Anthony R. Temple

Retrospective analysis of transient elevations in alanine aminotransferase during long-term treatment with acetaminophen in osteoarthritis clinical trials

ABSTRACT Background: In two recent osteoarthritis trials, alanine aminotransferase (ALT) elevations were observed more frequently in patients receiving acetaminophen 3.9 g daily than in patients receiving placebo, and the rates were higher than aminotransferase values observed in some previous osteoarthritis studies with acetaminophen. Objective: To retrospectively analyze ALT data from McNeil osteoarthritis clinical studies involving acetaminophen in order to assess the frequency and magnitude of ALT elevations and rate of ALT resolution while patients remained on acetaminophen treatment. A review of the literature revealed a few reports of isolated aminotransferase elevations occurring during acetaminophen therapy, but these reports were not included in the analysis because they did not include enough information to evaluate the frequency, magnitude, and rate of ALT elevations while patients remained on acetaminophen treatment. Research design and methods: Nine controlled clinical trials were identified in which at least one of the treatments was acetaminophen alone. Studies were included if patients had ALT and aspartate aminotransferase (AST) values obtained at baseline and an ALT value at an additional visit after initiating therapy. Seven studies met these criteria and were included in this analysis. In these studies, patients received acetaminophen 1950–4000 mg/day for 4 weeks up to 12 months. Laboratory testing was performed at weeks 0 and 4 in the three 4‐week studies; at weeks 0, 2, 4, 8, and 12 in the two 12‐week studies; at weeks 0, 1, 2, 4, 6, 8, and 13 in the 13‐week study; and at months 0, 1, 3, 6, 9, and 12 in the 12‐month study. The pooled data set consisted of patient demographics, dosing records, aminotransferase and bilirubin laboratory values, and adverse events. Results: There were no reports of hepatotoxicity or hepatic failure in any acetaminophen-treated patient (n = 1530). In the seven studies, 1039 patients had both baseline AST and ALT activity ≤ upper limit of the reference range and an on-treatment ALT measurement. While on long-term acetaminophen treatment, 181 of 1039 (17.4%) patients had an ALT value that exceeded the upper limit of the reference range. None of the 1039 patients had an on-treatment ALT level > 3 times upper limit of the reference range in conjunction with a serum bilirubin > upper limit of the reference range, and no patient had an ALT level > 10 times upper limit of the reference range. Of the 1039 patients, 44 (4.2%) had an on-treatment ALT level > 1.5 times upper limit of the reference range, and 31 of the 44 patients had a subsequent measurement of ALT. Of these 31 patients, 29 (93.5%) had documented resolution or decreasing ALT while on treatment. An ALT level > 1.5 times upper limit of the reference range was not associated with a higher frequency of symptoms potentially related to hepatic origin. Limitations: The studies included in this analysis were limited to McNeil studies, none of which were designed to specifically evaluate the patterns of ALT activity. Thus, the incidence of ALT elevations after any specific duration of dosing, and the temporal pattern of ALT elevations, cannot be accurately determined. In addition, methodological differences existed across the studies. Conclusion: This analysis involving > 1000 acetaminophen-treated patients shows that low-level, transient ALT elevations usually resolve or decrease with continued acetaminophen treatment, are unaccompanied by signs or symptoms of liver injury, and, as such, appear to be clinically insignificant. Maximum recommended daily doses of acetaminophen did not cause liver failure or dysfunction.

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.

One Year's Experience in a Regional Poison Control Center: The Intermountain Regional Poison Control Center

The Intermountain Regional Poison Control Center in Salt Lake City, Utah, has served as a regional poison center since 1971. Between 1972 and 1976 the call load has more than tripled, with the highest frequency of calls per population coming from counties most proximate to the center. Two-thirds of the cases involve children age five or less, with 18 or over being the next large group. Adolescents and school-age children comprised the smallest group of cases. Two predominant types of poisonings were encountered: accidental ingestions of toxic substances in children and intentional self-poisonings in adults, but the poison center handled almost every conceivable type of poisoning or toxic situation. A detailed analysis of the centers overall experience as well as these two major categories is presented.

Aminotransferase activities in healthy subjects receiving three-day dosing of 4, 6, or 8 grams per day of acetaminophen

Introduction. This multiple-dose pharmacokinetic study has a randomized, double-blind, placebo-controlled, parallel-group design with three dosing regimens. Healthy subjects received repeated doses of acetaminophen (4 then 6 g/d or 4 then 8 g/d) or placebo. Methods. The disposition of acetaminophen and its metabolites and the tolerability of increased acetaminophen doses over 3 days of continuous consumption were characterized. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities measured throughout the study were consistent across the acetaminophen 4, 6, and 8 g/d dose levels and with placebo. Results. Serum aminotransferase activities did not exceed the upper limit of the reference range (ULRR), except for one subject with an AST of 43 U/L (ULRR, 42 U/L), which was not considered clinically significant. All doses were generally well tolerated. Conclusions. In a multiple-dose pharmacokinetics study of 4, 6, and 8 g/d of acetaminophen for 3 days, multiple aminotransferase determinations demonstrated no clinically important elevations at 1, 1.5, or 2 times the maximum recommended acetaminophen dose.

Salicylate Poisoning Complicated by Fluid Retention

We have presented two cases of salicylate poisoning that demonstrate fluid retention in the face of adequate hydration, resembling the syndrome of inappropriate secretion of ADH. These cases necessitated marked alterations from normal fluid therapy. Mannitol was found to be an effective, albeit transient, diuretic for treating the acute symptoms associated with fluid retention, but only strict fluid restriction resulted in a prompt and satisfactory diuresis.

Telephone Management of Poisonings Using Syrup of Ipecac

Seven hundred and seventy-six cases were studied during a six-month period to see if induction of emesis could be successfully managed at home by telephone. Emesis was successful in 98.8% of cases. In 6.7% of all cases, symptoms were found at 4-hour follow-up that were referrable to the ingestion, but all were considered to be of minor consequence. No complications of vomiting occurred. Twenty-four hour follow-up investigation indicated no significant complications of induction of emesis or complications from managing the patient by telephone. It is our conclusion that, with appropriate telephone supervision, home-induced emesis of ingestions expected to produce mild to moderate symptoms is as effective as emergency room or physician office management of cases. Furthermore, the absence of adverse affects of complications arising from the induction of emesis at home in our cases confirms that this form of management is quite safe.

Cadmium, lead, and copper blood levels in normal children.

Cadmium, lead, and copper levels were measured in duplicate whole blood samples from 60 apparently normal children, ranging in age from 2 months to 13 years, who were hospitalized for elective surgery. Metals were measured by atomic absorption spectroscopy after the samples were chemically oxidized and digested. Cadmium was concentrated by dithizone extraction before analysis. Blood cadmium averaged 0.66 mug/100 gm, with a standard deviation of 0.25. No samples had cadmium concentrations less than could be detectable. The average concentration of lead was 15.7 mug/100 gm with a standard deviation of 6.33. Copper averaged 123 mug/100 gm with a standard deviation of 35.5. Tolerance intervals were calculated for each metal in order to estimate the bounds of whole blood metal values in normal children. The intervals containing 95% of normal values with a probability of .95 were 0.22-1.70 mug Cd/100 gm, 0.87-30.5 mug Pb/100 gm, and 40.0-206 mug Cu/100 gm.

Dosing and Antipyretic Efficacy of Oral Acetaminophen in Children

BACKGROUND A standardized approach to dosing acetaminophen in pediatric populations was published in 1983. That review proposed specific weight-related dosing for infants and children weighing 6 through 95 lb and an age-based schedule for children aged <4 months through 11 years. Subsequent clinical studies evaluating these and alternative doses of acetaminophen supported the recommended 10-15-mg/kg dose. OBJECTIVE This article reviewed published and unpublished pediatric antipyretic data to provide a critical assessment of the 10-15-mg/kg oral dose and the current pediatric oral dosing schedules for acetaminophen. METHODS Published literature and unpublished clinical trials that evaluated the antipyretic efficacy of acetaminophen in children were reviewed. The PubMed database was searched using the term acetaminophen or paracetamol, with study criteria limited to randomized, controlled trials; oral dosing; patient age <12 years; and publication between 1982 and August 2012. All of the sponsors unpublished antipyretic clinical studies completed between 1980 and August 2012 and involving at least 1 oral-formulation acetaminophen-only treatment arm were identified. Data from published literature containing sufficient detail to verify doses; dosing frequency; and, when necessary, estimates from figures, and from acetaminophen arms of the unpublished studies were analyzed. RESULTS Thirteen unpublished trials enrolled 705 children to receive an oral dose of 10-15 mg/kg of acetaminophen. This dose resulted in a rapid onset of temperature reduction, with a maximum temperature decrement of ~3 hours following administration. Results from 40 published clinical trials in which 2332 children received oral acetaminophen for fever support these findings. The most common adverse events reported in any of the reported studies were gastrointestinal in nature and generally mild in intensity. CONCLUSIONS Data support the recommended 10-15-mg/kg oral dose and demonstrate that the age and weight schedules for over-the-counter acetaminophen proposed in 1983 remain appropriate.

Studies of glucuronidation. IV. Evidences of different processes for o-aminophenol and p-nitrophenol.

Summary Evidences are presented that p-nitrophenol (PNP) and o-aminophenol (OAP) utilize different enzyme systems for their glucuronide conjugation. Included are differences between the two substrates in the kinetics of the reaction, the response to mutual inhibition and to inhibition by a breast-milk inhibitor of bilirubin metabolism, intracellular localization, ability of the responsible enzyme to be solubilized, activity of the conjugating processes in the Gunn rat and in postmortem human liver specimens, and the effects of temperature upon the rate of conjugation. These findings support a concept of multiplicity of UDP-glucuronyl transferase enzymes.

Taste as a Deterrent in Pediatric Poisonings

Seven hundred and two children were tested to see how much they would ingest of two commercially available potassium supplements, one an effervescent tablet and the other a powder. The results showed that the children would not ingest either formulation in amounts that even equalled a single adult therapeutic dose. The children appeared to be deterred by both the effervescent quality of the tablet and the unpleasant, metallic after-taste of the powder. An unpleasant taste may act as a deterrent to the child, keeping him from ingesting a toxic amount of a product, at least, when the product has relatively low toxicity.