A Topical Combination Regimen of Benzoyl Peroxide and Retinol Moisturizer for Mild to Moderate Acne.

Topical therapies, in many cases over-the-counter (OTC) formulations, are available for the treatment of acne, including benzoyl peroxide (BPO), salicylic acid, and retinoids. While these agents provide therapeutic efficacy, combination regimens can offer improved outcomes due to their ability to address multiple pathways involved in acne formation, making them better suited to address the multiple factors involved in acne pathogenesis and the breadth of complexion issues associated with the condition. The present study assessed the efficacy and tolerability of a daily regimen comprised of topical low-dose (2.5%) BPO applied in the morning and topical retinol applied in the evening in 33 subjects with mild to moderate acne who completed the study. A significant reduction in global total acne count from baseline to week 12 (primary endpoint) was achieved, in addition to significant improvements in Investigator Global Assessment (IGA) of acne severity and reductions in inflammatory and non-inflammatory lesions. Treatment also significantly improved acne-complexion graded efficacy parameters (tactile surface roughness, uneven skin tone, skin blotchiness, and lack of skin clarity), and was well-tolerated, with no statistically significant (P<0.05) increases in objective or subjective facial irritation. Significant improvements from baseline to week 12 were observed for both self-assessment of facial skin conditions and quality of life (QoL) scores. No product-related adverse events (AEs) were observed in the study subjects. J Drugs Dermatol. 2022;21(12):1340-1346. doi:10.36849/JDD.6845.

A systematic assessment of the epidemiologic literature regarding an association between acetaminophen exposure and cancer.

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.

Assessment of the biochemical pathways for acetaminophen toxicity: Implications for its carcinogenic hazard potential.

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.

Application of the DILIsym® Quantitative Systems Toxicology drug-induced liver injury model to evaluate the carcinogenic hazard potential of acetaminophen.

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® 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-p-benzoquinone-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 supratherapeutic 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.

A critical review of the acetaminophen preclinical carcinogenicity and tumor promotion data and their implications for its carcinogenic hazard potential.

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.

Greater efficacy of SPF 100+ sunscreen compared with SPF 50+ in sunburn prevention during 5 consecutive days of sunlight exposure: A randomized, double-blind clinical trial.

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.

SPF 100+ sunscreen is more protective against sunburn than SPF 50+ in actual use: Results of a randomized, double-blind, split-face, natural sunlight exposure clinical trial.

BACKGROUND: The value of additional photoprotection provided by use of high-sun 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.

A randomized, double-blind, placebo-controlled study of acetaminophen 1000 mg versus acetaminophen 650 mg for the treatment of postsurgical dental pain.

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 ≥50 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.