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.

Three-month efficacy and safety of acetaminophen extended-release for osteoarthritis pain of the hip or knee: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: To examine the efficacy and safety of two doses of long-acting acetaminophen in patients with osteoarthritis (OA) of the hip or knee. METHODS: This multicenter, randomized, double-blind, parallel-group, placebo-controlled study evaluated the efficacy and safety of acetaminophen extended-release (ER) 650 mg and 1300 mg given three times daily for the treatment of moderate to moderately severe OA of the hip or knee. Primary efficacy end points were mean change from baseline through 12 weeks in the Western Ontario and McMaster Universities Osteoarthritis Index pain and physical function subscale scores and mean patient global assessment of response to therapy at week 12. Safety assessments included monitoring vital signs, adverse events, study joint assessments, and clinical laboratory results at each study visit. RESULTS: Four hundred eighty-three patients were randomized to treatment and included in the intent-to-treat analysis. All groups were similar with respect to baseline demographics except for gender, weight, and body mass index. Acetaminophen ER 3900 mg was significantly superior to placebo for all three primary end points; acetaminophen ER 1950 mg was significantly superior to placebo only with respect to patient assessment of response to therapy. Study treatments were generally well tolerated, and there was no significant difference among the groups in the overall number of adverse events. CONCLUSIONS: Acetaminophen ER 3900 mg/d administered for up to 12 weeks was effective in treating moderate to moderately severe chronic OA pain of the hip or knee and was generally well tolerated.

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.

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.

Surveillance of loperamide ingestions: an analysis of 216 poison center reports.

BACKGROUND: Loperamide was approved for nonprescription use in 1988. While efficacy is well documented, there are few data on loperamide overdose and management. METHODS: Eight poison centers participated in a prospective study enrolling 216 patients. RESULTS: Where the amount ingested was known, it ranged from 0.03 to 0.94 mg/kg. One- to 3-year-olds were involved in 57.9% of ingestions. Ingestion was unintentional in 182 cases (84.3%), including 59 patients with therapeutic errors (27.3% of all cases). Dispensing cup errors were implicated in 23 cases; 15 patients assumed the dispensing cup was the unit of measure. No symptoms developed in 63.0%; 27.8% had related symptoms. No related symptoms were life-threatening, and no fatalities occurred. The most frequent symptoms were drowsiness (15.7%), vomiting (4.2%), and abdominal pain or burning (3.7%). The frequency of related symptoms was compared in patients receiving the most frequently utilized decontamination modalities: ipecac alone, activated charcoal alone, lavage and activated charcoal, and ipecac and activated charcoal. Compared to the 112 patients who received no decontamination, only the ipecac-treated group demonstrated a significant reduction in the frequency of related symptoms; 13.9% of patients given ipecac alone (without other gastric decontamination) had related symptoms compared to 33.0% of patients who received no decontamination. Three patients received naloxone for CNS symptoms related to loperamide; two responded and the response of the third was unknown. CONCLUSION: Within the range of doses implicated in this study (up to 0.94 mg/kg), there were no life threatening clinical effects and no fatalities. Development of a management protocol is complicated by the absence of a predictable clinical response in each dose range. The data suggest that children over six months with single acute ingestions up to 0.4 mg/kg, and possibly higher, can be safely managed at home, without gastric decontamination.

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.

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.

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.

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.

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.

Pediatric dosing of acetaminophen.

Acetaminophen (paracetamol, APAP) is one of the safest and most widely used analgesic-antipyretics in children. When compared to other analgesic-antipyretics, acetaminophen has been shown in many clinical studies to have equivalent efficacy. Based on available clinical and pharmacokinetic data, acetaminophen should be dosed with single doses in the range of 10-15 mg/kg at 4-hour intervals. However, many dosing schedules recommend inadequate amounts of acetaminophen. Dosing schedules based on weight can be constructed that will accurately keep each dose within the recommended range. Dosing also can be adapted to an age-based schedule, which will provide consistent dosing from infancy to adolescence. The principles used to derive the age-based dosing schedule have potential application for use with other pharmacologic agents, particularly nonprescription drugs.

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.