Mnemonic effects of asthma medication in children.

Asthmatic children receiving theophylline or steroid-theophylline combination therapy and normal nonasthmatics were given tests of visual retention and paired-associate learning. The performance of children receiving combination therapy was significantly worse than that of the nonasthmatics 6-8 hours after receiving steroid medication, but not 22-24 or 46-48 hours after medication. Children receiving theophylline alone did not differ from nonasthmatics on these tasks. These observations suggest that steroid-inclusive medication regiments can affect cognitive performance.

Variation in theophylline clearance rate with time in chronic childhood asthma.

Wide theophylline clearance rate (TCR) range between different individuals has been reported, but little is known about its change with the passage of time. Optimal theophylline therapy for asthma aimed at plasma or serum levels of 10 to 20 microng/ml is now strongly recommended. Significant TCR variability with time might easily result in theophylline levels in the toxic or subtherapeutic ranges. Thirty severe asthmatics (mean age, 13 yr) received 24 hr constant intravenous infusion of 1 mg/kg/hr aminophylline USP. TCR was determined after a steady state was reached. Twelve of these patients with persisting poorly controlled asthma underwent repeat infusion for TCR determination at intervals of 1 to 8 mo (mean, 4.7 mo). When these results were compared to the initial individual TCR, the mean absolute change was 28 +/- 24% (mean +/-SD). Thus, this significant individual variation in TCR with the passage of time (p less than 0.01) requires periodic monitoring of plasma theophylline levels in severe asthma treated by optimized theophylline dosage.

Developmental and genotypic effects on pituitary-adrenal function and alcohol tolerance in mice.

Lactating females of 2 lines of mice selectively bred for long (LS) and short (SS) ethanol-induced sleep time (a measure of alcohol tolerance) consumed either tap water or 10% ethanol in tap water on Days 2-14 postpartum. Effects of genotype and neonatal treatment on offspring open-field behavior, alcohol-induced sleep time, and adrenocortical responsiveness to alcohol or saline injection were studied. The LS mice had higher ethanol-induced sleep times than SS mice, and also higher plasma corticosterone levels following alcohol challenge. The LS mice also responded more to saline injection and to novelty stress, suggesting that they were generally more responsive to stressors than SS mice. Significant genotype-dependent effects of neonatal treatment on (1) adrenocortical responsiveness to injection stess and (2) alcohol tolerance were noted. However, these 2 effects did not appear to be causally related. Neonatal treatment had no effect on open-field activity or defecation in either genetic line.

Effects of 6-hydroxydopamine and reserpine on amphetamine-induced release of norepinephrine in rat cerebral cortex.

Amphetamine released 3-H-norepinephrine from rat cerebral cortex tissue which had previously accumulated the 3-H-amine. Destruction of noradrenergic nerve endings by pretreatment of the rats with 6-hydroxydopamine inhibited the accumulation of 3-H-norepinephrine by the tissue and reduced the proportion of the 3-H-amine which was released by amphetamine. Inhibition of storage of 3-H-norepinephrine within nerve endings by pretreatment of the animals with reserpine also reduced accumulation of 3-H-norepinephrine but did not reduce the proportion of the accumulated 3-H-amine which was released by amphetamine. The addition of desipramine (an inhibitor of neuronal uptake) further reduced the accumulation of 3-H-norepinephrine in animals pretreated with reserpine but had no further effect in animals pretreated with 6-hydroxydopamine. A greater proportion of the 3-H-norepinephrine was converted to 3-H-deaminated metabolites in tissues of reserpine-treated animals than in the tissues of control or 6-hydroxydopamine-treated rats. Amphetamine-induced release of 3-H-norepinephrine was partially calcium dependent in tissues from control animals. After reserpine treatment, amphetamine-induced release of norepinephrine was independent of calcium, whereas potassium-mediated release was still markedly calcium dependent. These experiments indicate that amphetamine releases 3-H-norepinephrine primarily from storage sites within central adrenergic nerve endings. An analysis of the time course of release from tissues of rats treated with reserpine suggests that amphetamine is equally capable of releasing 3-H-norepinephrine from granular sites which are susceptible to reserpine and from reserpine-insensitive sites.

Drug-induced changes of adenylate cyclase activity in cells from asthmatic and nonasthmatic subjects.

Monolayers of adherent mononuclear leukocytes prepared from normal subjects and asthmatic children whose bronchodilater therapy did not include sympathomimetic drugs, respond to relatively low concentrations of isoproterenol (ISO) and prostaglandin E1 with increased intracellular cyclic adenosine monophosphate (cAMP) levels. The magnitude of in vitro responses to ISO is decreased by previous contact of the cells with ISO or other, orally effective, adrenergic drugs. The desensitization is rapid, concentration- and time-dependent, and is readily reversible after removal of the desensitizing drug. The phenomenon exhibits pharmacologic specificity. Cells in which the response to restimulation with ISO was decreased exhibited full sensitivity to prostaglandin E1. No differences in these behaviors were detected in cells from normal or asthmatic subjects. The results suggest that earlier observations reporting decreased responses to beta adrenergic stimulation in asthmatics may have been due to the treatment of these patients with sympathomimetic agents and not caused by a disease-related beta adrenergic receptor dysfunction.

Regulation of cyclic AMP content in normal and malignant brain cells.

Pharmacologic characterization of the neurotransmitter-sensitive cyclic AMP-second messenger systems of brain has proven to be a complex and difficult endeavor. At least two types of receptor appear to be involved in the mediation of the effects of NE on cyclic AMP content. One of these receptor systems appears to mediate the potentiation by NE of the effect of adenosine of cyclic AMP accumulation. The cellular heterogeneity of brain has retarded the determination of the mechanism underlying the synergistic interaction of catecholamines and adenosine. An attempt to use clonal cell lines to examine the action of NE and adenosine on cyclic AMP content has resulted in the demonstration that adenosine acts in a hormone-like fashion to stimulate adenylate cyclase activity. However, the studies did not shed light on the mechanism of synergism. An increasing number of reports are appearing which support the idea that the responsiveness of cells to neuronally released NE may involve adaptive changes in the responsiveness of the cyclic AMP-second messenger system which compensate for chronic over- or underproduction of the first messenger, NE. Evidence was presented that such a regulatory process may be operative in rat cerebral cortex. Our studies of catecholamine-induced loss of responsiveness in human astrocytoma cells have led us to the conclusion that the loss in the capacity of the cells to accumulate cyclic AMP is a result of a loss in the capacity to synthesize cyclic AMP. However, it is probable that different cells make use of different mechanisms (e.g., changes in phosphodiesterase activity) to regulate their ability to respond to hormones or neurotransmitters. The physiologic importance of this level of regulation of responsiveness to hormones is not known at this time.

Inconsistent absorption from a sustained-release theophylline preparation during continuous therapy in asthmatic children.

During routine monitoring of hospitalized children with asthma receiving a sustained-release theophylline formulation, we frequently observe unpredictable fluctuations in serum theophylline concentration (STC). We evaluated eight asthmatic patients (ages 4 to 17 years) with inconsistent STCs to determine the cause of this phenomenon. Only minimal variation in STC and therefore theophylline clearance was noted during a 24-hour period of continuous intravenous aminophylline infusion. However, marked variability in STC was observed when measured every 2 hours for 48 hours after 6 days of continuous therapy orally. In addition, the time required to reach peak and trough STCs varied from dose to dose. Inasmuch as clearance was shown to be constant, the variability was attributed to inconsistent theophylline absorption. Unpredictable fluctuations of STC secondary to variable absorption from this sustained-release theophylline preparation may occur in certain patients. Appreciation of this potential variability is necessary for the proper interpretation of STC measurements and subsequent dosage adjustment.