative effects of drugs in a situation similar to daily life.

Predicting Drug-induced Memory and Sedation Changes Using Auditory Event-related Potentials.

Predicting Drug-induced Memory and Sedation Changes Using Auditory Event-related Potentials. Veselis et al. (page 896)Building on the work of researchers who have used specific components of event-related potentials (ERPs) to discriminate between the memory and sedative effects of drugs such as lorazepam and scopolamine, Veselis et al. present a new analysis of memory effects using ERPs obtained in a previous study. That placebo-controlled study used 65 healthy volunteers who randomly received intravenously placebo, midazolam, propofol, thiopental, fentanyl with ondansetron, or ondansetron alone in five different stable target concentrations. The concentrations (three increasing, two decreasing) were achieved using a computer-controlled infusion pump to produce mild, moderate, and maximal sedation levels without loss of consciousness. At each target concentration, volunteers were given a list of 16 words to learn. In addition, ERPs were recorded while participants were asked to give a button-press response to a deviant auditory stimulus (target tone, standard oddball paradigm, 80:20 ratio, to elicit a P3 response). Then the researchers determined the predictive probabilities of various ERP components for memory (recognition of the words at the end of the day) and sedation (log reaction time to the deviant stimulus).Results showed that the N2 latency of the ERP consistently predicted log reaction time in all groups. The N2P3 amplitude of the ERP was most predictive of memory performance for subjects to whom midazolam, propofol, and thiopental were administered. Midazolam and propofol affect memory differentially from their sedative effects, as indexed by specific components of the auditory ERP. Relating electrophysiologic changes to the memory and sedative effects of drugs allows researchers to independently measure these effects without the confounding subjective perceptions of the participants. These changes can then be related to brain images from positron emission tomography or magnetic resonance imaging to more accurately localize and quantify the neuroanatomic regions mediating these drug effects.

Comparative analysis of the sedative effects of mequitazine and other antihistaminic drugs: review of the literature

Background: Antihistamines (H 1-receptor antagonists) are widely prescribed to treat symptoms of seasonal and perennial allergic rhinitis and chronic urticaria. Drowsiness and impairment of cognition and psychomotor performance have been reported as adverse events in many trials, and all antihistamines appear to have some sedative properties. Sedation, however, may be a direct result of allergic rhinitis, and the degree of sedation may depend on each individual's response to antihistamine therapy, and thus cannot be predicted. Objective: The purpose of this review was to compare the adverse sedative effects of mequitazine with those of other antihistamines used in clinical practice. Methods: A literature search was conducted to identify all available publications from the MEDLINE ® and Excerpta Medica databases on mequitazine and review articles on nonsedating antihistamine drugs in peer-reviewed journals from 1975 to 1999. Additional publications on mequitazine were provided by the manufacturer of the drug. The clinical outcomes of drowsiness and fatigue in patients with allergic rhinitis were the focus of this comparative analysis. Conclusions: The classification of antihistamines based on their chemical structure alone is misleading. Based on our review of all available product literature on mequitazine and recently published reviews of nonsedating antihistaminic drugs, mequitazine demonstrates a clinically proven low-sedation profile, similar to that seen with current antihistamines, which are frequently reported to be nonsedating. Mequitazine has a low propensity to induce drowsiness, comparable to that of cetirizine and loratadine. Thus, it differs from truly sedative antihistaminic drugs, such as dexchlorpheniramine, which produce drowsiness and fatigue in patients with atopy to a degree that is measurably different from placebo.

Clozapine's antipsychotic effects do not depend on blockade of 5-HT3 receptors.

Sixteen known 5-HT3 receptor blockers, including clozapine, fully or partially reverse the inhibitory effect of 1 microM GABA on [35S]TBPS binding, indicating that they are also GABA(A) antagonists, some of them selective for subsets of GABA(A) receptors. The 5-HT3 receptor blocker, ondansetron, has been reported to produce some antipsychotic and anxiolytic effects. However, no antipsychotic effects have been reported for a large number of highly potent 5-HT3 receptor blockers. Like clozapine, ondansetron partially reverses the inhibitory effect of GABA on [35S]TBPS binding. Additivity experiments suggest that ten 5-HT3 receptor blockers tested at low concentrations preferentially block subtypes of GABA(A) receptors that are among those blocked by clozapine. Wiley and Porter (29) reported that MDL-72222, the most potent GABA(A) antagonist described here, partially generalizes (71%) with clozapine in rats trained to discriminate an interoceptive clozapine stimulus, but only at a dose that severely decreases responding. Tropisetron (ICS-205,930) exhibits both GABA-positive and GABA-negative effects. R-(+)-zacopride is 6-fold more potent than S-(-)-zacopride as a GABA(A) antagonist. We conclude that the observed antipsychotic and, possibly, anxiolytic effects of some 5-HT3 receptor blockers are due to selective antagonism of certain GABA(A) receptors, and not to blockade of 5-HT3 receptors. We speculate that the anxiolytic and sedative effects of clozapine and several other antipsychotic drugs may be due to selective blockade of alpha1beta2gamma2 GABA(A) receptors which are preferentially located on certain types of GABAergic interneurons (probably parvalbumin positive). Blockade of these receptors will increase the inhibitory output of these interneurons. So far, no highly potent GABA(A) antagonists with clozapine-like selectivity have been identified. Such compounds may exhibit improved clozapine-like antipsychotic activity.

Behavioural toxicity of medicinal drugs. Practical consequences, incidence, management and avoidance.

Behavioural toxicity is relatively common among medicinal drug users and evidence shows that drugs frequently produce adverse effects that prevent their users from performing everyday operations in a normal manner. Epidemiological research generally indicates that the use of sedative drugs is associated with an increased risk of becoming involved in injurious accidents. Empirical studies have also demonstrated adverse effects of sedative drugs on the performance of healthy volunteers and patients in laboratory tests designed to measure psychomotor and cognitive function, and in real life-tests measuring on-the-road driving performance. Empirical studies also indicate that behavioural toxicity can vary widely between individual drugs depending on differences in dose, dosing regimen, duration of treatment, pharmacokinetics or mechanisms of actions. Besides sedation, other CNS adverse effects such as aggression, paranoia, social withdrawal or lack of motivation may disrupt or prevent the initiation of normal performance, thus imposing a burden on the ability of the patients to function in a normal manner. Emotional disturbances are rare as indicated by the small number of case reports that mention their existence. Yet theses disturbances sometimes involve severe reactions that are more debilitating than sedation. Behavioural toxicity can be minimised by avoidance of pharmacodynamic and pharmacokinetic drug interactions, adjustment of dosage regimens to a patient's individual response to a drug, nocturnal administration of drugs that are expected to produce sedation and patient education on the potential risks of the drugs they receive. Much of this information can be gained from experimental literature comparing the effect of individual drugs on performance. Unfortunately this is presently incomplete, since most research on behavioural toxicity has been confined to psychiatric drugs. Yet, in the interest of the patient, it should be the responsibility of drug manufacturers and regulators to always identify problematic drugs.

健常日本人におけるコンピュータ眼球運動解析とＶｉｓｕａｌ Ａｎａｌｏｇｕｅ Ｓｃａｌｅを用いたＮｉｔｒａｚｅｐａｍの薬物動態 薬力学相関に対する評価

The effects of drugs on the central nervous system can be evaluated using a large number of tests in human. Since each test has a different sensitivity, to obtain pharmacodynamic parameters direct comparison of the results obtained by different tests is sometimes misleading. Thus, the choice of methods for evaluation likely affects the results of studies on sedative effects of drugs . Analysis of saccadic eye movement is reported to be a highly selective method to evaluate the sedative effect of benzodiaze-pines. This study was performed using computerized eye movement analysis to validate their application for evaluation of the effects of the anxiolytic, nitrazepam.A randomized, double-blind, placebo-controlled cross-over study was carried out with eight healthy volunteers. Nitrazepam (5 mg) or its placebo was administered in each occasion with a 2 week wash-out period. Pharmacodynamic tests (saccadic eye movement, smooth persuit and VAS) were performed before intake and 30, 45, 60, 75, 90, 105, 120, 135, 150, 180, 240, 360 and 480 minutes after the drug administration. Serum nitrazepam concentrations were measured by HPLC. Pharmacokinetic parameters of nitrazepam were as follows: Cmax: 75.78±28.86 ng/ml, tmax: 1.56±1.24 hr, t1/2: 27.10±6.09 hr. The tmax and t1/2 were similar to those reported in Caucasians. However, the Cmax of Japanese subjects was about two-fold higher than that of Caucasians. A significant decrease in saccadic peak velocity was observed in every subject after nitrazepam administration (treatment effect, p=0.002). Saccadic latency was significantly prolonged in the nitrazepam group (treatment effect, p=0.04). No significant effects on smooth pursuit performance were found (p=0.07).The concentration-effects relationship for saccadic peak velocity was described by a linear-model or clock-wise type.Measurement of saccadic peak velocity and saccadic latency have been used successfully to characterize the sedative effects of nitrazepam in healthy subjects. The computerized eye movement analysis is a simple, sensitive and reproducible method without pre-test exercise and can be applied for the evaluation of effects of other CNS acting drugs.

Ventilation and conscious sedation

H ' O W OFTEN has every anesthesiologist . been involved in a conversation like this? Hey Jim, why don't you step out and get a cup of coffee? Tell me about your patient. Oh, thanks, Sue. Nothing to worry about. It's just a MAC. Just a MAC! Unfortunately, the concept of monitored anesthesia care, (MAC) which usually includes the administration of sedative and/or analgesic medications to provide conscious sedation, often engenders an attitude of nonchalance and assumed safety. This perspective is shared by many of those involved in perioperative patient care: Patients, surgeons, nurses, operating room staff, and even some anesthesiologists tend to believe that conscious sedation is somehow safer than general anesthesia. However, conscious sedation is far from innocuous, significantly depressing ventilatory drive in patients whose airways and ventilation are not under our control. In fact, given our limited ability to accurately predict the response of individual patients to medications and to monitor their level of consciousness and adequacy of ventilation, one might consider the risks of conscious sedation to be equal to those of general anesthesia. Although it has proven to be relatively safe, several recent reports have underscored the potential risks of conscious sedation, both when administered alone (eg, for endoscopic procedures), and when administered as an adjunct to local or regional anesthesia. In a review of 900 closed insurance claims for major anesthetic mishaps, Caplan et al discovered 14 cases of sudden cardiac arrest in young, healthy surgical patients who received sedation during spinal anesthesia. A common thread was that patients received medications such as fentanyl, diazepam, droperidol, and thiopental until they were in a sleeplike state with no spontaneous verbalization. All suffered catastrophic neurological injury. 1 Do these cases represent an idiosyncratic interaction between conscious sedation and regional anesthesia or were they a predictable consequence of the depressant effects of the sedatives and analgesics these patients received combined with decreased sensory input resulting from regional anesthesia? Experiential and laboratory data describing ventilatory depression as a consequence of intravenous sedation abound. Before describing the effects of specific sedative drugs on ventilatory drive, we'll briefly review some basic mechanisms of ventilatory control.

Histamine and Seizures : Implications for the Treatment of Epilepsy.

Experimental studies have indicated that the central histaminergic neuron system plays an important role in the inhibition of seizures through stimulation of histamine H1 receptors, especially in the developmental period. This has therapeutic implications for currently available drugs that act at histamine receptors. H1 receptor antagonists, including classical antihistamines and anti-allergy drugs, occasionally induce convulsions in healthy children and patients with epilepsy. In particular, promethazine, carbinoxamine, mepyramine (pyrilamine) and ketotifen should be used with caution in these patients. These drugs are widely used as components of over-the-counter medications. The use of the d-chlorphenamine (d-chlorpheniramine) activation study with EEG monitoring is useful for assessing the seizure susceptibility of patients who have had convulsions secondary to administration of H1 receptor antagonists.H2 receptor antagonists have also occasionally been reported to induce convulsions in critically ill and polymedicated patients, and patients with chronic renal or hepatic failure. However, experimental findings have not been consistent with these clinical reports, such that the role of these receptors and their ligands in inducing seizures cannot be confirmed.Recently, H3 receptor antagonists, which enhance endogenous histamine release in the brain, have been demonstrated to have a potent anticonvulsant action. Therefore, these compounds may represent a new avenue for the development of antiepileptic drugs. Considering that H3 receptor antagonists also induce arousal patterns on the EEG, it is possible that they will not be associated with the sedative effects of many conventional antiepileptic drugs.

Possibilities of classification of topographically distributed neurophysiological multi-channel data

Progress in quantifying states of cerebral function and in the further development of automated EEG processing demands the application of suitable methods for the reduction of neurophysiological multi-channel data as well as their automatic classification. The method used here for reducing multi-channel data was to gain distributions of parametric descriptors from EEG data from computer-aided topographic electroencephalometry (CATEEM), for example the relative and absolute band power in the frequency bands delta, theta, alpha 1, alpha 2, beta 1, beta 2, total power, median and mode frequency, and other parameters. These values were subjected to cluster analysis. The classification of EEG parameters was carried out by means of discrimination analysis and neural networks. The practicability of both procedures was demonstrated in the reduction and classification of EEG data in the context of a normed study involving 104 healthy adults. These data have been used as the basis for a new evaluation study of 60 additional intraoperative EEG recordings obtained with CATEEM. In that newly started study, the effects of sedative and anaesthetic drugs on EEG behavior and psychophysiologic behavior remain to be investigated.

Placebo-effects contribute to differences in the acquisition of drug discrimination by humans

Adult human volunteers (n = 50) were trained to discriminate triazolam (TRZ, 0.32mg/70kg, p.o.) from placebo. Based on a criterion that required greater than 80% capsule-appropriate responding during each of four test sessions, 19 subjects were designated non-discriminators (NDs) and 31 were designated discriminators (Ds). NDs and Ds did not differ significantly in age, weight, gender or previous drug use and generally reported similar effects following TRZ. NDs reported greater effects following placebo than Ds on several measures, including 'good', 'bad', 'high' and sedative drug effects, suggesting that NDs in this study were 'placebo reactors'. These results show that NDs and Ds of TRZ differed in self-reported responses and suggest a close relationship between acquisition of a drug discrimination and self-reported effects of drugs. Moreover, greater placebo effects may hinder acquisition of TRZ discrimination.

A method for frequent measurement of sedation and analgesia in sheep using the response to a ramped electrical stimulus

A method for the frequent, precise measurement of the analgesic and sedative (or anesthetic) effects of drugs after bolus administration to sheep was developed. A ramped pulsed DC electrical stimulus was delivered to the hind limb of sheep via subcutaneous needles by use of a peripheral nerve stimulator modified to allow control of current ramp rate and pulse frequency, and limb withdrawal was used as an endpoint. The optimal stimulus pattern was found to be a pulse frequency of 20 Hz, with a 5-sec ramp time and measurement intervals of 30 sec. The effects of a range of analgesic and sedative drugs on the threshold current to produce limp withdrawal were examined. Administration of the sedative/anesthetic drugs propofol and thiopentone intravenously and of the analgesic xylazine both intravenously and intramuscularly resulted in a reproducible dose-dependent rise in the threshold current required to produce limb withdrawal. Administration of the opioids alfentanil and pethidine produced agitation, making measurements unreliable. It is concluded that this device allows repeated reproducible measurements of analgesia and sedation to be made in sheep at a frequency sufficient to characterize the initial effects of analgesic and sedative drugs, particularly after intravenous administration.

Fluoxetine

Fluoxetine was developed as an antidepressant drug. It is more effective than placebo, but a dose-effect relation has not been established. Fluoxetine is almost as effective as tricyclic antidepressant drugs, but the available studies do not allow accurate comparisons. Fluoxetine may be less effective than tricyclic antidepressant drugs for the treatment of inpatients with severe melancholic depression, and it should not be the first choice of a drug for them. Fluoxetine may be most appropriate for patients with moderate depression who can be treated as outpatients. If there is little improvement after treatment for four to six weeks, an alternative treatment should be offered. Fluoxetine does not have the anticholinergic, hypotensive, and sedative effects of tricyclic antidepressant drugs and has no particular cardiovascular effects; overdoses do not cause serious toxic effects. Nausea, anorexia, insomnia, and nervousness--the most common side effects--may be controlled with a careful adjustment to the dose. Clinically important drug interactions may occur with monoamine oxidase inhibitors, tricyclic antidepressant drugs, and other drugs. The published data on the antidepressant effect of fluoxetine do not fully explain its popularity. One may speculate that fluoxetine has psychobiologic effects not strictly related to the biology of depression and that it acts primarily as a mood- or affect-modulating agent.

Influence of microwave exposure on chlordiazepoxide effects in the mouse staircase test

To ascertain whether behavioral effects of benzodiazepines are altered by exposure to microwave radiation, we compared the performance of male, Swiss CD1 mice in the staircase test 30 min after pretreatment with chlordiazepoxide (8, 16, and 32 mg/kg, IP) and immediately following a 5-min exposure to microwave radiation (4, 12, and 36 W/kg, continuous wave, 1.8 or 4.7 GHz). In this paradigm, chlordiazepoxide reduction in the number of rears (NR) and number of steps ascended (NSA) is postulated to reflect anxiolytic and sedative drug effects, respectively. In sham-exposed mice, increasing doses of chlordiazepoxide increased NSA without affecting NR, increased NSA and decreased NR, then decreased both NSA and NR. Microwave exposure generally did not alter NSA or NR in mice pretreated with lower doses of chlordiazepoxide. However, in mice pretreated with 32 mg/kg chlordiazepoxide, exposure to 36 W/kg microwave radiation significantly reversed the reductions in NSA and NR at 4.7 GHz but not at 1.8 GHz. These findings indicate that exposure to microwave radiation can selectively alter effects of chlordiazepoxide in this psychopharmacological paradigm.

Effects of diazepam and hydromorphone in triazolam-trained humans under a novel-response drug discrimination procedure

Seven healthy normal male and female volunteers (21-31 years) were trained to discriminate between the benzodiazepine triazolam (0.32 mg/70 kg, PO; e.g., drug A) and placebo (e.g., drug B) under a three-choice, instructed novel response drug discrimination procedure. Once the criterion for discrimination was met (i.e., > 85% correct responding on four consecutive sessions), dose-effect curves were determined for triazolam (0.1-0.56 mg/70 kg), the benzodiazepine diazepam (10-32 mg/70 kg) and the opioid agonist hydromorphone (1-6 mg/70 kg). Subjects met the criterion for discrimination within four to six sessions. Triazolam and diazepam produced dose-related increases in triazolam-appropriate responding and no novel-appropriate responding at any dose tested. In contrast, hydromorphone generally increased novel-appropriate responding in a dose-related manner with placebo-appropriate responding and some triazolam-appropriate responding at intermediate doses occurring also. Triazolam and diazepam produced qualitatively similar increases on several measures of sedative drug effects; hydromorphone increased ratings of "like novel" and sedative-like effects in subjects who discriminated hydromorphone as novel relative to those who did not. These results indicate that the novel response drug discrimination procedure enhances the specificity of the triazolam-placebo discrimination.

Mechanisms of Obstructive Sleep Apneas in Infants

During sleep, infants with obstructive sleep apneas are characterised by snoring, laborious breathing, and profuse sweating. During wakefulness, they may have breath-holding spells, and during feeding, difficult breathing and swallowing coordination. Abnormal weight, difficult growth, and recurring ear infections may also develop. During sleep apneas, cinefluoroscopy shows approximation of tongue and hypopharyngeal tissues, with an obliteration of the air space. The obstructed breaths occur mainly in REM, and light NREM sleep, associated with total short sleep time, and frequent arousals. Preterm infants, and term neonates are more prone to obstructive apneas than older healthy infants. Apneas are more frequently seen in boys and in case of excess in body weight. Obstructive apneas are frequently associated with upper airway anatomic abnormalities: malformations, soft tissue infiltration, and neurologic lesions impairing muscle contractions. Alterations of the autonomic nervous control may induce airways obstructions. Contributing factors include mucopolysaccharide storage disease, hypothyroidism, or Down's syndrome. Superimposed factors may occur, such as nasal obstruction, secretions in the airways, or tissue edema. Pressure- and chemo-sensitive reflexes may also favor obstruction. Environmental factors also contribute to the development of sleep apneas: body position, neck flexion, sleep deprivation, or the effects of sedative drugs.

Microdialysis study of the effects of sedative drugs on extracellular histamine in the striatum of freely moving rats.

Microdialysis study of the effects of sedative drugs on extracellular histamine in the striatum of freely moving rats.

Saccadic eye movements as a quantitative measure of the sedative effect of drugs

On separate test days, seven healthy test subjects were given a single oral dose each of moclobemide (150 mg), desipramine (50 mg), amitriptyline (50 mg) or placebo in randomized order and under double-blind conditions. Horizontal 30° saccades were recorded 30 minutes prior to administration, and 30, 60 and 90 minutes, and 2, 3, 6 and 9 hours thereafter. The amplitude, peak velocity and duration of 15 saccades were recorded during each session. Moclobemide had only a very minor effect on the normal state of alertness: a significant, moderate degree of fatigue was noted only two hours after administration. In comparison with placebo, desipramine increased alertness slightly by lessening physiological fatigue under the test conditions. Amitriptyline caused relatively marked fatigue which peaked two hours after the tablet was taken and continued, decreasing gradually for up to nine hours.

A pharmacodynamic study of quazepam and triazolam

AbstractA double‐blind single oral dose study in 10 healthy volunteers was performed during the day to compare the diurnal effects of quazepam (15 mg) and triazolam (0.25 mg) on psychomotor performance. The central effect of the two benzodiazepines was assessed by means of a computer analysis of visually guided saccadic eye movements (SEM), critical flicker fusion threshold (CFFT), and choice reaction time (CRT). The results obtained suggest that: computer analysis of SEM is more sensitive than CRT and CFFT to detect sedative drug effects at a subclinical level; the presumed equipotent doses of quazepam and triazolam tested do not show the same sedative activity; the minimal impairment produced by quazepam on CNS function does not seem to be related to the property to bind to BZ1 receptors; the pharmacodynamic profile of quazepam seems to be characteristic of a “non‐sedative” agent, while triazolam behaves as a “sedative” benzodiazepine.