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Biomedical subjects

W Z Potter

Publications and source records attributed to W Z Potter.

At least 109 records · Page 6Linked to original sources
PubMed1990

Antidepressants, metabolites, and apparent drug resistance.

Antidepressant drugs are extensively metabolized prior to elimination from the body. These metabolites usually have biological and chemical properties different from those of the parent drug. This article explores the pharmacodynamic consequences of such metabolism as possibly contributing to failure to respond to or tolerate a drug. Differential side effects, especially of tricyclic antidepressant metabolites, are considered. Next, shifts in effects of presumed serotonin uptake inhibitors are described. Problems involving active metabolites of more novel compounds such as bupropion, amoxapine and trazodone range from possible reversal of response to prohibitive side effects. Finally, principles are deduced for identifying those cases in which metabolic considerations are most likely to be relevant to observed drug resistance.

Amoxapine↗
PubMed1990

Psychotropic medications and work performance.

The drug classes used to treat the major psychiatric disorders--antidepressants, antimanic agents, antipanic drugs, and neuroleptics--all produce side effects that may affect work performance. An understanding of the pharmacology of psychotropic drugs will enable the clinician to recognize the most common adverse effects of these drugs on performance. For example, tertiary amine tricyclic antidepressants and benzodiazepines may decrease alertness. The slowed visual accommodation produced by amine tricyclics or low-potency neuroleptics may adversely affect fine-motor control. Likewise, various psychotropic drugs, including neuroleptics and lithium (at toxic levels), may cause motor incoordination. However, the clinician should bear in mind that failure to provide treatment for psychiatric disorders is far more disruptive than are any side effects of such treatment.

Humans↗
PubMed1990

Plasma norepinephrine in chronic schizophrenia.

Several lines of evidence indicate altered noradrenergic function in schizophrenia. The authors examined resting, standing, and change (standing minus resting) in plasma norepinephrine levels in 14 drug-free patients with chronic schizophrenia or schizoaffective disorder and in 33 age- and sex-matched healthy volunteers. Schizophrenic patients had significantly higher resting and standing plasma norepinephrine levels and significantly greater change. Resting and standing levels were significantly related to positive and negative symptoms. There was a significant positive correlation between resting plasma and CSF norepinephrine levels and a significant negative correlation between CSF homovanillic acid and resting, standing, and change in plasma norepinephrine levels.

Adult↗
PubMed1990

Lysergic acid diethylamide (LSD) administration selectively downregulates serotonin2 receptors in rat brain.

A dosage regimen of lysergic acid diethylamide (LSD) that reliably produces behavioral tolerance in rats was evaluated for effects on neurotransmitter receptor binding in rat brain using a variety of radioligands selective for amine receptor subtypes. Daily administration of LSD [130 micrograms/kg (0.27 mumol/kg) intraperitoneally (IP)] for 5 days produced a decrease in serotonin2 (5-hydroxytryptamine2, 5-HT2) binding in cortex (measured 24 hours after the last drug administration) but did not affect binding to other receptor systems (5-HT1A, 5-HT1B, beta-adrenergic, alpha 1- or alpha 2-adrenergic, D2-dopaminergic) or to a recognition site for 5-HT uptake. The decrease was evident within 3 days of LSD administration but was not demonstrable after the first LSD dose. Following 5 days of LSD administration the decrease was still present 48 hours, but not 96 hours, after the last administration. The indole hallucinogen psilocybin [1.0 mg/kg (3.5 mumol/kg) for 8 days] also produced a significant decrease in 5HT2 binding, but neither the nonhallucinogenic analog bromo-LSD [1.3 mg/kg (2.4 mumol/kg) for 5 days] nor mescaline [10 mg/kg (40.3 mumol/kg) for 5 or 10 days] affected 5-HT2 binding. These observations suggest that LSD and other indole hallucinogens may act as 5-HT2 agonists at postsynaptic 5-HT2 receptors. Decreased 5-HT2 binding strikingly parallels the development and loss of behavioral tolerance seen with repeated LSD administration, but the decreased binding per se cannot explain the gamut of behavioral tolerance and cross-tolerance phenomena among the indole and phenylethylamine hallucinogens.

Animals↗
PubMed1989

Diurnal variation in the concentrations of catecholamines and indoleamines in the median eminence and in the intermediate and posterior lobes of the pituitary gland of the male rat.

Diurnal changes in monoamine concentrations were studied in the median eminence and in the intermediate and posterior lobes of the pituitary gland of the male rat. The concentrations of serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), noradrenaline (NA) and dopamine (DA) were analyzed at 7 time points over a 24-h period. Diurnal variation was analyzed by analysis of variance (ANOVA) with time of day as a class variable as well as by 24 h and 12 h cosine curve fittings. There were marked time-dependent changes in the median eminence concentrations of 5-HT (ANOVA: P = 0.0085), 5-HIAA (P = 0.003) and NA (P = 0.0003). Cosine curves with 24-h periods fit the data points with peaks around 13.00 h. DA levels also varied with an apparent 24-h rhythm in the median eminence, but the changes did not reach the level of significance in the ANOVA. In the intermediate lobe of the pituitary gland, the concentrations of DA varied significantly during the course of the 24-h cycle (P = 0.0011) and were well-fitted to a 24-h cosine wave. The 5-HIAA levels also showed marked diurnal changes (P = 0.025) with an evident 12-h rhythm. In contrast, NA and 5-HT concentrations did not appear to vary during the 24-h cycle. In the posterior lobe of the pituitary gland. DA had a 24-h rhythm (P = 0.0005) similar to the intermediate lobe. NA and indoleamine levels did not show any significant variation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Ten day administration of desipramine produces an increase in KL/KH for beta-receptors in rat hippocampus.

The action of chronic desipramine administration on agonist and antagonist binding to beta-adrenoceptors was investigated in rat frontal cortex and hippocampus. Ten day treatment with desipramine (10 mg/kg per day i.p.) resulted in a significant 34% decrease in the density of beta-adrenoceptors in membranes from rat frontal cortex but not hippocampus. The KD values for antagonist (iodocyanopindolol) did not change in either tissue after the desipramine treatment. Desipramine had no effect on the affinity of the agonist isoproterenol in frontal cortex. The percentage of receptors in the high affinity state for isoproterenol (% RH) decreased by 11% in the membranes from frontal cortex after desipramine administration. In contrast, in hippocampal membranes, desipramine treatment produced a decrease in KH (dissociation constant for isoproterenol binding to the high affinity state) and consequently a 137% increase in the ratio of dissociation constants for isoproterenol to the low and high affinity conformations (KL/KH; an putative index of coupling). This observation is new and suggests possible supercoupling of beta-adrenoceptors in hippocampus during desipramine treatment. Thus, in addition to desensitization of beta-adrenoceptors in rat frontal cortex ten day administration of desipramine causes a change compatible with supercoupling of beta-receptors in hippocampal membranes.

Animals↗
PubMed1989

Characterization of beta 1- and beta 2-adrenoceptor subtypes in the rat sinoatrial node and stellate ganglia by quantitative autoradiography.

We characterized beta-adrenoceptors in rat sinoatrial node (SA) and stellate ganglia by incubating consecutive tissue sections with [125I]iodocyanopindolol, with or without the beta 1-selective (CGP 20712A) or the beta 2-selective (ICI 118,551) antagonists, followed by quantitative autoradiography. In the stellate ganglia, ICI 118,551 displaced more than 90%, and CGP 20712A less than 5%, of the binding sites. CGP 20712A displaced about 50% of the binding sites in the SA, and about 65% in the rat atria. The SA has a high percentage of beta 2-adrenoceptors and the stellate ganglia contains almost exclusively beta 2-adrenoceptor binding sites, implicating beta 2-adrenoceptors in the control of heart rate in the rat.

Animals↗
PubMed1989

Fenfluramine and dextroamphetamine treatment of childhood hyperactivity. Clinical and biochemical findings.

Twenty boys (mean age, 9 +/- 2 years) with attention deficit disorder with hyperactivity received three weeks each of dextroamphetamine sulfate (0.5 mg/kg/d), fenfluramine hydrochloride (0.6 mg/kg/d increased to 2.0 mg/kg/d), and placebo in a double-blind, random-order, crossover design. Half the boys also met criteria for conduct disorder. Dextroamphetamine produced immediate and marked improvement in disruptive, overactive behaviors. Fenfluramine had no effect on any behavioral measure at either the low or high dosage. Both drugs decreased levels of urinary norepinephrine, 3-methoxy-4-hydroxyphenylglycol (MHPG), and vanillylmandelic acid. Fenfluramine, however, also produced a significant decrease in plasma MHPG levels and a larger decrease in urinary norepinephrine levels. It reduced urinary epinephrine levels as well, an effect opposite to that of dextroamphetamine. These findings suggest that different mechanisms of action are involved in the ability of the two drugs to reduce levels of MHPG and vanillylmandelic acid. Fenfluramine increased plasma prolactin levels and decreased platelet serotonin levels. Despite the structural similarity of the two drugs, some common overall effects on catecholamine metabolism, and similar effects on weight, fenfluramine had none of the motor activity or therapeutic effects of dextroamphetamine.

Attention Deficit Disorder with Hyperactivity↗
PubMed1989

Effects of renal clearance on plasma concentrations of homovanillic acid. Methodologic cautions.

Recently, there has been considerable interest in plasma concentrations of homovanillic acid (HVA) in various psychiatric disorders. Homovanillic acid is a weak organic acid, and its excretion probably resembles that of other organic acids (eg, p-aminohippuric acid) that are actively secreted by the kidney. Alterations in renal plasma flow can affect clearance of organic acids, resulting in changes in plasma concentrations. In our study, concentrations of plasma HVA and urinary HVA (from 24-hour urine collections) were measured in 20 prepubescent boys who received 3 weeks of placebo, dextroamphetamine sulfate, and fenfluramine hydrochloride in a randomized, double-blind, counterbalanced study of the treatment of attention-deficit disorder. Plasma HVA concentrations were significantly lower during fenfluramine treatment than during amphetamine treatment. This difference, however, seemed to be caused by alterations in renal clearance of HVA rather than changes in production. Whole-body production of HVA, as indexed by total urinary HVA excretion, was unaffected by the different treatments, while renal clearance of HVA did differ significantly between amphetamine and fenfluramine treatment. It seems that alterations in renal clearance can affect plasma HVA concentrations, which should be taken into account when plasma HVA is studied.

Child↗
PubMed1989

Intravenous alprazolam challenge in normal subjects. Biochemical, cardiovascular, and behavioral effects.

Alprazolam, a novel benzodiazepine derivative is thought to be effective in the treatment of anxiety, panic, and depressive disorders. There is considerable interest in alprazolam's mechanism of action, particularly whether its profile of actions might resemble that of the alpha 2 adrenoreceptor agonist, clonidine. The present study assessed the biochemical, cardiovascular, and behavioral responses of healthy volunteers to acute intravenous infusions of alprazolam and placebo. Alprazolam reduced ACTH and cortisol while increasing growth hormone. There was a transient reduction in plasma norepinephrine and only modest effects on cardiovascular parameters. Subjects became quite sedated after intravenous alprazolam. This pharmacodynamic profile resembles that previously reported for traditional benzodiazepines, although alprazolam may be a more potent stimulator of growth hormone release. Alprazolam's effects on growth hormone resemble those of clonidine, but unlike clonidine, alprazolam has relatively little effect on plasma catecholamine and cardiovascular parameters. This suggests that alpha 2 mechanisms do not play a primary role in alprazolam's mode of action. Since alprazolam infusion affects three different measures (ACTH/cortisol, growth hormone, and plasma norepinephrine) thought to be dysregulated in depression, challenge with intravenous alprazolam may prove to be a useful "probe" in affective disorders.

Adrenocorticotropic Hormone↗
PubMed1989

A neuroanatomical and biochemical basis for attention deficit disorder with hyperactivity in children: a defect in tonic adrenaline mediated inhibition of locus coeruleus stimulation.

Attention deficit disorder with hyperactivity (ADDH) is characterized by a high level of inappropriate activity, distractability and impulsivity as well as learning deficits. In mammals, the protective mechanism for acquisition of sensory information, processed for its survival value, can be termed "vigilance". In ADDH, a low threshold for novel or sensory stimuli, results in a "hard wired" mammalian response, orienting, followed by exploratory behavior, the orienting reaction. This behavior is mediated in the brainstem through sensory neurons in the reticular formation regulating the discharge of locus coeruleus noradrenergic neurons. It is proposed that adrenaline acts as a tonic inhibitor of these neurons, modulating the level of sensory stimulation necessary to elicit locus coeruleus excitation. An imbalance in adrenaline formation or alpha-2 adrenergic receptor number (or affinity) leads to the inability to maintain the appropriate threshold for discharge of locus coeruleus neurons. The consequences are inability to maintain focused attention, difficulty in falling asleep or light levels of sleep, inattention to consumptive behavior, and probable inappropriate response for reward as all these behaviors require disruption of processing of sensory stimuli. Cognitive deficits may occur secondarily.

Animals↗