Disposition of acetaminophen at 4, 6, and 8 g/day for 3 days in healthy young adults.

The objective of this study was to determine the disposition and tolerability of 1, 1.5, and 2 g acetaminophen every 6 h for 3 days. Group I healthy adults received acetaminophen (4 then 6 g/day) or placebo; Group II received acetaminophen (4 then 8 g/day) or placebo. Acetaminophen and metabolites were measured in plasma and urine. Hepatic aminotransferases were measured daily. At steady state, acetaminophen concentrations were surprisingly lower than predicted from single-dose data, although sulfate formation clearance (fCL) was lower as expected, indicating cofactor depletion with possible sulfotransferase saturation. In contrast, glucuronide fCL was unexpectedly higher, strongly suggesting glucuronosyltransferase induction. This is the first evidence that acetaminophen induces its own glucuronidation. No dose-dependent differences were detected in fCL of thiol metabolites formed via cytochrome P4502E1. Hepatic aminotransferases stayed within reference ranges, and the incidence and frequency of adverse events were similar for acetaminophen and placebo. Although dose-dependence of acetaminophen disposition was reported previously, this study shows a novel finding of time-dependent disposition during repeated dosing. Unexpected increases in glucuronide fCL more than offset decreases in sulfate fCL, thus increasing acetaminophen clearance overall. Thiol metabolite fCL remained constant up to 8 g/day. These findings have important implications in short-term (3 day) tolerability of supratherapeutic acetaminophen doses in healthy adults.

Acute and chronic effects of aspirin toxicity and their treatment.

Salicylate poisoning remains a major clinical hazard, usually resulting from accidental ingestions in preschool children, suicidal overdoses in adults and teenagers, and therapeutically acquired intoxication in all ages. Alkalemia or acidemia, alkaluria or aciduria, hypoglycemia or hyperglycemia, and water and electrolyte imbalances may occur; nausea, vomiting, tinnitus, hyperpnea, hyperpyrexia, disorientation, coma, and/or convulsions are common. With chronic, therapeutically induced salicylism, these symptoms may be mistaken for symptoms resulting from the illness for which the salicylates were administered. For acute ingestions, the magnitude of the poisoning is clearly dose related. Blood level determinations are good prognostic indicators for acute ingestions but are of limited value in chronic, therapeutically induced salicylism. Fluid and electrolyte management is the mainstay of therapy. Diuresis, hemodialysis, and hemoperfusion are effective, but the latter two rarely are necessary.

Review of comparative antipyretic activity in children.

Fever is one of the most common medical complaints referred to physicians for diagnosis and therapy. In addition, consumers frequently medicate themselves for fever associated with common, self-limited illnesses. The pathogenesis of fever suggests that pharmacologic therapy, which lowers the hypothalamic set-point, is an essential element in treatment. Not all fevers need to be treated; however, when indicated, therapy with antipyretics is necessary. The major antipyretic agents, acetaminophen, aspirin, and pyrazolone derivatives, are equally effective in reducing fever. However, after comparing side effects and risks of toxicity, acetaminophen may be the preferred agent in children.

Poison prevention education.

Physicians can significantly decrease the frequency and severity of poisoning by educating parents and families in poison prevention. Appropriate strategies for poison prevention education require an examination of epidemiologic characteristics of exposures and potential intervention techniques. Parents should be taught immediate first-aid steps, such as initiating basic life-support measures and irrigation and dilution, that can be taken before seeking medical assistance. Other consumer actions, such as inducing emesis, require medical supervision. The poison control center is the best source for information and advice on treating poisoning. To decrease the frequency of poisoning, parents should be taught to purchase, store, and handle potentially toxic products appropriately. The purchase of household chemicals and drugs in child-resistant safety packaging should be encouraged. To decrease the severity of poisoning, parents should post the phone number of the local poison center, be able to initiate first-aid measures, and keep ipecac syrup on hand. Ideally, a physician should establish a preventive education schedule and discuss poison prevention with parents at regular well-child visits, beginning when the child is very young.

Pathophysiology of aspirin overdosage toxicity, with implications for management.

The principal pathophysiologic effect of toxic doses of salicylates are characterized by (1) stimulation of the respiratory center of the brain, leading to hyperpnea and respiratory alkalosis; (2) uncoupling of oxidative phosphorylation, leading to increased oxygen utilization and glucose demand, increased oxygen utilization and glucose demand, increased glyconeogenesis, and increased heat production; (3) inhibition of Krebs cycle enzymes, leading to decreased glucose availability and increased organic acids; (4) alterations in lipid metabolism and amino acid metabolism, enhancing metabolic acidosis; and (5) increased fluid and electrolyte losses, leading to dehydration, sodium depletion, potassium depletion, and loss of buffer capacity. The principal toxic manifestations of respiratory alkalosis and metabolic acidosis, altered glucose availability and depletion, fluid and electrolyte losses, and hypermetabolism result in serious morbidity and are potentially fatal. Therapy of salicylate intoxication should be aimed principally at replacement of fluid electrolytes, correction of acidemia, administration of glucose, and prevention of further salicylate absorption and enhancement of salicylate elimination.

The relative severity of acute versus chronic salicylate poisoning in children: a clinical comparison.

To evaluate the relative severity of acute vs chronic salicylate poisoning in children, 112 cases (65 acute and 47 chronic) of salicylate poisoning (salicylate concentration greater than or equal to 20 mg/100 ml) admitted to The Children's Hospital Medical Center in Boston and Primary Children's Medical Center in Salt Lake City between the years 1967 and 1978 were analyzed. Hyperventilation (P less than .01), dehydration (P less than .001), and severe central nervous system manifestations (P less than .001) occurred more frequently in the chronic group and remained more frequent (P less than .01) when patients having disease states capable of producing these signs and symptoms were removed from statistical analysis. At three separate salicylate concentration ranges (20 to 39, 40 to 59, and greater than or equal to 60 mg/100 ml) hyperventilation, dehydration, and severe CNS manifestations tended to occur with greater frequency in the chronic group. When severity of salicylate poisoning was categorized based on a combination of signs and symptoms, mild cases occurred more frequently in the chronic group. Finally, systemic acidosis (pH less than 7.32) was found more frequently in the chronic group (P less than .01), more frequently in patients with severe manifestations than in those with mild manifestations, and in patients with dehydration (P less than .01) and severe CNS manifestations (P less than .05). Based on the variables evaluated, chronic salicylism produces a greater morbidity than does acute salicylate poisoning in the pediatric patient.

Observations on the current status of poison control centers in the United States.

The history, effectiveness, and services of regional poison control centers are reviewed. In addition, the American Association of Poison Control Centers' criteria for designation as a regional poison control center are presented.

Acute iron poisoning in children.

Acute accidental iron poisoning is a common serious and potentially fatal intoxication in the young child. Approximately 1 per cent of such poisoning have a fatal outcome, and outcome is closely related to the early onset of coma or shock. Long-term prognosis is excellent for all survivors of the acute episode, although there are occasional obstructive complications occurring four to six weeks later.

Pharmacokinetic model for salicyclate in cerebrospinal fluid, blood, organs, and tissues.

The developed pharmacokinetic model, an extension of the Bischoff--Dedrick model, simultaneously predicts the kinetic behavior of salicylate in cerebrospinal fluid, blood, organs, and tissues. The model, which is entirely different from conventional compartment models, is derived from basic considerations of drug distribution with biochemical and physiological meaning. The dog was studied at three different dosages of salicylate: therapeutic, moderate intoxication, and severe intoxication. The predicted kinetics of salicylate in cerebrospinal fluid, blood, plasma, liver, muscle, and adipose tissue by the model agreed well with the experimental data. The effectiveness of hemoperfusion treatment for the severely intoxicated dog by albumin-coated activated carbon and its effect on the kinetic behavior of salicylate in cerebrospinal fluid, blood, organs and tissues were studied. The model was also applied to predict the kinetic changes of salicylate in the body during and after the extracorporeal treatment. The predicted results also agreed with the experimental data.

Toward a digital neuromorphic pitch extraction system.

This paper presents the design of a biologically based signal processing system implemented using standard digital inferior colliculus (IC) technology. The four-stage AM detection system is a step toward a full-pitch detection system and based on known mammalian physiology. The system is operational and has been successfully realized in field programmable grid array (FPGA) technology. Details of the system architecture, its operating principles, and the design decisions necessary to realize successfully neuromorphic systems in digital technology are given.

Observations on the current status of poison control centers in the United States.

The history, effectiveness, and services of regional poison control centers are reviewed. In addition, the American Association of Poison Control Centers criteria for designation as a regional poison control center are presented.

Acute iron poisoning in children.

Acute accidental iron poisoning is a common serious and potentially fatal intoxication in the young child. Approximately 1 per cent of such poisonings have a fatal outcome, and outcome is closely related to the early onset of coma or shock. Long-term prognosis is excellent for all survivors of the acute episode, although there are occasional obstructive complications occurring four to six weeks later.

Gastrointestinal decontamination in the management of the poisoned patient.

Ipecac syrup is the agent of choice to promote emesis in awake, alert, and cooperative patients who have ingested poison. Lavage is a reasonable alternative when ipecac fails or emesis is contraindicated. Activated charcoal is effective in minimizing absorption of ingested toxins, and saline cathartics may be useful to hasten the elimination of activated charcoal and possibly of enteric-coated or sustained release medications.

A multicenter randomized controlled trial of a liquid loperamide product versus placebo in the treatment of acute diarrhea in children.

This randomized, double-blind, placebo-controlled trial of 48 hours' duration conducted in 13 primary care ambulatory practices in the United States and Mexico was used to compare the efficacy and safety of loperamide with placebo for the treatment of acute diarrhea in children aged 2 through 11 years. Two hundred fifty-eight children with acute nonspecific diarrhea were enrolled. Children were randomly assigned to treatment with loperamide HCl 0.5 mg/5 mL (n = 130) or placebo (n = 128). The first dose of loperamide consisted of either 1.0 mg (children 2 through 5 years of age) or 2.0 mg (children 6 through 11 years of age) of study medication under the observation of study personnel. This was followed by 1 mg after each unformed stool, with a total daily dose of up to 3.0 mg in the children 2-5 years of age, 4.0 mg in the children 6-8 years of age, and 6.0 mg in the children 9-11 years of age. The primary outcome measures were time to last unformed stool, time to first unformed stool, number of unformed stools during six consecutive 8-hour periods, and overall rating of efficacy/acceptability. Secondary outcomes included abdominal pain/cramping, vomiting, and fever. Children who received loperamide had significantly shorter time to last unformed stool (p = 0.0017) and fewer numbers of unformed stools (p = 0.0237) than children who received placebo. The end-of-study overall efficacy/acceptability rating of loperamide was significantly better than for placebo (p = 0.0107). All other clinically important outcome measures related to diarrhea relief favored loperamide. There was no significant difference in the incidence of drug-related adverse events between treatment groups, although total adverse events were reported more frequently (p = 0.048) by the loperamide group (15%) compared with the placebo group (7%). In conclusion, this controlled study provides data demonstrating that at recommend doses, loperamide is well tolerated and significantly shortens the duration and severity of symptoms of acute nonspecific diarrhea in children 2 through 11 years of age.

Recent advances in diagnosis and management of croup.

Croup is a syndrome of inspiratory stridor, cough, and hoarseness, due to varying degrees of laryngeal obstruction. It is a viral disease and must be differentiated from epiglottitis. In addition to a careful clinical assessment, neck films are the most valuable diagnostic tool in differentiating these two. The principle modes of therapy for croup include provision of adequate hydration, ensuring maximum available humidification, sedation, and administration of intermittent positive pressure breathing (IPPB) with nebulized racemic epinephrine. The latter mode of therapy will provide symptomatic relief and may eliminate the need for hospitalization and tracheostomy. Steroids offer little benefit in treating this disease, and antibiotics offer none.