Edwin J. Mikkelsen

Brief report: Open trial effects of beta-blockers on speech and social behaviors in 8 autistic adults

We began open trials of beta-blockers, as adjunctive medication, in eight consecutive autistic adults. The immediate result across all patients was a rapid diminution in aggressivity (Ratey et al., 1987). As time on the drug increased, subtler changes in speech and socialization emerged. While results of open trials must be interpreted with caution, these changes were significant and lasting. We speculate that these effects may be the result of a lessening of the autistic individuals state of hyperarousal. As the individual becomes less anxious, defensive and dearousing behaviors are relinquished and more social and adaptive behaviors appear. There is a concomitant improvement in language, though it is unclear whether lost skills are recouped or new ones developed. Further research is indicated.

Autism: the treatment of aggressive behaviors

Eight consecutive cases of adults with the diagnosis of early infantile autism and who were treated with a betablocker are presented. Each had been on various and multiple drug, educational, and behavioral regimens to help control aggressive and self-abusive behavior. Most had been institutionalized from an early age, and a broad range of IQs and speech capacities are represented. Results show the betablockers to have a remarkable effect potentiating measurable diminution in previously intractable aggressive behavior and in many cases the decrease or withdrawal of their neuroleptic.

Renal effects of acute calcium blockade with nifedipine in hypertensive patients receiving beta‐adrenoceptor‐blocking drugs

The effects on blood pressure and renal function of a single 20‐mg sublingual dose of nifedipine were investigated in 10 patients with mild to moderate arterial hypertension insufficiently treated on beta‐blocker monotherapy. Nifedipine induced a prompt and marked reduction of both systolic and diastolic blood pressure (average maximal reduction 30/22 mm Hg, P < 0.001). Despite the beta blockade, heart rate rose 25%. Only insignificant increments of glomerular filtration rate and renal plasma flow were registered, whereas calculated renal vascular resistance (RVR) was markedly reduced (P < 0.001). Urinary excretion rate of albumin and beta‐2 microglobulin rose after nifedipine, reflecting changes in glomerular as well as tubular function. Mean blood pressure seemed to be a major determinant of the excretion of proteins. There was a marked increase in the excretion of sodium after nifedipine and urine volume rose from a mean of 8.2 ± 1.3 to 12.5 ± 1.8 ml/min (P <0.01). The changes in sodium excretion rate correlated with the renal hemodynamic changes. Uric acid excretion rate rose remarkably after nifedipine and the magnitude of the changes seemed intimately related to the basal level of RVR. The results indicate that nifedipine therapy may be advantageous in patients whose hypertension is insufficiently controlled with beta blockers alone. Renal blood flow is maintained and there is a desirable diuretic action and enhancement of uric acid excretion.

Behavior and Motor Activity Response in Hyperactive Children and Plasma Amphetamine Levels Following a Sustained Release Preparation

Abstract Amphetamine has been clearly documented to be an efficacious treatment for hyperactive children. Recently, pharmacokinetics of elixir, tablet, and sustained-release preparations have been studied in hyperactive children. Sustained release has been thought to provide a prolonged clinical response. In this study, nine hyperactive children, selected by specific exclusion-inclusion criteria, were administered single oral doses of sustained-release d-amphetamine and placebo; plasma levels, behavioral response, and motor activity were observed in double-blind design. The results, as with the earlier studies, indicate that significant clinical response is not observed beyond 4 hours and that responses occur only during the absorption phase and are not correlated with specific plasma levels of d-amphetamine.

Neurologic Status in Hyperactive, Enuretic, Encopretic, and Normal Boys

Abstract The neurological status of 30 hyperactive, 40 enuretic, and 22 normal boys was investigated using the physical and neurological examination for soft signs (PANESS), a structured 44-item neurological exam with a 4-point scale for each item. There was a strong negative correlation between age and the PANESS score, indicating that the examination is also a kind of developmental scale. Age-adjusted mean PANESS score of hyperactive children was significantly higher than both the normal and enuretic groups, but there was no significant difference between the latter two groups in PANESS scores adjusted for age. PANESS scores correlated significantly with other measures of higher central nervous system function such as IQ, number of errors on the Bender test, and abnormal electroencephalograms (available in the hyperactive boys). Reliability of the examination as a whole by two independent raters was significant. Use of the PANESS in this study demonstrated a lag in neurodevelopmental maturity not necessarily specific to diagnostic category.

Urinary catecholamines and amphetamine excretion in hyperactive and normal boys.

Urinary catecholamines and metabolites and urinary amphetamine excretion were examined for hyperactive and normal boys following a single dose of dextroamphetamine (0.5 mg/kg) and placebo. Hyperactive children showed a significantly faster rate of excretion of amphetamine which could not be accounted for by previous exposure to drug or by signs of neurological involvement. Urinary norepinephrine (NE) was significantly higher for hyperactive than for normal children, but NE excretion did not correlate with motor activity or any measures of arousal. The single dose of amphetamine produced a significant rise in urinary epinephrine excretion (EP) for the normal children but not for the hyperactive group, supporting the notion of a more sluggish catecholamine response to stimulants for hyperkinetic children.

Enuresis and Encopresis: Ten Years of Progress

OBJECTIVE To review the progress made over the past decade with regard to the treatment of enuresis and encopresis, as well as advances in the understanding of etiological mechanisms. METHOD Separate computerized literature (English language only) searches of Medline and PsycINFO databases were conducted under the parameter of enuresis and children-adolescents, as well as encopresis and children-adolescents. RESULTS There has been a substantial decrease in published research concerning the use of imipramine to treat enuresis compared with the prior two decades, accompanied by a corresponding increase in the number of papers concerning desmopressin acetate (DDAVP), which has become the primary pharmacological treatment. Genetic studies of large pedigrees have further confirmed the importance of heritable factors. With regard to encopresis, the research has focused primarily on pathophysiological factors related to the colon and anal sphincter. CONCLUSIONS The widespread use of DDAVP has been the primary addition to treatment strategies over the past decade. The bell-and-pad method of conditioning, the only major treatment that has enduring benefit after being withdrawn, is the most cost-effective and appears to be underutilized. Research into etiological mechanisms has focused primarily on the mechanism of action of DDAVP and advances in the understanding of genetic factors. Advances in the treatment and etiological understanding of encopresis have been less impressive.

The hyperactive child syndrome: Peripheral sympathetic nervous system function and the effect of d-amphetamine

We evaluated sympathetic nervous system function in medication-free hyperactive children by measuring plasma levels of norepinephrine (NE) and dopamine-beta-hydroxylase and then comparing the effects of two therapeutics doses of d-amphetamine to placebo in these patients. The medication-free hyperactive patients and controls had similar plasma NE levels and blood pressures while recumbent, and a similar increase in NE on standing, but the patients had a larger pressor response on standing. In the hyperactive patients d-amphetamine significantly increased blood pressure, pulse rate, and NE levels. The change in NE levels correlated with the change in amphetamine levels. The medication-free patients, when more anxious, had higher plasma NE levels.

Effect of imipramine on norepinephrine and blood pressure in enuretic boys.

The effect of imipramine, desmethylimipramine, and methscopolamine on blood pressure (BP) and plasma norepinephrine (NE) was measured in enuretic boys in a double‐blind, placebo‐controlled study. Measurements were obtained on the thirteenth day of medication (75 mg at bedtime). The tricyclic drugs induced a rise in diastolic BP as well as an increase in plasma NE but there was no significant relationship between the increments in plasma NE and BP. The plasma concentration of drug correlated with the drug‐induced BP rise. This is the fifth study to demonstrate a hypertensive effect of tricyclic drugs in children in contrast to the systolic hypotension usually seen in adult patients. It is not clear from our data whether children have different cardiovascular compensatory reflexes or whether they experience a greater stimulant effect from the drug.

Serum potassium and uric acid changes during treatment with timolol alone and in combination with a diuretic

Timolol, 10 to 40 mg daily, given to 103 patients with uncomplicated arterial hypertension induced significant increments of serum potassium at all dose levels (p < 0.05). The magnitude of the increments was dependent on daily timolol dosage. When hydrochlorothiazide and amiloride were added, serum potassium decreased (p < 0.001), but a major determinant of the magnitude of the decrease was the dosage change of the timolol. Serum uric acid was influenced in a paradoxical way during timolol monotherapy; there was a rise in all 3 dosage groups (p < 0.02) but the lowest group showed the largest increase and vice versa. On addition of hydrochlorothiazide and amiloride, there was a further increase in serum uric acid, the magnitude of which depended on the concomitant reduction in the dose of timolol, with reductions in dose causing a larger rise in serum uric acid and increments, a smaller rise. The increments of serum uric acid were greater in females than in males during both treatment periods. The results indicate that beta blockers induce dose‐dependent rises in serum potassium and may counteract undesirable effects of diuretics on serum potassium. Beta blockers seem to have a paradoxical effect on serum uric acid and may aggravate the hyperuricemia induced by diuretics.