ObjectivesSpeed of onset can be critical to an analgesic's efficacy treating acute pain. To enhance onset, a new oral acetaminophen formulation intended to be fast acting was developed. Two studies evaluated the analgesic onset, efficacy, and safety of this fast-acting acetaminophen (FA-acetaminophen) tablet relative to commercial acetaminophen caplets (ES-acetaminophen) and commercial ibuprofen liquid-filled gelatin capsules (LG-ibuprofen).MethodsTwo single-center, single-dose, inpatient, randomized, double-blind, triple-dummy, placebo-controlled, parallel group design clinical trials were conducted using the postoperative dental impaction pain model. Subjects were healthy men and women aged 17-50 years experiencing moderate-to-severe pain after surgical extraction of at least three impacted third molars. In both studies, four treatment groups were evaluated: 1,000 mg acetaminophen as two 500 mg FA-acetaminophen tablets, 1,000 mg as two 500 mg ES-acetaminophen caplets, 400 mg ibuprofen as two 200 mg LG-ibuprofen capsules, and placebo. To maintain blinding, each subject received six units of study medication. Times to confirmed perceptible pain relief (TCPR) and meaningful pain relief (TMPR) were obtained using the double-stopwatch method. Pain intensity and relief were measured over 6 h following drug administration using a 0-10 numerical rating scale. Time to use of rescue medication (naproxen sodium) and subject global evaluations of study medications at 6 h were collected. Pharmacokinetic blood sampling and safety assessments were performed.ResultsStudies 1 and 2 enrolled 240 and 420 subjects, respectively. No clinically important differences among treatment groups were observed for any demographic or baseline characteristics. Efficacy results showed all active treatments statistically superior to placebo. In Study 1, TCPR was statistically significantly shorter for FA-acetaminophen compared to ES-acetaminophen and LG-ibuprofen. In Study 2, no statistically significant differences in TCPR were noted across the active treatment groups. In Study 1, FA-acetaminophen 1,000 mg provided significantly shorter TMPR compared with LG-ibuprofen but not compared with ES-acetaminophen. In Study 2, no significant differences in TMPR were noted across the active treatment groups. In both Study 1 and 2 at 15 min after administration of study drug, PID and PAR scores were greater for FA-acetaminophen than LG-ibuprofen.ConclusionsBoth studies suggested FA-acetaminophen had faster onset of action compared to ES-acetaminophen and LG-Ibuprofen. In light of the difference in TCPR and TMPR results between Study 1 and 2, an additional study is needed to further investigate time to analgesic onset of FA-acetaminophen compared with ES-acetaminophen and LG-Ibuprofen.Study registry numbersStudy 1: NCT02735122; Study 2: NCT03224403

JNJ-10450232 (NTM-006) is a non-opioid, non-NSAID analgesic and antipyretic compound with structural similarity to acetaminophen. Preclinical models show comparable analgesia relative to acetaminophen and no evidence of hepatotoxicity associated with overdose. Moreover, it was safe and generally well tolerated in a First-in-Human Study. This single-dose, single-center, inpatient, randomized, double-blind study in moderate-to-severe acute pain following third molar extraction compared efficacy and safety of 250 mg and 1000 mg JNJ-10450232 (NTM-006), 1000 mg acetaminophen, and placebo during the 24 h following administration. While onset of action of 1000 mg JNJ-10450232 (NTM-006) was relatively slower compared with acetaminophen, its duration of action was sustained up to 24 h being superior beginning 7 h after administration. No clinically important differences among treatment groups in nature or severity of adverse events were observed and no serious adverse events were reported. Increased bilirubin, potentially due to UGT1A1 inhibition and ingestion of blood from oral surgery, was the most commonly reported adverse event and the only event reported by ≥ 5% of subjects across treatment groups. These data support further evaluation of JNJ-10450232 (NTM-006) for the treatment of moderate-to-severe pain. CLINICALTRIALS.GOV ID: NCT02209181.

JNJ-10450232 (NTM-006) is a new molecular entity that comprises structural similarities to acetaminophen and provides comparable analgesia in animals and humans without causing the hepatotoxicity associated with acetaminophen overdose in preclinical models. This double-blind, placebo-controlled, first-in-human study evaluated the safety, tolerability, and pharmacokinetics of JNJ-10450232 (NTM-006) following single (50-6000 mg) and multiple (250-2500 mg twice daily for 8 days) doses in healthy male volunteers. JNJ-10450232 (NTM-006) was absorbed within 1-3 h, except at high doses at which Cmax was delayed and bimodal, while increases in AUC were more than dose proportional. CL/F and Vd/F decreased approximately 3-fold with increasing single doses up to 6000 mg and multiple doses up to 1000 mg, resulting in similar t½ values that ranged from 8 to 10 h across doses. JNJ-10450232 (NTM-006) was generally safe and well tolerated, and no dose-limiting toxicities were observed. Transient increases in indirect bilirubin were noted at post-baseline timepoints due to UGT1A1 inhibition, without any evidence of adverse hepatic effects. Macular rash and generalized erythema were the most common drug-related adverse events after multiple doses.

Plasma T3 and T4 levels, and thyroid free (f) and bound (b) thyroid hormones contents, were determined by radioimmunoassay in adult male and female Rana perezi over 1 year. Plasma T3 levels show a significant seasonal cycle in both male and female frogs, increasing from January to peak in July (71-74 pg/ml) to decrease in August-October. Plasma T4 concentrations also varied seasonally, and sex differences were apparent. Basal T4 levels from the end of summer to the end of winter and higher values (682-651 pg/ml) in spring and early summer occur in female frogs; males have lowest levels in October (59.78 +/- 13.92 pg/ml) and higher levels during the rest of the year, except for a significant decrease in April. The thyroid content of fT3 and fT4 displayed similar seasonal patterns, with peak values in April and July-August. Sex differences are again present. The thyroid contents of bT3 are high between March and July in both sexes, with values in females being greater than those in males. The bT4 content follows a similar seasonal pattern in males and females and shows a minimum in March and a maximum in summer. Thyroid releasing capacity seems to change depending on the season and sex.

Objective: OTC Medicine Safety, a free, easily accessible, in-classroom educational program available through Young Minds Inspired (https://ymiclassroom.com/lesson-plans/otcmedsafety), was developed to improve adolescents’ knowledge of safe use of medicines. In a proof-of-concept study, students increased knowledge about safe, appropriate use of over-the-counter (OTC) medicines. In this study, we assessed whether the OTC Medicine Safety program effectively increased students’ knowledge and if students retained this knowledge over time. Methods: We measured student knowledge before implementation (baseline, Quiz 1) immediately after implementation (Quiz 2), and 10 weeks after baseline (Quiz 3) in 3 test schools. We measured knowledge at similar intervals in 3 control schools (no program implementation). Results: Baseline knowledge was low (average 39.3% of 36 questions answered correctly). Among intervention schools, scores significantly improved immediately (average correct 62.9%) after implementation and were retained at 10 weeks (59.8%) (p < .001). Change in score from baseline among intervention schools immediately after the lesson implementation was significantly higher than corresponding changes from baseline among control schools (intervention: +23.0 vs control: -3.2) and at 10 weeks (intervention: +19.9 vs control: -2.9), p < .001. Conclusion: The OTC Medicine Safety Program effectively improved students’ knowledge of safe medicine-taking practices and students retained this knowledge at 10 weeks.

Given the lack of validated patient-reported outcomes (PRO) instruments assessing cold symptoms, a new pediatric PRO instrument was developed to assess multiple cold symptoms: the Child Cold Symptom Questionnaire (CCSQ). The objective of this research was to evaluate the measurement properties of the CCSQ. This observational study involved daily completion of the self-report CCSQ by children aged 6–11 years in their home for 7 days. These data were used to develop a scoring algorithm and item-scale structure and evaluate the psychometric properties of the resulting scores. Analyses included evaluation of item and dimensionality performance (item response distributions and confirmatory factor analysis) and assessment of test–retest reliability in stable patients, construct validity (convergent and known groups validity), and preliminary responsiveness. Qualitative exit interviews in a subgroup of the children with colds and their parents were conducted. More than 90% of children had no missing data during the testing period, reflecting an excellent completion rate. For most items, responses were distributed across the options, with approximately normal distributions. Test–retest reliability was adequate, with intra-class correlation coefficients ranging from 0.63 to 0.83. A logical pattern of correlations with the validated Strep-PRO instrument provided evidence supporting convergent validity. Single- and multi-item symptom scores distinguished between children who differed in their cold severity based on global ratings, providing evidence of known groups validity. Preliminary evidence indicates the CCSQ is responsive to changes over time. The findings demonstrate that the CCSQ items and multi-item scores provide valid and reliable patient-reported measures of cold symptoms in children aged 6–11 years. They provide strong evidence supporting the validity of these items and multi-item scores for inclusion as endpoints in clinical trials to evaluate the efficacy of cold medicines.

No pediatric patient-reported outcome instruments specific to the common cold are found in the literature. This study involved development and content validity testing of patient-reported outcome items (questions and response options) assessing cold symptoms in children aged 6–11 years. Draft patient-reported outcome instructions, items, response scales, and recall periods were developed based on the literature and existing measures. Qualitative interviews were conducted with children (n = 39) who were currently (n = 31) or had recently (n = 8) experienced a cold and ten parents of a subset of children aged 6–8 years. The interviews were conducted over two rounds and included open-ended concept elicitation questioning, a free-drawing task, a card sorting task, and a task involving circling parts of the body, followed by cognitive debriefing of draft items. Thematic analysis of verbatim transcripts was performed to analyze the qualitative data. The findings were used to support revisions to the draft patient-reported outcome. Ten symptom concepts were reported by the children during concept elicitation. The creative tasks helped the children to describe their symptoms, generally using consistent language to do so, irrespective of age. Nineteen patient-reported outcome items were developed and subject to cognitive debriefing. Debriefing with both children and parents informed several small revisions and provided evidence that the majority of children found most patient-reported outcome items easy to understand, and that the items were mainly interpreted consistently and as intended. This in-depth qualitative study has supported identification of relevant symptom concepts and the development and refinement of patient-reported outcome items to assess those concepts. The findings support the content validity of the items and suggest that they can be used with confidence in children aged 9 years and older. For children aged 6–8 years, it is recommended the items are administered with initial adult supervision to explain the more difficult concepts or through parent/interviewer administration.

Objective: The objective of this study was to improve understanding of medicine safety knowledge among 6th grade students before and after participation in the OTC Literacy program. Methods: Among 1031 students attending 17 schools, the percentage of correct responses was calculated for total score and each learning objective; paired t-tests assessed pre-/post-program performance. Results: Program participation improved medicine-related knowledge in total score, for boys and girls, and in each type of school locale (ps < .001). Conclusions: Students who participated in the OTC Literacy program increased their medicine-related knowledge about safe, responsible use of OTC medicines in a variety of school locales. Early education can improve knowledge and may decrease medicine errors and misuse by fostering good life-long habits and attitudes about medicines.

Diphenhydramine pharmacokinetics were characterized following a single oral dose in children aged 2 to 17 years using a weight- and age-based dosing schedule with more tiers than the current age-based dosing schedule recommended by the nonprescription drug monograph. This study was conducted in 42 subjects, aged 2 to 17 years. Doses were based on a weight-age dosing schedule, ranging from 6.25 to 50 mg. An oral dose was administered with water about 2 hours after a light breakfast. Plasma samples were obtained up to 48 hours after dosing and analyzed for diphenhydramine. Pharmacokinetic parameters were estimated using noncompartmental methods, and the relationship of oral clearance with age was assessed using linear regression. Over an 8-fold range of doses, Cmax and AUC increased ∼90 % to ∼140% across age groups, with a similar Tmax (1.5 hours). Oral CL/F increased with age, but after allometric scaling, no maturation-related change in CL/F was apparent. Mild somnolence was the most commonly reported adverse event (95% of the subjects). A weight-age dosing schedule using an 8-fold range of doses achieved Cmax and AUC that increased about 2-fold across age groups. No effect of maturation on CL/F was observed after allometric scaling.

OBJECTIVE:Compare efficacy and safety of 10 to 15 mg/kg with 20 to 30 mg/kg acetaminophen in febrile children 6 months to ≤ 11 years from 3 double-blind, randomized, single or multiple dose studies.METHODS:Doses were compared on sum of the temperature differences (SUMDIFF), maximum temperature difference (MAXDIFF), temperature differences at each time point, and dose by time interactions. Alanine aminotransferase (ALT) was evaluated in the 72-hour duration study.RESULTS:A single dose of acetaminophen 20 to 30 mg/kg produced a greater effect on temperature decrement and duration of antipyretic effect over 8 hours than a single dose of 10 to 15 mg/kg. When equivalent total doses (i.e., 2 doses of 10 to 15 mg/kg given at 4-hour intervals and 1 dose of 20 to 30 mg/kg) were given over the initial 8-hour period, there were no significant temperature differences. Over a 72-hour period, 10 to 15 mg/kg acetaminophen administered every 4 hours maintained a more consistent temperature decrement than 20 to 30 mg/kg acetaminophen administered every 8 hours. Following doses of 60 to 90 mg/kg/day for up to 72 hours, no child had a clinically important increase in ALT from baseline. The number of children with reported adverse events was similar between doses.CONCLUSIONS:Data demonstrate the antipyretic effect of acetaminophen is dependent on total dose over a given time interval. These 3 studies provide clinical evidence that the recommended standard acetaminophen dose of 10 to 15 mg/kg is a safe and effective dose for treating fever in pediatric patients when administered as a single dose or as multiple doses for up to 72 hours.

Phenylephrine HCl 10 mg has been used as a nasal decongestant for over 50 years, yet only limited pharmacokinetic and metabolic data are available. The purpose of this study was to evaluate single-dose pharmacokinetics and safety of phenylephrine HCl 10, 20, and 30 mg and to assess cardiovascular tolerability compared with baseline and placebo in healthy volunteers.

Published analyses have noted elevated alanine aminotransferase (ALT) activity in patients taking up to 4000 mg/day of acetaminophen. Data from 3 osteoarthritis trials of acetaminophen 3900–4000 mg/day in which ALT and aspartate aminotransferase (AST) were recorded within approximately 2 weeks of therapy initiation were retrospectively analyzed. Patients with baseline ALT or AST above the upper limit of the reference range (ULRR) were excluded. Among 466 patients, 376 (80.7%) had no ALT elevations within approximately 2 weeks of treatment initiation. Elevations >1.5 and >3.0 times ULRR occurred in 4.5% and 0.9% of patients, respectively. Elevations were transient as most resolved (72.9%) or declined (22.4%) with continued treatment beyond 2 weeks. Within approximately 2 weeks of therapy initiation, no patient had ALT > 5 times ULRR or ALT > 3 times ULRR combined with bilirubin >2 times ULRR. ALT elevations were transient and asymptomatic; almost all resolved or declined while on continued therapy and appear not to be clinically important. Clinical trials.gov ID numbers: NCT00240799, NCT00240786

Background: Although acetaminophen is one of the oldest and most widely used of all analgesic drugs, the incremental benefit of the 1000-mg dose compared with the 650-mg dose has been questioned.Objective: The aim of this study was to assess the relative efficacy of acetaminophen 1000 mg versus acetaminophen 650 mg over a 6-hour period in patients experiencing at least moderate postsurgical dental pain.Methods: This single-center, randomized, double-blind, placebo-controlled, single-dose study enrolled patients aged 16 to 50 years who experienced at least moderate pain after surgical removal of impacted third molars. Each patient received either acetaminophen 1000 mg (n = 239), acetaminophen 650 mg (n = 241), or placebo (n = 60) when they had at least moderate pain and a score on the 100-mm Visual Analog Scale (VAS) postsurgically. Pain intensity and pain relief were measured over 6 hours (VAS 0-100 mm).Results: All 540 patients (52% female; age range, 16-30 years; 95% white) were included in the efficacy analysis. For the primary efficacy endpoint (weighted sum of the pain intensity difference from baseline [PID] and pain relief [PAR] scores over 6 hours [SPRID6]), acetaminophen 1000 mg demonstrated a 24% improvement compared with acetaminophen 650 mg (529.4 vs 427.3; P = 0.001). In addition, acetaminophen 650 mg was significantly superior compared with placebo (P < 0.001). The weighted sum of PID over 6 hours (SPID6), the weighted total pain relief over 6 hours (TOTPAR6), and the percentage of patients with >50% of the maximum possible TOTPAR6 score were significantly greater for patients treated with acetaminophen 1000 mg compared with those receiving acetaminophen 650 mg (P <= 0.006) or placebo (P < 0.001) and for patients treated with acetaminophen 650 mg compared with placebo (P < 0.001). Time to rescue, rescue rates through 4 and 6 hours, and patient global assessment demonstrated similar findings. Patients treated with acetaminophen 1000 mg or 650 mg had a significantly different distribution in times to confirmed perceptible and meaningful pain relief compared with those receiving placebo (P < 0.001). Adverse events were reported by 18.5% of patients, with no clinically important difference between active treatment groups and placebo.Conclusions: Acetaminophen 1000 mg provided clinically meaningful and statistically significantly greater efficacy in treating postsurgical dental pain compared with acetaminophen 650 mg and placebo. The outcomes of this study are limited to the single-dose design of this study. ClinicalTrials.gov identifier: NCT01115673. (Clin Ther. 2012;34:2247-2258) (c) 2012 Elsevier HS Journals, Inc. All rights reserved.

Two studies were conducted to characterize multiple-dose pharmacokinetics and potential drug interactions of ibuprofen and pseudoephedrine combined in a suspension and to evaluate safety of this combination in children with common cold, flu, or sinusitis. In the pharmacokinetic study, 24 healthy children aged 4-11 years were administered ibuprofen -pseudoephedrine suspension at 7.5 and 1.125 mg/kg, respectively, every 6 hours for 5 doses. Serial blood samples were drawn over 6 hours after final dose for assessment of steady-state pharmacokinetics. In the open-label, multicenter safety study, more than 100 children aged 2-11 years experiencing symptomatic rhinitis were enrolled. Ibuprofen -pseudoephedrine suspension was administered as needed at similar mg/kg doses every 6-8 hours for up to 3 days. Subjects enrolled in the pharmacokinetic study showed no accumulation of either drug; their weight-adjusted clearances were independent of age, and results were comparable with those from previous single-ingredient studies. For ibuprofen, oral clearance (Cl/F) was 77.5 ± 16.4 mL/kg/h and volume of distribution (Vd/F) was 0.147 ± 0.037 L/kg. For pseudoephedrine, Cl/F was 12.3 ± 2.2 mL/kg/min and Vd/F was 2.52 ± 0.47 L/kg. In the safety study, adverse events were reported for 18.4% of subjects; most were mild to moderate intensity. There was little difference in incidence of adverse events among different age and weight groups. In conclusion, administration of combined ibuprofen and pseudoephedrine in children demonstrated similar pharmacokinetics when compared with reports of the pharmacokinetics for the single-ingredient products, consistent with no apparent drug interactions. The combination suspension was generally well tolerated.