Differential residual effects of zaleplon and zopiclone on actual driving: a comparison with a low dose of alcohol

STUDY OBJECTIVES: To compare residual effects of zaleplon 10 mg, zopiclone 7.5 mg, and placebo, and a social dose of alcohol on car driving, memory, and psychomotor performance. DESIGN: Two-part placebo controlled, crossover study. Part 1 was single blind, Part 2 double blind. SETTING: University research institute. PARTICIPANTS: Thirty healthy volunteers (15 men and 15 women, mean age 32 +/- 7 years) INTERVENTIONS: In Part 1 alcohol and alcohol-placebo drinks were administered around noon. In Part 2 single oral doses of zaleplon 10 mg, zopiclone 7.5 mg and placebo were administered at bedtime. MEASUREMENT AND RESULTS: A highway driving test, laboratory tests of word learning, critical tracking and divided attention, and subjective assessments of sleep, mood, and effects of treatments on driving. Driving started 40 minutes after a second alcohol dose in Part 1, and 10 hours after drug intake in Part 2. The results demonstrated that alcohol, at average plasma concentrations of approximately 0.030 g/dl, significantly impaired performance in all tests. Zaleplon's residual effects did not differ significantly from those of placebo in any test. In contrast, zopiclone had significant residual effects on driving, divided attention, and memory. The magnitude of impairment in the driving test observed the morning after zopiclone 7.5 mg was twice that observed with alcohol. CONCLUSION: Zaleplon 10 mg has no residual effects on driving when taken at bedtime, 10 hours before driving. In contrast, zopiclone 7.5 mg can cause marked residual impairment. Patients should be advised to avoid driving the morning after zopiclone administration.     

A dose-ranging study of the effects of mequitazine on actual driving, memory and psychomotor performance as compared to dexchlorpheniramine, cetirizine and placebo

BACKGROUND: Mequitazine is a so-called 'non-sedative' second-generation antihistamine even though it has never been firmly established that this drug's sedative potential actually differs from that of the 'sedative' first-generation antihistamines. OBJECTIVE: The present study compares the sedative effects of three doses of mequitazine on actual driving, psychomotor performance and memory with those of a first- and a second-generation antihistamine. METHODS: Eighteen healthy volunteers received on separate days a single dose of 5, 10 and 15 mg mequitazine, 10 mg cetirizine, 6 mg dexchlorpheniramine and placebo. Drug effects were assessed using two actual driving tests (highway-driving test and car-following test), cognitive and psychometric tests (tracking, divided attention, memory, reasoning and critical flicker fusion), pupil size and questionnaires. RESULTS: Highway-driving data revealed an overall effect of Treatment on the standard deviation of lateral position (SDLP). Dexchlorpheniramine impaired driving performance as indicated by a significant rise in SDLP. Mequitazine significantly increased SDLP in a dose-related manner, but the separate dose effects failed to reach statistical significance. Divided attention performance was also affected by Treatment. Reaction time (RT) during mequitazine treatments increased in a dose-related manner and significantly differed from placebo at the highest dose. Subjects reported to be less alert after treatment with dexchlorpheniramine. Cetirizine did not affect performance in any of the tasks. CONCLUSION: It was concluded that mequitazine is mildly sedating. The effects of mequitazine are comparable to those of other second-generation antihistamines, in that it causes mild driving impairment, particularly at higher doses.     

Prolonged nocturnal driving can be as dangerous as severe alcohol-impaired driving

In industrialized countries one-fifth of all traffic accidents can be ascribed to sleepiness behind the wheel. Driver sleepiness can have many causes, including the use of medicinal drugs or prolonged driving. The present study compared the effects of prolonged highway driving at night with driving impairment caused by alcohol. A cross-over balanced design tested 14 healthy young men who drove three sessions during night-time on the open road. The driving sessions were of 2, 4 and 8 h (03:00-05:00, 01:00-05:00 and 21:00-05:00 hours) duration. Standard deviation of lateral position (SDLP, cm), measuring the weaving of the car in the last driving hour of each session, was the primary parameter. Only 2 h of continuous nocturnal driving were sufficient to produce driving impairment comparable to a blood alcohol concentration (BAC) of 0.05%; after 3 h of driving impairment corresponds to a BAC of 0.08%. In conclusion, a maximum of two continuous nocturnal driving hours should be recommended.     

The effects of "anti-platelet" drugs on bleeding time and platelet aggregation in normal human subjects.

The effects on hemostasis of several commonly used drugs previously described as inhibiting platelet function were evaluated in a randomized, double-blind study of 54 normal volunteers. The subjects were each given a single dose of aspirin, chlorpromazine, glyceryl guaiacolate, diphenhydramine, indomethacin or lactose placebo. A single dose of aspirin significantly prolonged the template bleeding time and inhibited secondary platelet aggregation two and 24 hours after ingestion. Single doses of indomethacin and chlorpromazine affected aggregation at two hours but had no effect on bleeding time, although multiple doses of indomethacin did prolong bleeding time. Glyceryl guaiacolate inhibited aggregation one hour after ingestion but had no effect on bleeding time. Diphenhydramine did not affect either. These findings suggest that standard doses of many commonly used "anti-platelet" drugs may have little clinical effect on the hemostatic mechanism in normal man. Results of in-vitro platelet-drug incubations may not be directly applicable to in-vivo hemostasis.     

The effects of terfenadine with and without alcohol on an aspect of car driving performance

Twelve healthy female volunteers received acute doses of terfenadine, 60 mg, 120 mg, 240 mg or placebo, followed by a 'social' dose of alcohol equivalent to 0.5 g absolute alcohol/kg body weight. Performance was assessed on laboratory analogues of car driving both before and after alcohol administration. Terfenadine (240 mg) was found to significantly impair performance alone and following alcohol. The results demonstrate the importance of establishing the behavioural effects of drugs over a range of doses.     

Interaction studies in mice of SCH 29851, a potential nonsedating antihistamine,with commonly used therapeutic agents

SCH 29851 was studied for its ability to interact with selected drugs used in man. The non-sedating antihistamine terfenadine and the sedating antihistamine diphenhydramine were also studied for comparison.SCH 29851 at 80 mg/kg po in mice, a dose about 50 times its ED₅₀ for blocking histamine-induced paw edema in the same species, potentiated the anticonvulsant effects of diazepam. At the high dose of 320 mg/kg po, about 80 times its ED₅₀ for antihistamine effects, SCH 29851 potentiated the ability of high doses of ethanol and hexobarbital to induce loss of righting reflexes (LRR). However, no potentiation was seen when SCH 29851 was studied with lower doses of ethanol or phenobarbital that had anticonvulsant effects but did not cause LRR. At this high dose of 320 mg/kg po, SCH 29851 also did not interact with the antihypertensive drugs propranolol and -methyldopa, the anti-ulcer drug cimetidine, the nasal decongestant pseudoephedrine, or the CNS stimulant d-amphetamine.A nearly identical profile of interactions was seen with terfenadine, including potentiation of diazepam at 50 times its antihistamine ED₅₀, potentiation of ethanol- and barbiturate-induced LRR at 80 times its antihistamine ED₅₀, and lack of interaction effects at 320 mg/kg po with each of the other tested drugs.The demonstration in this study of the significant interactions between diphenhydramine and many of the tested drugs is consistent with the clinical experience in man that this drug does have sedating properties and significant interactions with drugs like ethanol and diazepam.The similarity of the results obtained in this study with SCH 29851 and terfenedine suggests that these drugs will not differ significantly in clinical use. It seems likely, therefore, that antihistaminic effects will be achieved without significant sedative-hypnotic actions or interactions with drugs commonly used in man, e.g. ethanol, barbituates, and benzodizepines. However, confirmation of this prediction necessarily awaits the results of clinical trials.     

Antihistamines and driving ability: evidence from on-the-road driving studies during normal traffic.

BACKGROUND: All antihistamines are capable of crossing the blood-brain barrier and thus may cause sedation. Most antihistamine users are ambulatory patients and therefore presumably drive a car. OBJECTIVE: To summarize the effects of antihistamine drugs on driving ability. DATA SOURCES AND STUDY SELECTION: A literature search (MEDLINE and cross-references) was performed using the keywords driving and antihistamine. Sixteen studies using the on-the-road driving test during normal traffic were included in the review. Studies were double-blind and placebo-controlled and included a positive control. RESULTS: First-generation antihistamines (diphenhydramine, triprolidine, terfenadine, dexchlorpheniramine, clemastine) significantly impair driving performance after both one-time and repeated (daily) administration. Second-generation antihistamines (cetirizine, loratadine, ebastine, mizolastine, acrivastine, emedastine, mequitazine) may also impair driving performance, but the magnitude and extent of impairment depend on the administered dose, sex, and time between testing and treatment administration. Tolerance develops after 4 to 5 days of administration, but impairment is not absent. Third-generation antihistamines (fexofenadine and levocetirizine) have been shown to produce no driving impairment after both one-time and repeated administration. CONCLUSIONS: First- and second-generation antihistamines may significantly impair driving performance. In the context of driving safety but also taking into account the cardiotoxic properties of some of the second-generation antihistamines, we advise treating patients with third-generation antihistamines such as fexofenadine and levocetirizine.     

A review of the cardiac systemic side-effects of antihistamines: ebastine

The cardiac safety of ebastine, a long-acting, non-sedating antihistamine, has been thoroughly assessed in phase I–III clinical studies. Ebastine alone at the recommended doses of 10 mg and 20 mg has no clinically relevant effect on QTc interval in adults and in special patient populations (elderly, children or subjects with hepatic or renal impairment). Ebastine administered at 60 and 100 mg/day (3–5 times the maximum recommended dose) for 1 week had statistically significantly smaller effects (3.7 and 10.3 msec, respectively) on the QTc interval than terfenadine (18 msec) at three times the recommended dose (360 mg/day). The mean QTc interval prolongation observed with ebastine 100 mg/day was small and not clinically meaningful, although the results were statistically significant vs. placebo. The effect of ebastine 60 mg/day was not statistically different from placebo. Steady-state drug interaction studies demonstrated that the co-administration of ebastine 20 mg with ketoconazole or erythromycin produced significant increases in systemic exposure for ebastine, which were accompanied by small increases in QTc (approximately 10 msec above ketoconazole or erythromycin alone). Results from individual studies suggest that, when coadministered with ketoconazole, ebastine produces similar changes in QTc interval measurements compared to loratadine and cetirizine. Pooled data from clinical efficacy trials of ebastine 1–30 mg/day administered for 2–3 weeks showed no clinically relevant cardiac effects as assessed by serial electrocardiographs and Holter monitoring. The overall cardiac safety profile based on currently available information suggests that ebastine, like loratadine and cetirizine, has a lower potential for causing adverse cardiovascular effects than terfenadine.     

Sensitivity to triazolam in the elderly

BACKGROUND. Elderly persons frequently appear to be sensitive to the effects of many drugs that depress the central nervous system. We studied the effect of age on the pharmacokinetics and pharmacodynamics of the benzodiazepine hypnotic agent triazolam, now the most frequently prescribed hypnotic drug in the United States. METHODS. Twenty-six healthy young subjects (mean age, 30 years) and 21 healthy elderly subjects (mean age, 69 years) participated in a four-way crossover study. After a single-blind adaptation trial with placebo, each subject received, in random order and in double-blind fashion, single doses of placebo, 0.125 mg of triazolam, and 0.25 mg of triazolam. For 24 hours after the administration of each of the three study medications, plasma triazolam levels were determined and psychomotor performance, memory, and degree of sedation were assessed. RESULTS. Plasma triazolam concentrations increased in proportion to the dose, but the elderly subjects had higher plasma concentrations due to reduced clearance of the drug. The degree of sedation as rated by an observer and the reduction in the subjects' performance on the digit-symbol substitution test were both greater in the elderly than in the young subjects after they were given the same doses. The relation of the plasma triazolam concentration to the degree of impairment was similar for the two groups. As part of the study, information was presented 1 1/2 hours after the administration of the drugs; the subjects' ability to recall the information 24 hours later was impaired by both doses of triazolam, and the percent decrease was similar in the young and elderly groups. CONCLUSIONS. Triazolam caused a greater degree of sedation and greater impairment of psychomotor performance in healthy elderly persons than in young persons who received the same dose. These effects resulted from reduced clearance and higher plasma concentrations of triazolam rather than from an increased intrinsic sensitivity to the drug. On the basis of these results, the dosage of triazolam for elderly persons should be reduced on average by 50 percent.     

An evaluation of the effects of high-dose fexofenadine on the central nervous system: a double-blind, placebo-controlled study in healthy volunteers.

BACKGROUND: As regards central nervous system (CNS) effects there are three types of antihistamines. Those that cross the blood-brain barrier and cause widespread impairment of cognitive and psychomotor function; those that cross into the brain and, although without much impairment at low clinical doses, have a dose-related relationship to impairment; and those that do not cross into the brain and therefore possess no intrinsic potential for impairing CNS function. OBJECITVE: To investigate the acute effects of fexofenadine (360 mg) on various aspects of cognitive and psychomotor function in comparison to placebo and promethazine (positive internal control), an antihistamine known to produce psychomotor and cognitive impairment. METHODS: Fifteen healthy volunteers received fexofenadine 360 mg, promethazine 30 mg and placebo in a 3-way cross-over, double-blind study. For each treatment condition, subjects were required to perform a series of tests of cognitive function and psychomotor performance at baseline and 1, 3, 5 and 7 h post-dose. The test battery consisted of critical flicker fusion (CFF), choice reaction time (CRT), compensatory tracking task (CTT) and a subjective assessment of sedation (LARS). RESULTS: Fexofenadine was not distinguishable from placebo in any of the objective and subjective tests for up to seven hours following drug administration. However, all measures were significantly impaired following the administration of promethazine, which confirms the sensitivity of the test battery for sedation. The effects of fexofenadine and placebo were not significantly different from one another, whereas promethazine caused an overall reduction in CFF thresholds when compared to placebo (P < 0.05). There was an overall significant increase (impairment) in recognition, motor and total reaction time (P < 0.05), and both the tracking accuracy and reaction time aspects of CTT were significantly impaired (P < 0.05) following the administration of promethazine. In contrast, the effects of fexofenadine could not be distinguished from the placebo condition. Subjective ratings of sedation were significantly higher with promethazine when compared to placebo (P < 0.05) and fexofenadine (P< 0.05). CONCLUSIONS: Fexofenadine at a dose of 360mg is demonstrably free from disruptive effects on aspects of psychomotor and cognitive function in a study where the psychometric assessments have been shown to be sensitive to impairment, as evidenced by the effects of the verum control promethazine 30 mg. The identification of an antihistamine (fexofenadine) devoid of central effects even at supraclinical doses separates it from currently available first and second generation drugs with no objective evidence of CNS side-effects on cognition and psychomotor function, and highlights the need for the introduction of a third generation of non-sedative antihistamines.     

The meaning of lung dose

For a physician to understand how to prescribe appropriate doses of drugs via aerosol requires a basic understanding of the technical issues involved. Drugs are usually prescribed in terms of "nominal dose" (total dose of drug prescribed). This dose is device-specific, as recommended doses are different for different devices. The effective component of the nominal dose is the "lung dose", which is the mass of drug delivered to the lung. A given clinical effect should, in general, be produced by a given lung dose irrespective of the delivery device. However, the effect of a lung dose depends on several factors, including: 1) site of deposition 2) rate of clearance of the drug from airway 3) site of action of the drug.
Confirmation that a particular lung dose will produce a desired clinical effect usually requires that a clinical trial be performed. The lung dose should be reflected by data on lung deposition, but interpreting such data requires that the following are considered: 1) Lung deposition figures can be stated in different ways: a) percentage of the nominal dose b) percentage of the mass of drug leaving the aerosolgenerating device c) percentage of the mass of drug entering the mouth or nose. 2) The radiation from an inhaled aerosol is attenuated as it leaves the lung. Approaches vary as to how this correction is done, affecting the quoted data on percent deposition. 3) In children, lung deposition is age-dependent, but the effect of age on delivery is different for different devices.
There are major differences in the efficiency of delivery for different devices with a range of 6–60%. When "adaptive aerosol delivery" nebulizers become available, they should provide an accurate dose of drug to the lung with very low variability. In summary, the concept of lung dose is useful in understanding the related technical aspects, and it has the potential to allow drugs to be prescribed more accurately.     

Falls,injuries from falls,health related quality of life and mortality in older adults with vision and hearing impairment-Is there a gender difference?

Background

Vision and hearing decline with age. Loss of these senses is associated with increased risk of falls, injuries from falls, mortality and decreased health-related quality of life (HRQOL). Our objective was to determine if there are gender differences in the associations between visual and hearing impairment and these outcomes.

Methods

2340 men and 3014 women aged 76–81 years from the Health in Men Study and the Australian Longitudinal Study on Women's Health were followed for an average of 6.36 years. Dependent variables were self-reported vision and hearing impairment. Outcome variables were falls, injuries from falls, physical and mental components of HRQOL (SF-36 PCS and MCS) and all-cause mortality.

Results

Vision impairment was more common in women and hearing impairment was more common in men. Vision impairment was associated with increased falls risk (odds ratio (OR) = 1.77, 95% CI = 1.35–2.32 in men; OR = 1.82, 95% CI = 1.44–2.30 in women), injuries from falls (OR = 1.69, 95% CI = 1.23–2.34 in men, OR = 1.79, 95% CI = 1.38–2.33 in women), and mortality (hazard ratio (HR) = 1.44; 95% CI = 1.17–1.77 in men; HR = 1.50, 95% CI = 1.24–1.82 in women) and declines in SF-36 PCS and MCS. Hearing impairment was associated with increased falls risk (OR = 1.38, 95% CI = 1.08–1.78 in men; OR = 1.45, 95% CI = 1.08–1.93 in women) and declines in SF-36 PCS and MCS. Overall there were no gender differences in the association between vision and hearing impairment and the outcomes.

Conclusion

In men and women aged 76–81 years, there were no gender differences in the association between self-reported vision and hearing impairment and the outcomes of falls, mortality and HRQOL.     

Hippocampal alpha 7 and alpha 4 beta 2 nicotinic receptors and working memory

Nicotine and other nicotinic receptor agonists have been found in a variety of studies to improve memory, while nicotinic receptor blockade can impair memory. The critical neural mechanisms for nicotinic involvement with memory are still under investigation. Initial evidence supports the involvement of the ventral hippocampus. Lesions in this area block nicotine-induced memory improvement and mecamylamine-induced impairment. Local ventral hippocampal application of the nicotinic channel blocker mecamylamine impairs memory in the 8-arm radial maze. Both alpha 4 beta 2 and alpha 7 nicotinic receptors seem to be involved. Ventral hippocampal infusions of high doses of the alpha 4 beta 2 nicotinic antagonist dihydro-beta-erythrodine (DH beta E) and the alpha 7 nicotinic antagonist methyllycaconitine (MLA) impair memory performance on the 8-arm radial maze. However, high doses of these drugs may limit specificity and they cause preconvulsant effects, which in themselves may affect memory. The current study used the more challenging 16-arm radial maze to determine the effects of lower doses of these drugs on memory and to differentiate effects on working and reference memory. Adult female Sprague-Dawley rats were trained on a working and reference memory task in the 16-arm radial maze and then were implanted with bilateral chronic guide cannulae directed to the ventral hippocampus. After recovery from surgery, the rats received acute intrahippocampal infusions of dose combinations of DH beta E and MLA. In the first study, DH beta E (0 and 6.75 microg/side) and MLA (0, 6.75, 13.5 and 27 microg/side) were administered in a counter-balanced order. In the second study, lower doses of DH beta E (0, 1.6375, 3.275 and 6.75 microg/side) were administered alone or with MLA (0 and 6.75 microg/side) in a counter-balanced order. In the first study, DH beta E caused a significant increase in both working and reference memory errors. MLA at a dose of 27 microg/side caused a significant increase in working memory errors, but this dose had no significant effect on reference memory errors. Interestingly, no additive effects were seen with combined administration of DH beta E and MLA in this study, and at the doses used, no effects were seen on response latency. In the second study, lower doses of DH beta E did not cause a significant deficit in working memory performance. Co-administration of MLA with these subthreshold doses did precipitate a memory impairment. The current results confirm the specificity of the memory deficits caused by these drugs. These results support the involvement of alpha 4 beta 2 and alpha 7 nicotinic receptors in the ventral hippocampus as being critical for memory function.     

Scopolamine impairs the response-to-change following observation of the environment but not after its exploration by the rat

The tendency to select the T-maze arm that has been changed in brightness between two successive trials (response-to-change) was investigated in rats injected with scopolamine (Sc) or saline (NaCl) 20 min before the test. In the "passive" version of the test, when in trial 1 rats could inspect the white-black arms through clear partitions blocking the entrance to the arms, a dose of when in trial 1 rats could inspect the white-black arms through clear partitions blocking the entrance to the arms, a dose of 1.0 mg/kg Sc decreased significantly the number of changed arm choices in trial 2, as compared to saline controls. A lower dose of Sc (0.5 mg/kg) was ineffective. In the "active" test version, when in trial 1 the rats were allowed to explore the white-black arms, doses of 1.0 and 2.0 mg/kg Sc did not affect the preference for the changed arm in trial 2. NaCl rats showed a significant preference for the changed arm choices in both tests. The scopolamine effects on response-to-change, i.e., impairment of performance in the passive but not in the active version, were essentially the same as those found by us previously in hippocampal rats.     

Bronchodilator effects of terbutaline and aminophylline alone and in combination in asthmatic patients.

In 17 patients with moderate to severe asthma, we compared acute bronchodilator effects of the following drugs or drug combinations using a double-blind crossover design: terbutaline, 5; aminophyline 400; terbutaline, 5, plus aminophyline, 400; terbutaline, 2.5; aminophylline, 200; terbutaline, 2.5, plus aminophyline, 200 mg; and placebo. The higher doses of terbutaline and aminophylline alone produced comparable bronchodilation and similarly frequent adverse side effects; low doses of each drug also had comparable effects. The high-dose combination produced significantly (P less than 0.05) greater bronchodilatation than either drug alone. The low dose combination had bronchodilator effects comparable to those produced by the higher dose of either drug alone. These findings suggest therapeutic advantages in combining high doses of theophylline and an oral beta adrenergic agonist (terbutaline) in asthma not well controlled on high doses of either drug alone and in combining these drugs in lower doses in patients experiencing intolerable side effects from a high dose of either drug.     

The effect of combining subtherapeutic concentrations of different ionophorous antibiotics on anticoccidial action in chickens

The mode of action of polyether, ionophorous drugs against Eimeria infections in chickens was studied by feeding subeffective doses of drugs separately and in combination, in comparison with the full dose of each drug. Thus, monensin, lasalocid and salinomycin (50, 35 and 30 ppm, respectively) were compared with a full dose of the same drugs. The combinations of ionophorous antibiotics were as effective in controlling Eimeria tenella and E. acervulina infections as the single antibiotic mixed in the feed at recommended prophylactic concentrations. When intracellular sporozoites of E. tenella were treated with the drugs in vitro, the effects on morphology were similar, regardless of which drug was used.The additive effects of these drugs in the chicken, and their similar effects on intracellular sporozoites suggest that they have a similar mode of action on Eimeria sporozoites, despite differences in ion selectivity.     

Comparison of the Effect of the β1-Blocking Drugs Atenolol and Metoprolol on Bronchial Asthma

Twenty patients with severe or medium severe asthma were given atenolol (Atenor® (CI – Pharma) and/or metoprolol (Soleken® Hässle) for tachycardia, hyperkinetic tremor, arterial hypertension or symptoms of angina pectoris. These cardioselective β-blocking drugs caused only a very slight decrease in PF values. There was no difference between atenolol and metoprolol as regards the PF values A 24 hourly dose of 100 mg atenolol caused a distinct fall in diastolic pressure as compared with the same amount of metoprolol. Both these two β₁-blockers moderated the tachvcardia which occurs in asthma; atenolol in this dose had a slightly stronger action.
The subjective condition of five patients with severe or medium severe asthma was considerably relieved by atenolol and/or metoprolol. The relief manifested as a lessening of dyspnoea and improvement of the general status. No essential change was observed in the PF values despite the subjective effects. The most noteworthy change was the amelioration of tachycardia which had continued longer than expected in these patients. The heart rate dropped from 140–120/min to 90–70/min and dyspnoea was relieved at the same time.     

Effects of two doses of alcohol on simulator driving performance in adults with attention-deficit/hyperactivity disorder

Prior studies have documented greater impairments in driving performance and greater alcohol consumption among adults with attention-deficit/hyperactivity disorder (ADHD). This study examined whether alcohol consumption produces a differentially greater impairment in driving among adults with ADHD in comparison to a community control group. The present study compared 50 adults with ADHD (mean age 33 years) and 40 control adults (mean age 29 years) on the effects of 2 single, acute doses of alcohol (0.04 and 0.08 blood alcohol concentration) and a placebo on their driving performance. The authors used a virtual reality driving simulator, examiner and self-ratings of simulator performance, and a continuous performance test (CPT) to evaluate attention and inhibition. Approximately half of the adults in each group were randomized to either the low or high dose alcohol treatment arms. Alcohol consumption produced a greater impact on the CPT inattention measures of the ADHD than the control group. Similar results were obtained for the behavioral observations taken during the operation of the driving simulator. Driving simulator scores, however, showed mainly a deleterious effect of alcohol on all participants but no differentially greater effect on the ADHD group. The present results demonstrated that alcohol may have a greater detrimental effect on some aspects of driving performance in ADHD than control adults.     

Drug interference with measurement of metanephrines in urine

The influence of 35 commonly used drugs on measurement of metanephrines in urine was evaluated. Two concentrations of drugs were chosen for study based on usual doses and the percent of dose excreted unchanged in the urine. At "medium" drug concentrations, only phenylephrine falsely elevated metanephrine levels, whereas at a 10-fold higher drug concentration, guanethidine, hydrocortisone, imipramine, isoetharine, levodopa, phenobarbital, and phenylephrine caused positive interference. Propranolol and theophylline caused a negative interference at the two concentrations studied. The significance of these results is discussed.     

Kinetics and cardiac effects of propranolol in humans

Summary Six healthy volunteers received single 20-mg intravenous (IV) and 80-mg oral doses of propranolol on two occasions in random sequence. Serum propranolol concentrations were determined by gas chromatography in multiple samples drawn during 24 h after each dose. Mean (±SE) kinetic variables for IV propranolol were: elimination half-life (t1/2), 5.3 (±0.6) h; volume of distribution, 2.3 (±0.3) l/kg; total clearance, 4.9 (±0.3) ml/min/kg; predicted extraction ratio, 0.23 (±0.02). After single oral doses, t1/2 (3.8±0.2 h) tended to be smaller than after the IV dose, and actual systemic availability (0.60±0.07) was less than that based on the predicted extraction ratio. During multiple oral dosage (80 mg every 12 h), observed steady state serum levels (47±5 ng/ml) tended to be less than those predicted based on the single oral dose (61±5 ng/ml), thus providing no evidence for reduced propranolol clearance at steady-state. Echocardiographic measurements of left ventricular performance (posterior wall velocity, diastolic dimensions) made during the single-dose oral study indicated significant impairment of function; impairment was maximal at 3 h post-dosage, and corresponded to the time of the peak serum propranolol concentration (341 ng/ml).Supported in part by Grant Oc 10/6-3 from Deutsche Forschungsgemeinschaft, Bonn-Bad Godesberg, FRG; and by Grant MH-34223 from the United States Public Health Service