Elizabeth A. Lane

Treatment of childhood hyperactivity with desipramine: Plasma drug concentration, cardiovascular effects, plasma and urinary catecholamine levels, and clinical response

Twenty‐nine boys with attention deficit disorder/hyperactivity were randomly assigned to receive desipramine (DMI; n = 17) or placebo (n = 12) for 14 days in a noncrossover, double‐blind study. There was immediate behavioral improvement with DMI at day 3 that was sustained for 2 weeks; behavioral improvement did not correlate with plasma concentrations of DMI, hydroxy‐DMI, or their sum at either days 3 or 14. There were no untoward side effects; there was a drug‐induced increase in pulse and diastolic blood pressure. During drug therapy, the urinary excretion of norepinephrine, vanillymandelic acid, and 3‐methoxy‐4‐hydroxyphenylglycol (MHPG) was decreased at both days 3 and 14. The plasma MHPG level was decreased at days 3 and 14 and (standing) plasma NE levels increased at day 14. The decreases in both urinary and plasma MHPG levels showed significant correlations with behavioral improvement during the second week. These data corroborate previous findings on sympathomimetic effects of tricyclic antidepressants in children and support a noradrenergic mechanism in the mediation of drug effects on attention deficit disorder/hyperactivity.

Dose-related effects of ethanol on visual sustained attention and event-related potentials

The effects of acute ethanol intoxication on visual sustained attention were investigated in male social drinkers. Four doses ranging from 0 (placebo) to 1.05 g/kg lean body weight, with periodic maintenance dosing of 0.12 g/kg, were given in separate sessions. The task required subjects to monitor a series of blurred digits presented singly at a rate of one per sec and to respond to occasional (p = 0.25) target digits with a speeded button press. Detection performance deteriorated as a function of both dose and time on task. In addition, the factors of dose and time on task interacted to produce a more rapid performance decrement under the higher doses. Early event-related potential (ERP) components (N1 and P2) were not greatly affected, suggesting that the performance decrement reflects central rather than peripheral factors. Later components related to cognitive appraisal processes (N2, P3), in contrast, varied in both amplitude and latency. Ethanol yielded dose-related delays in N2 and P3 latencies, which paralleled reaction time increases. The amplitude of N2 also decreased over time on task, and P3 amplitude decreased both as a function of dose and time on task. ERP and performance data were interpreted as demonstrating an adverse effect of ethanol on central processing capacity.

Alcohol intoxication reduces visual sustained attention

Effects of alcohol intoxication on visual sustained attention were studied using a vigilance task entailing detection of degraded target stimuli. Data were obtained in separate sessions under four ethanol doses, ranging from 0 (placebo) to 1.05 g/kg lean body weight, with periodic maintenance dosing of 0.12 g/kg. Intoxication lowered the overall level of detection performance, and in addition produced dose-related increases in the rate of performance decrement over time. Analysis of performance data using techniques derived from Signal Detection Theory indicated that the decrements were due specifically to alterations in perceptual sensitivity. Examination of eye movements and blinks indicated that the effects of ethanol were not mediated peripherally. Rather, alcohol appears to have deleterious effects on central processing capacity and the availability of capacity over time. The alcohol-related failure of sustained attention may contribute to increased accident risk in tasks requiring continuous performance.

Effects of adinazolam and diazepam, alone and in combination with ethanol, on psychomotor and cognitive performance and on autonomic nervous system reactivity in healthy volunteers

SummaryEffects on psychomotor and cognitive performance of adinazolam (15 or 30 mg), alone and in combination with ethanol (0.8 g/kg), were studied in healthy male volunteers and compared to effects of 10 mg diazepam.Adinazolam 30 mg produced relatively long-lasting impairments on tests of tracking, attention, verbal and nonverbal information processing, and memory. Adinazolam 15 mg resulted in descreased visual information processing. Adinazolam decreased supine mean arterial pressure, but only the 15 mg resulted in a tendency for decreased plasma norepinephrine concentrations.After standing for 5 min, 30 mg adinazolam was associated with increased heart rate.Although ethanol consumption produced additive decrements on a continuous performance task, there was little evidence to support a synergistic effect.Adinazolam 30 mg was accompanied by increased self-reports of side effects, especially drowsiness.

Effects of Ethanol on Drug and Metabolite Pharmacokinetics

SummaryPharmacokinetic interactions of ethanol with other drugs, including its effects upon drug metabolite disposition, are reviewed in terms of clearance concepts. This approach is particularly useful in understanding the mechanisms of ethanol-drug interactions, i.e. in separating the effects of ethanol upon drug clearance, volume of distribution and plasma protein binding. The application of clearance concepts provides the basis for understanding the qualitative differences in ethanol interactions with low and high hepatic extraction ratio drugs.The effects of short and long term ethanol consumption upon different types of drug metabolism (oxidative, acetylation and glucuronidation) have been considered. Long term ethanol consumption may increase the clearance of a drug by induction of oxidative metabolism whereas short term consumption may decrease the clearance of such a drug. Clearance by N-acetylation appears to be increased in the presence of ethanol, and clearance by conjugation to glucuronic acid is decreased for some drugs by single-dose consumption of ethanol.

Abnormal neuroendocrine responsivity to acute I.V. clomipramine challenge in depressed patients

The neuroendocrine responsivity to an acute serotonergic challenge with low-dose i.v. clomipramine was studied in seven drug-free depressed patients and seven age-matched healthy control subjects. The depressed patients had higher baseline prolactin concentrations than the healthy subjects, and their prolactin response to clomipramine, assessed as either the percent of baseline or the log-transformed concentration, was significantly different (delayed and blunted peak response) compared to healthy controls. The growth hormone response was exaggerated in the depressed patients, and there were also trends toward blunting in their cortisol and adrenocorticotropic hormone responses. These results are consistent with previous findings of altered neuroendocrine responses to a variety of putative serotonin agonists in depressed patients.

Clinical studies on norepinephrine metabolism: how to interpret the numbers.

Metabolism, synthesis rates, and pharmacokinetics of major metabolites of endogenous norepinephrine were investigated in 38 drug-free depressed patients receiving a low monoamine diet on a closed ward. In a group of 21 patients, plasma and cerebrospinal fluid (CSF) concentrations of 3-methoxy-4-hydroxyphenyl-glycol (MHPG) correlated positively, but not significantly. In two groups of eight patients each, effects of desipramine and zimelidine on the central production rate of MHPG were examined using CSF and urine data. Both desipramine and zimelidine significantly reduced the central production rate of MHPG.

Effects of fluvoxamine, alone and in combination with ethanol, on psychomotor and cognitive performance and on autonomic nervous system reactivity in healthy volunteers

The effects of fluvoxamine (50 or 100 mg), alone and in combination with ethanol (0.8 g/kg), on psychomotor and cognitive performance and on autonomic nervous system reactivity were studied in healthy male volunteers. Fluvoxamine produced neither serious psychomotor or cognitive impairment nor alterations in autonomic nervous system functioning at these doses. There was no evidence that fluvoxamine exacerbated, or improved, ethanol-induced impairments of memory or any other measures evaluated. Fluvoxamine tended to improve recognition, but not free recall, of words.

Fluvoxamine treatment of alcoholic amnestic disorder

The serotonin uptake inhibitor fluvoxamine was assessed in treatment of alcohol-induced Korsakoffs syndrome (KS) using fixed (4 weeks, 200 mg/day) or individualized (6 weeks, plasma concentration > or = 400 ng/ml) dosing in randomized placebo-controlled double-blind crossover studies. Cognitive functions and concentrations of the major cerebrospinal fluid (CSF) metabolites of serotonin (5-HIAA), norepinephrine (MHPG), and dopamine (HVA) were determined in abstinent, nondepressed KS patients (aged 45-75), at baseline and placebo (3-4 weeks), and after 3-4 (n = 10) or 6 (n = 4) weeks of fluvoxamine administration. Fluvoxamine decreased CSF 5-HIAA compared to placebo (P < 0.003) without consistent changes in HVA or MHPG. Reductions in 5-HIAA correlated with improvements on the Wechsler Memory Scale Memory Quotient (P < 0.05), independent of effects on attention/vigilance or Beck Depression Inventory scores. Reductions in 5-HIAA correlated with plasma fluvoxamine (P < 0.03) only for fluvoxamine concentrations below 450 ng/ml. These findings suggest improvement of memory consolidation and/or retrieval in patients with Korsakoffs syndrome by fluvoxamine via serotonergic mechanisms.

Drug pharmacokinetics and the carbon dioxide breath test

The interrelationship of the pharmacokinetics of a drug and the expiration of carbon dioxide formed as a metabolite have been studied. The pharmacokinetic characteristics of the drug that affect the usefulness of the carbon dioxide excretion as a measure of liver function were examined by means of computer simulations. The parent drug extraction ratio, fraction demethylated, volume of distribution, and absorption rate of an oral dosage form all contribute to the carbon dioxide breath test result. A drug that would be a useful substrate when the carbon dioxide breath test is used as a probe for changes in liver function should be at least 50% metabolized by demethylation, have a hepatic extraction ratio of 0.2–0.5, and be administered in a form that is rapidly absorbed.