Famotidine treatment of children with autistic spectrum disorders: pilot research using single subject research design.

Using single subject research design, we performed pilot research to evaluate the safety and efficacy of famotidine for the treatment of children with autistic spectrum disorders. We studied 9 Caucasian boys, 3.8-8.1 years old, with a DSM-IV diagnosis of a pervasive developmental disorder, living with their families, receiving no chronic medications, and without significant gastrointestinal symptoms. The dose of oral famotidine was 2 mg/kg/day (given in two divided doses); the maximum total daily dose was 100 mg. Using single-subject research analysis and medication given in a randomized, double-blind, placebo-controlled, cross-over design, 4 of 9 children randomized (44%) had evidence of behavioral improvement. Primary efficacy was based on data kept by primary caregivers, including a daily diary; daily visual analogue scales of affection, reciting, or aspects of social interaction; Aberrant Behavior Checklists (ABC, Aman); and Clinical Global Improvement scales. Children with marked stereotypy (meaningless, repetitive behaviors) did not respond. Our subjects did not have prominent gastrointestinal symptoms and endoscopy was not part of our protocol; thus, we cannot exclude the possibility that our subjects improved due to the effective treatment of asymptomatic esophagitis. The use of famotidine for the treatment of children with autistic spectrum disorders warrants further investigation.

Trivalent chromium and the diabetes prevention program.

The Diabetes Prevention Program is a new, 150 million dollar, NIH-sponsored study designed to determine whether non-insulin-dependent diabetes mellitus can be prevented or delayed in persons with impaired glucose tolerance. Four thousand subjects will be randomly assigned to one of four study groups and followed for 4.5 years. Study groups include intensive lifestyle intervention with diet and exercise; metformin (Glucophage) or troglitazone (an investigational drug) with standard diet and exercise; and a control group. Insulin resistance is an important pathogenic factor in impaired glucose tolerance. Trivalent chromium, a dietary supplement that potentiates the action of insulin, was not included in the program. Like metformin and troglitazone, trivalent chromium decreases insulin resistance and has an acceptable side-effect profile; furthermore, it is available at a fraction of their cost. Trivalent chromium should have been included in the Diabetes Prevention Program; it is unfortunate that it was omitted.

Oral famotidine: a potential treatment for children with autism.

Famotidine (Pepcid, a histamine-2 receptor blocker, is marketed for the treatment of peptic ulcer disease, gastroesophageal reflux, and the treatment of pathological hypersecretory conditions, including the Zollinger-Ellison syndrome. Recent reports indicate that it is also effective in relieving the deficit (or withdrawal) symptoms of adults with schizophrenia. Autism, a neuropsychiatric disorder which presents within the first few years of life, is defined by deficient social interaction, communication, language, play, and a markedly restricted repertoire of activities and interests. Similarities between the deficit symptoms of schizophrenia and the social deficit symptoms of autism suggest the hypothesis that famotidine may be useful in treating children with autism. Histamine serves as a neurotransmitter and neuromodulator in the brain. H2-receptors in the brain predominantly transmit inhibitory signals; when these receptors are stimulated in animals, spontaneous activity and exploratory behavior decrease; blockade of H2-receptors would therefore be expected to reverse this inhibition.

Free radical scavenging enzyme activity and related trace metals in clozapine-induced agranulocytosis: a pilot study.

We hypothesized that patients who had experienced clozapine-induced agranulocytosis would have abnormalities in their free radical scavenging enzyme activity (FRESA) and levels of related trace metals. We therefore measured FRESA profiles and related trace metals in four groups: post-clozapine agranulocytosis (POST CLOZ AGRAN) (N = 9); clozapine no agranulocytosis (CLOZ NO AGRAN) (N = 12); West Coast controls (WC CONTROLS) (N = 14); and Long Island Jewish Medical Center controls (LIJ CONTROLS) (N = 12). Glutathione peroxidase (GSH-Px, P1) levels in plasma were slowest in the POST CLOZ AGRAN group (34.3 +/- 6.9 IU/dl [standard deviation; SD]; p < 0.002); red blood cell glutathione peroxidase (GSH-Px, RBC) was highest in the WC CONTROLS (38.7 +/- 4.7 IU/g hemoglobin [Hgb]; p < 0.008); and selenium (SE) levels in plasma were lower in both the POST CLOZ AGRAN group (111.6 +/- 14.7 ng/ml) and the CLOZ NO AGRAN group(115.0 +/- 17.8) than in the WC CONTROLS (142.5 +/- 18.3; p < 0.0006). SE was also lower in the POST CLOZ AGRAN group than in the LIJ CONTROLS (129.1 +/- 21.6; p < 0.04). The presence of at least one of the following: (1) GSH-Px, P1 < 37.6 IU/dl; (2) GSH-Px, RBC < 31.0 IU/g Hgb; or (3) SE < 112.4 ng/ml, distinguished POST CLOZ AGRAN subjects from the WC CONTROLS, but not from the LIJ CONTROLS. Data from this cross-sectional pilot study suggest that abnormalities in the body's antioxidant defense system may be involved in the pathogenesis of clozapine-associated agranulocytosis. If confirmed in large-scale, prospective studies, these preliminary findings have potential clinical application in the screening and prophylaxis of clozapine agranulocytosis.

Developmental changes in renal tubular function.

Use of the standard measure of renal function, glomerular filtration rate when corrected for body size, indicates fully functional renal capacity by one year of age, which remains relatively constant until the fourth decade of life, when it begins to gradually decline with advancing age. The active tubular secretion and reabsorption of cations and anions provide an occasion for drug interactions which are difficult to predict without knowledge of the exact mechanisms involved. Data support developmental changes in net tubular secretion for some substances. For digoxin, the larger ratio of digoxin clearance to creatinine clearance that is observed in children decreases during adolescence to the lower ratio observed in adults, and this decrement is better correlated with sexual maturation than with chronologic age. Thus for drugs with significant renal excretion of active drug or metabolite, the clarification of net renal tubular mechanisms would provide important clinical information.

Maternal reports of pregnancy, genital, and related fantasies in preschool and kindergarten children.

OBJECTIVE: To test the hypothesis that there is no difference in the proportion of young boys with pregnancy fantasies versus young girls with penis fantasies and to explore the prevalence of pregnancy, genital, and related fantasies in 2-through 6-year-old children. METHOD: The parents of 171 preschool and kindergarten children attending two private schools in New York City received questionnaires regarding the above fantasies. They were completed by the mothers of 31 girls and 34 boys (overall response rate of 38%). RESULTS: There was no statistically significant difference in the proportion of girls reported to have penis/gender fantasies and the proportion of boys reported to have pregnancy fantasies. Reports of at least one fantasy were more common for girls (p < .006), as were reports of breast-feeding, other nurturing, and other reproductive fantasies (p < .03) and reports of wanting to urinate like a boy (p < .05). Reports of an "interest" in vaginas and breasts, as opposed to a fantasy about having them, were more common in boys (p < .03). CONCLUSION: These data support the "overinclusive phase" of Fast's differentiation model of gender identity. Developmentally appropriate androgynous fantasies must be distinguished from gender identity disorder, a psychiatric condition that can emerge in the same age group.

Changes in salivary antipyrine pharmacokinetics during adolescence, correlated with age, hormonal levels and Tanner stage.

To evaluate the effect of puberty on antipyrine metabolism, we measured antipyrine pharmacokinetics in 17 healthy subjects aged 6-21 years. The subjects received a single oral dose of antipyrine, 18 mg/kg. Salivary antipyrine levels were determined 3, 6, 9, 12 and 24 h after dosing. Age, weight, body surface area and Tanner stage were highly intercorrelated. Volume of distribution (liters) was highly correlated with all of these factors. The weight-corrected clearance of antipyrine declined significantly with age (r = 0.55, p less than 0.025). Patients were classified as immature and other based on serum hormone levels (immature = females with serum estradiol less than 25 pg/ml and males with serum testosterone less than 25 ng/dl). The uncorrected antipyrine clearance was significantly lower in the immature group (mean +/- SD 22.65 +/- 6.04 ml/min) than in others (mean +/- SD 41.30 +/- 13.26; p less than 0.01). This difference disappeared when the weight-corrected antipyrine clearance was compared for these two groups. The change in uncorrected antipyrine clearance with sexual maturation appeared to be due to increased body size, probably related to the adolescent growth spurt.

Pubertal changes in net renal tubular secretion of digoxin.

To evaluate the effect of puberty on the net renal tubular secretion of digoxin, we measured the ratio of digoxin clearance to creatinine clearance in 23 patients aged 4 to 21 yr and correlated this ratio with both sexual maturity (Tanner stage) and chronologic age. All subjects were at steady-state levels for digoxin treatment; all had normal serum creatinine values for age as well as normal serum potassium levels. Mean ratio for immature children (n = 14, Tanner 1 through 3.5) was 1.45 +/- 0.66. Mean ratio for mature adolescents (n = 9, Tanner 4 through 5) was 0.95 +/- 0.28. The difference between the two groups was significant (P less than 0.05). When patients were regrouped by age using either 13 or 15 yr as a cutoff, the difference in ratios was no longer statistically significant. Based on 45 subjects (new and from our previous study) aged 2 mo to 80 yr, there was a significant decrease in the clearance ratio with increasing age, but when the 23 subjects aged 4 to 21 yr were analyzed separately, the correlation between ratio and age was not significant. It appears that the decrease in net renal tubular secretion of digoxin from childhood to adulthood correlates better with full sexual maturation at puberty (Tanner 4 through 5) than with chronologic age. This observation may represent a developmental change in pharmacokinetics with broader significance than for digoxin disposition alone.

Noninvasive diagnosis of persistent fetal circulation versus congenital cardiovascular defects.

Congenital cardiovascular anomalies associated with right-left atrial or ductal shunts must be excluded before a diagnosis of persistent fetal circulation (PFC) can be made. Despite the advent of 2-dimensional echocardiography (2-D echo), this differentiation can be difficult and may require cardiac catheterization with selective angiography. Fifteen consecutive cases were analyzed in which difficulty was encountered with this differential diagnosis, and experience with the use of cardiac auscultation, the 12-lead electrocardiogram (ECG), arterial blood gas determinations and 2-D echo, both alone and with injection of venous contrast material, is reviewed. Electrocardiographic abnormalities of ventricular axis, hypertrophy or dominance (p = 0.002) and suspicion of cardiovascular disease on 2-D echo (p = 0.011) were the most useful findings in differentiating patients with PFC from those with congenital cardiovascular abnormalities. The ECG was the most sensitive test (100% sensitivity, 90% specificity), while 2-D echo was the most specific (100% specificity, 75% sensitivity). Evidence of right-left shunting at atrial or ductal levels or both did not differentiate between the groups; both groups had evidence of such shunts. A decision tree was developed to facilitate this differential diagnosis, which uses the ECG and 2-D echo. If the ECG reveals no abnormalities of ventricular axis, dominance or hypertrophy, the 2-D echo shows no structural abnormalities, and total anomalous pulmonary venous return and coarctation/interruption of the aorta are specifically excluded, a congenital cardiovascular anomaly is effectively eliminated. We suggest that this approach can optimize the management of the cyanotic newborn with suspected PFC by eliminating the risks of cardiac catheterization and angiography without missing the diagnosis of a major structural cardiovascular anomaly.

Maturation and renal digoxin clearance.

To evaluate the effect of maturation on the renal disposition of digoxin, the ratio of digoxin clearance to creatinine clearance was determined in 35 patients who were 3 days to 79 yr old. All were at steady-state levels for digoxin treatment. A mean ratio of 1.49 +/- 0.67 (SD) was obtained in the group of prepubertal children and infants greater than or equal to 2 mo of age. The mean ratio decreased to 0.82 +/- 0.25 (SD) in the adult group; adults were defined as sexually mature adolescents or older (P less than 0.005). The decrease in net renal tubular secretion of digoxin appears to occur at puberty. This observation can provide one explanation for the apparently larger doses of digoxin required by infants and children than by adults. It may also represent a developmental change in renal tubular physiology with broader significance than for digoxin disposition alone.

Acute effects of vasodilators on left-to-right shunts in infants and children.

Based on the favorable experience with vasodilator therapy in adult heart disease and the results of acute dogs experiments, we undertook the hemodynamic evaluation of hydralazine and phentolamine during diagnostic cardiac catheterization. We studied seven infants and children with left-to-right (leads to R) shunts at atrial, ventricular, or ductal levels to determine whether vasodilator therapy might be useful in the treatment of infants with congestive heart failure (CHF) due to large L leads to R shunts. Shunts, flows, and resistances were measured by the indicator dilution and Fick techniques before and after administration of the drug. At a dose sufficient to produce an effect, the shunt flow increased after each drug. There is no evidence from studies at cardiac catheterization of therapeutic efficacy for vasodilators in the treatment of CHF due to cardiac L leads to R shunts.