ABSTRACT Acetaminophen (APAP) has been formulated as immediate‐, modified‐, and extended‐release tablets (APAP‐IR, ‐MR, and ‐ER, respectively). However, there was concern that APAP‐MR previously available in Europe could form a bezoar after a large overdose, leading to delayed absorption and atypical pharmacokinetics (PK) compared to APAP‐IR, and that current treatment guidelines developed for APAP overdose to prevent severe hepatotoxicity are inappropriate for APAP‐MR. In contrast, APAP‐ER caplets available in the United States are designed with an IR layer and an erodible ER layer. Using modeling and simulation, predicted PK and hepatotoxicity biomarkers following various acute overdose and repeated supratherapeutic ingestion (RSTI) scenarios with APAP‐IR and APAP‐ER were compared to investigate the differences between these two formulations. The existing APAP‐IR representation within DILIsym v8A, a quantitative systems toxicology model of drug‐induced liver injury, was updated, and an APAP‐ER model was developed, using newly acquired in vitro (e.g., tiny‐TIMsg) and clinical data. The model and simulated populations (SimPops) representing healthy adults were extensively validated, before simulating PK and three clinically useful hepatic biomarkers after various overdose scenarios. On average, APAP exposure after acute overdose and RSTI in healthy adults was predicted to be slightly lower for APAP‐ER compared to APAP‐IR, partially due to lower APAP absorption for APAP‐ER, while not markedly impacting the expected time course of APAP plasma concentrations. Similar hepatic biomarker profiles were predicted for both APAP formulations. Based on these results, the APAP overdose consensus treatment guidelines updated in 2023 are not further impacted by this report.

Nocturnal heartburn (NHB) is a symptom that affects up to 25% of the general population and has been shown to cause sleep disruption that adversely affects quality of life and psychomotor performance. Few studies have evaluated the association between occasional NHB and sleep disturbances; therefore, this connection may be underappreciated and left untreated by the primary care provider and patient, with potentially significant negative clinical consequences and effects on quality of life. This review sought to describe what is currently known about the interplay between occasional NHB and sleep disruption, and identify whether acid suppression therapy can improve symptoms of occasional NHB and associated sleep disruptions. The pathophysiology of heartburn-induced sleep disruption appears to follow a bidirectional cycle due to the normal physiologic changes that occur in the upper gastrointestinal tract during sleep and due to the potential for heartburn symptoms to cause sleep arousal. The majority of the identified studies suggested that pharmacologic interventions for acid reduction, including proton pump inhibitors or histamine type-2 receptor antagonists (H2RAs), improved objective and/or subjective sleep outcomes among individuals with gastroesophageal reflux disease (GERD) and NHB. Several studies specific to famotidine demonstrated that treatment with 10 mg or 20 mg reduced nighttime awakenings due to NHB. In conclusion, NHB symptoms can cause sleep dysfunction that can have a profound adverse downstream effect on quality of life, next-day functioning, and health-related outcomes. The current approach to managing occasional NHB is similar to that associated with GERD, highlighting the need for studies specific to the occasional heartburn population. Health care providers should investigate NHB as one of the potential causes of sleep complaints, and patients with heartburn should be questioned about sleep quality, recalled arousals, next-day vitality, early fatigue, and next-day functioning.

Acne vulgaris is a multifactorial skin disease, characterized by proliferation of bacteria, hyperkeratinization, inflammation, and excess sebum production. Acne sufferers want to address all aspects of their acne, including the disease state of the lesions and cosmetic complexion issues, such as marks, tone, and redness. One first-line topical treatment for mild to moderate acne that dermatologists recommend is a combination of benzoyl peroxide (BPO), to target the bacteria, and a retinoid, to promote surface cell turnover. A daily regimen of 2.5% BPO and a stabilized cosmetic retinol was evaluated for its ability to improve acne and overall complexion. This is a novel OTC regimen for a holistic approach for both acne and complexion concerns. A 12-week, multi-center, evaluator-blinded clinical study of an acne treatment regimen (2.5% BPO applied in the morning and retinol in the evening) was conducted to evaluate its efficacy and tolerance in subjects (aged 12-30) with mild to moderate acne. The primary efficacy variable was percent change from baseline to week 12 in total lesion counts, with secondary assessments: Investigator Global Acne assessment, and additional Investigator efficacy assessments on complexion, self-assessments, and skin tolerance. A total of 33 subjects completed the study. The regimen of BPO and retinol significantly reduced total lesion counts over the 12-week study compared with baseline (P ˂ .05). Subjects reported significant improvements (P ˂ .05) in their acne, overall skin appearance and complexion. This offers patients an OTC option for addressing the acne lesions along with complexion endpoints (pigmentation, redness, overall complexion evenness) while being well-tolerated.

Introduced in the 1950s, acetaminophen is one of the most widely used antipyretics and analgesics worldwide. In 1999, the International Agency for Research on Cancer (IARC) reviewed the epidemiologic studies of acetaminophen and the data were judged to be "inadequate" to conclude that it is carcinogenic. In 2019 the California Office of Environmental Health Hazard Assessment initiated a review process on the carcinogenic hazard potential of acetaminophen. To inform this review process, the authors performed a comprehensive literature search and identified 136 epidemiologic studies, which for most cancer types suggest no alteration in risk associated with acetaminophen use. For 3 cancer types, renal cell, liver, and some forms of lymphohematopoietic, some studies suggest an increased risk; however, multiple factors unique to acetaminophen need to be considered to determine if these results are real and clinically meaningful. The objective of this publication is to analyze the results of these epidemiologic studies using a framework that accounts for the inherent challenge of evaluating acetaminophen, including, broad population-wide use in multiple disease states, challenges with exposure measurement, protopathic bias, channeling bias, and recall bias. When evaluated using this framework, the data do not support a causal association between acetaminophen use and cancer.

In 2019 California's Office of Environmental Health Hazard Assessment (OEHHA) initiated a review of the carcinogenic hazard potential of acetaminophen. In parallel with this review, herein we evaluated the mechanistic data related to the steps and timing of cellular events following therapeutic recommended (<= 4 g/day) and higher doses of acetaminophen that may cause hepatotoxicity to evaluate whether these changes indicate that acetaminophen is a carcinogenic hazard. At therapeutic recommended doses, acetaminophen forms limited amounts of N-acetyl-p-benzoquinone-imine (NAPQI) without adverse cellular effects. Following overdoses of acetaminophen, there is potential for more extensive formation of NAPQI and depletion of glutathione, which may result in mitochondrial dysfunction and DNA damage, but only at doses that result in cell death - thus making it implausible for acetaminophen to induce the kind of stable, genetic damage in the nucleus indicative of a genotoxic or carcinogenic hazard in humans. The collective data demonstrate a lack of a plausible mechanism related to carcinogenicity and are consistent with rodent cancer bioassays, epidemiological results reviewed in companion manuscripts in this issue, as well as conclusions of multiple international health authorities.

In 2019 the California Office of Environmental Health Hazard Assessment (OEHHA) initiated a review of the carcinogenic hazard potential of acetaminophen, including an assessment of the long-term rodent carcinogenicity and tumor initiation/promotion studies. The objective of the analysis herein was to inform this review process with a weight-of-evidence assessment of these studies and an assessment of the relevance of these models to humans. In most of the 14 studies, there were no increases in the incidences of tumors in any organ system. In the few studies in which an increase in tumor incidence was observed, there were factors such as absence of a dose response and a rodent-specific tumor supporting that these findings are not relevant to human hazard identification. In addition, we performed qualitative analysis and quantitative simulations of the exposures to acetaminophen and its metabolites and its toxicity profile; the data support that the rodent models are toxicologically relevant to humans. The preclinical carcinogenicity results are consistent with the broader weight of evidence assessment and evaluations of multiple international health authorities supporting that acetaminophen is not a carcinogenic hazard.

In 2019, the California Office of Environmental Health Hazard Assessment (OEHHA) initiated a review of the carcinogenic hazard potential of acetaminophen. The objective of the analysis herein was to inform this review by assessing whether variability in patient baseline characteristics (e.g. baseline glutathione (GSH) levels, pharmacokinetics, and capacity of hepatic antioxidants) leads to potential differences in carcinogenic hazard potential at different dosing schemes: maximum labeled doses of 4 g/day, repeated doses above the maximum labeled dose (>4-12 g/day), and acute overdoses of acetaminophen (>15 g). This was achieved by performing simulations of acetaminophen exposure in thousands of diverse virtual patients scenarios using the DILIsym (R) Quantitative Systems Toxicology (QST) model. Simulations included assessments of the dose and exposure response for toxicity and mode of cell death based on evaluations of the kinetics of changes of: GSH, N-acetyl-pbenzoquinone-imine (NAPQI), protein adducts, mitochondrial dysfunction, and hepatic cell death. Results support that, at therapeutic doses, cellular GSH binds to NAPQI providing sufficient buffering capacity to limit protein adduct formation and subsequent oxidative stress. Simulations evaluating repeated high-level supra therapeutic exposures or acute overdoses indicate that cell death precedes DNA damage that could result in carcinogenicity and thus acetaminophen does not present a carcinogenicity hazard to humans at any dose.

Recently, a study evaluating the difference in sunburn protection offered by SPF 50+ and SPF 100+ sunscreens over the course of 5 consecutive days in a beach environment facilitated a unique opportunity to evaluate the protection sunscreens provide against the induction of cutaneous pigmentation. A randomized, double-blinded, split body/face study assessing the efficacy of two broad spectrum sunscreens (SPF50+ and 100+) was conducted in the beach setting of St Petersburg, Florida. Fifty-five healthy subjects (1 phototype I, 22 phototype II, and 32 phototype III; average age 45.2 years [range: 19-59]) were enrolled. Subjects were permitted unrestricted access to test sunscreens and instructed to apply to the designated side as they normally would. Objective assessments of daily and cumulative changes in cutaneous pigmentation were conducted by colorimetry (ΔL*, Δb*, ΔITA°) and diffuse reflectance spectroscopy (DRS) (Δ melanin). SPF 100+ sunscreen offered greater protection against pigmentation induction as determined by a lower ΔL* and an increased Δb* on the SPF 50+ treated side (P < .001), which resulted in a mean ΔITA° of −7.57 on the SPF 50+ side and −5.78 on the SPF 100+ side. This pigmentation differential was supported by DRS assessments indicating greater melanin induction on the SPF 50+ side, Δ melanin (SPF50+ 0.18 ± 0.09 vs SPF100+ 0.15 ± 0.09, P = .01). Although pigment formation occurred on both sides, compared with SPF 50+ sunscreen, objective assessments show that the SPF 100+ sunscreen offered significantly greater protection against the induction of cutaneous pigmentation in actual use.

BACKGROUND:Beach vacations are high-risk settings for overexposure to ultraviolet radiation. OBJECTIVE:To compare the sunburn protective efficacy of SPF 50+ and SPF 100+ sunscreens under actual use at the beach. METHODS:A prospective, randomized, double-blind, single-center, split-body/face study of 55 healthy individuals. Each participant applied both sunscreens to randomized sides of the face/body for up to 5 consecutive days. Blinded clinical evaluation of erythema by a single grader and objective instrumental assessments, colorimetry, and diffuse reflectance spectroscopy were performed the morning after each sun exposure. RESULTS:After 5 days, 31 (56%) participants had more sunburn on the SPF 50+ side compared to 4 (7%) on the SPF 100+ side. Overall, mean erythema intensity showed statistically significantly less erythema on the SPF 100+ side compared with the SPF 50+ side. The first observation of sunburn exclusively on the SPF 50+ side occurred after 1 day of sun exposure, whereas that for SPF 100+ occurred after 3 days of sun exposure. LIMITATIONS:Only initial sunscreen application was monitored, only 1 participant with skin phototype I was recruited, and participants were recruited from a local beach area. CONCLUSION:SPF 100+ was significantly more effective in protecting against ultraviolet radiation-induced erythema and sunburn than SPF 50+ in actual use in a beach vacation setting.

Background: The value of additional photoprotection provided by use of highesun protection factor (SPF) sunscreens is controversial, and limited clinical evidence exists. Objective: To compare the sunburn protection provided by SPF 100+ and SPF 50+ sunscreen in conditions of actual use. Methods: A total of 199 healthy men and women (>= 18 years) participated in a natural sunlight, single-exposure, split-face, randomized, double-blind study in Vail, Colorado. Each participant wore both sunscreens simultaneously during activities, with no use restrictions other than designation of the treatment area. Erythema was clinically assessed on the day following exposure. Comparative efficacy was evaluated through bilateral comparison of sunburn between treatment areas and erythema score, as evaluated separately for each treatment area. Results: Following an average 6.1 +/- 1.3 hours of sun exposure, investigator-blinded evaluation identified 55.3% of the participants (110 of 199) as more sunburned on the SPF 50+ protected side and 5% (10 of 199) on the SPF 100+ protected side. After exposure, 40.7% of the participants (81 of 199) exhibited increased erythema scores (by >= 1) on the SPF 50+ protected side as compared with 13.6% (27 of 199) on the SPF 100+ protected side. Limitations: Single-day exposure may not extrapolate to benefits of longer-term protection. Conclusion: SPF 100+ sunscreen was significantly more effective in protecting against sunburn than SPF 50+ sunscreen in actual use conditions.

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.

More than 100 genes causing inherited retinal diseases have been mapped to chromosomal locations, but less than half of these genes have been cloned. Mutations in many retina/pineal-specific genes are known to cause inherited retinal diseases. Examples include mutations in arrestin, rhodopsin kinase, and the cone–rod homeobox gene,CRX. To identify additional candidate genes for inherited retinal disorders, novel retina/pineal-expressed EST clusters were identified from the TIGR Human Gene Index database and mapped to specific chromosomal sites. After known human gene sequences were excluded, and repeat sequences were masked, 26 novel retina and pineal gland cDNA clusters were identified. The retinal expression of each novel EST cluster was confirmed by PCR assay of a retinal cDNA library, and each cluster was localized in the genome using the GeneBridge 4.0 radiation hybrid panel.In silicoexpression data from the TIGR database suggest that these EST clusters are retina/pineal-specific or predominantly expressed in these tissues. This combination of database analysis and laboratory investigation has localized several EST clusters that are potential candidates for genes causing inherited retinopathy.

Acarbose, an alpha-glycosidase inhibitor, treats diabetes mellitus by delaying the digestion and intestinal absorption of dietary carbohydrates. In effective doses, acarbose induces some passage of carbohydrates into the colon. The effect of such chronic carbohydrate transfer on colonic structure and function is unknown. We studied the effects of 1 year of acarbose administration in diabetes mellitus on fecal energy, protein, and fat, including short-chain fatty acids (SCFA) output, fecal pH, and several metabolizing bacterial species. Changes in colonic histology and epithelial cell proliferation were investigated in rectal biopsies. Fecal macronutrient output was unaffected by acarbose, but pH decreased and total SCFA, butyrate, and acetate output were markedly greater. Breath hydrogen output increased after acarbose, but digoxin-metabolizing bacteria and diacylglycerol (DAG) production were unaltered. Compared with the control, acarbose did not induce hyperplasia or change rectal proliferation. However, total fecal SCFA and butyrate output correlated inversely with proliferation in the rectal upper crypt-a biomarker of risk for colonic neoplasia. In conclusion, long-term acarbose administration does not adversely affect colonic function or fecal nutrient output. If increased fecal SCFA and butyrate reduces upper-crypt proliferation, then acarbose may reduce the risk of colonic neoplasia.