Effect of Sunscreen Application on Plasma Concentration of Sunscreen Active Ingredients: A Randomized Clinical Trial.

Importance: A prior pilot study demonstrated the systemic absorption of 4 sunscreen active ingredients; additional studies are needed to determine the systemic absorption of additional active ingredients and how quickly systemic exposure exceeds 0.5 ng/mL as recommended by the US Food and Drug Administration (FDA). Objective: To assess the systemic absorption and pharmacokinetics of the 6 active ingredients (avobenzone, oxybenzone, octocrylene, homosalate, octisalate, and octinoxate) in 4 sunscreen products under single- and maximal-use conditions. Design, Setting, and Participants: Randomized clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) was conducted in 48 healthy participants. The study was conducted between January and February 2019. Interventions: Participants were randomized to 1 of 4 sunscreen products, formulated as lotion (n = 12), aerosol spray (n = 12), nonaerosol spray (n = 12), and pump spray (n = 12). Sunscreen product was applied at 2 mg/cm2 to 75% of body surface area at 0 hours on day 1 and 4 times on day 2 through day 4 at 2-hour intervals, and 34 blood samples were collected over 21 days from each participant. Main Outcomes and Measures: The primary outcome was the maximum plasma concentration of avobenzone over days 1 through 21. Secondary outcomes were the maximum plasma concentrations of oxybenzone, octocrylene, homosalate, octisalate, and octinoxate over days 1 through 21. Results: Among 48 randomized participants (mean [SD] age, 38.7 [13.2] years; 24 women [50%]; 23 white [48%], 23 African American [48%], 1 Asian [2%], and 1 of unknown race/ethnicity [2%]), 44 (92%) completed the trial. Geometric mean maximum plasma concentrations of all 6 active ingredients were greater than 0.5 ng/mL, and this threshold was surpassed on day 1 after a single application for all active ingredients. For avobenzone, the overall maximum plasma concentrations were 7.1 ng/mL (coefficient of variation [CV], 73.9%) for lotion, 3.5 ng/mL (CV, 70.9%) for aerosol spray, 3.5 ng/mL (CV, 73.0%) for nonaerosol spray, and 3.3 ng/mL (CV, 47.8%) for pump spray. For oxybenzone, the concentrations were 258.1 ng/mL (CV, 53.0%) for lotion and 180.1 ng/mL (CV, 57.3%) for aerosol spray. For octocrylene, the concentrations were 7.8 ng/mL (CV, 87.1%) for lotion, 6.6 ng/mL (CV, 78.1%) for aerosol spray, and 6.6 ng/mL (CV, 103.9%) for nonaerosol spray. For homosalate, concentrations were 23.1 ng/mL (CV, 68.0%) for aerosol spray, 17.9 ng/mL (CV, 61.7%) for nonaerosol spray, and 13.9 ng/mL (CV, 70.2%) for pump spray. For octisalate, concentrations were 5.1 ng/mL (CV, 81.6%) for aerosol spray, 5.8 ng/mL (CV, 77.4%) for nonaerosol spray, and 4.6 ng/mL (CV, 97.6%) for pump spray. For octinoxate, concentrations were 7.9 ng/mL (CV, 86.5%) for nonaerosol spray and 5.2 ng/mL (CV, 68.2%) for pump spray. The most common adverse event was rash, which developed in 14 participants. Conclusions and Relevance: In this study conducted in a clinical pharmacology unit and examining sunscreen application among healthy participants, all 6 of the tested active ingredients administered in 4 different sunscreen formulations were systemically absorbed and had plasma concentrations that surpassed the FDA threshold for potentially waiving some of the additional safety studies for sunscreens. These findings do not indicate that individuals should refrain from the use of sunscreen. Trial Registration: ClinicalTrials.gov Identifier: NCT03582215.

Effect of Sunscreen Application Under Maximal Use Conditions on Plasma Concentration of Sunscreen Active Ingredients: A Randomized Clinical Trial.

Importance: The US Food and Drug Administration (FDA) has provided guidance that sunscreen active ingredients with systemic absorption greater than 0.5 ng/mL or with safety concerns should undergo nonclinical toxicology assessment including systemic carcinogenicity and additional developmental and reproductive studies. Objective: To determine whether the active ingredients (avobenzone, oxybenzone, octocrylene, and ecamsule) of 4 commercially available sunscreens are absorbed into systemic circulation. Design, Setting, and Participants: Randomized clinical trial conducted at a phase 1 clinical pharmacology unit in the United States and enrolling 24 healthy volunteers. Enrollment started in July 2018 and ended in August 2018. Interventions: Participants were randomized to 1 of 4 sunscreens: spray 1 (n = 6 participants), spray 2 (n = 6), a lotion (n = 6), and a cream (n = 6). Two milligrams of sunscreen per 1 cm2 was applied to 75% of body surface area 4 times per day for 4 days, and 30 blood samples were collected over 7 days from each participant. Main Outcomes and Measures: The primary outcome was the maximum plasma concentration of avobenzone. Secondary outcomes were the maximum plasma concentrations of oxybenzone, octocrylene, and ecamsule. Results: Among 24 participants randomized (mean age, 35.5 [SD, 1.5] years; 12 (50%] women; 14 [58%] black or African American; 14 [58%]), 23 (96%) completed the trial. For avobenzone, geometric mean maximum plasma concentrations were 4.0 ng/mL (coefficient of variation, 6.9%) for spray 1; 3.4 ng/mL (coefficient of variation, 77.3%) for spray 2; 4.3 ng/mL (coefficient of variation, 46.1%) for lotion; and 1.8 ng/mL (coefficient of variation, 32.1%). For oxybenzone, the corresponding values were 209.6 ng/mL (66.8%) for spray 1, 194.9 ng/mL (52.4%) for spray 2, and 169.3 ng/mL (44.5%) for lotion; for octocrylene, 2.9 ng/mL (102%) for spray 1, 7.8 ng/mL (113.3%) for spray 2, 5.7 ng/mL (66.3%) for lotion, and 5.7 ng/mL (47.1%) for cream; and for ecamsule, 1.5 ng/mL (166.1%) for cream. Systemic concentrations greater than 0.5 ng/mL were reached for all 4 products after 4 applications on day 1. The most common adverse event was rash, which developed in 1 participant with each sunscreen. Conclusions and Relevance: In this preliminary study involving healthy volunteers, application of 4 commercially available sunscreens under maximal use conditions resulted in plasma concentrations that exceeded the threshold established by the FDA for potentially waiving some nonclinical toxicology studies for sunscreens. The systemic absorption of sunscreen ingredients supports the need for further studies to determine the clinical significance of these findings. These results do not indicate that individuals should refrain from the use of sunscreen. Trial Registration: ClinicalTrials.gov Identifier: NCT03582215.

Surgeons' Perceptions of the Causes of Preventable Harm in Arterial Surgery: A Mixed-Methods Study.

BACKGROUND: System factors contributing to preventable harm in vascular patients have not been previously reported in detail. The aim of this exploratory mixed-methods study was to describe vascular surgeons' perceptions of factors contributing to adverse events (AEs) in arterial surgery. A secondary aim was to report recommendations to improve patient safety. METHODS: Vascular consultants/registrars working in the British National Health Service were questioned about the causes of preventable AEs through survey and semi-structured interview (response rates 77% and 83%, respectively). Survey respondents considered a recent AE, indicating on a 5 point Likert scale the extent to which various factors from a validated framework contributed toward the incident. Semi-structured interviews were conducted to obtain detailed accounts of contributory factors, and to elicit recommendations to improve safety. RESULTS: Seventy-seven surgeons completed the survey on 77 separate AEs occurring during open surgery (n = 41) and in endovascular procedures (n = 36). Ten interviewees described 15 AEs. The causes of AEs were multifactorial (median number of factors/AE = 5, IQR 3-9, range 0-25). Factors frequently reported by survey respondents were communication failures (36.4%; n = 28/77); inadequate staffing levels/skill mix (32.5%; n = 25/77); lack of knowledge/skill (37.3%; n = 28/75). Themes emerging from interviews were team factors (communication failure, lack of team continuity, lack of clarity over roles/responsibilities); work environment factors (poor staffing levels, equipment problems, distractions); inadequate training/supervision. Knowledge/skill (p = .034) and competence (p = .018) appeared to be more prominent in causing AEs in open procedures compared with endovascular procedures; organisational structure was more frequently implicated in AEs occurring in endovascular procedures (p = .017). To improve safety, interviewees proposed team training programmes (5/10 interviewees); additional protocols/checklists (4/10); improved escalation procedures (3/10). CONCLUSION: Vascular surgeons believe that AEs in arterial operations are caused by multiple, modifiable system factors. Larger studies are needed to establish the relative importance of these factors and to determine strategies that can effectively address system failures.

Acute Thrombotic Occlusion of the Popliteal Artery following Knee Dislocation: A Case Report of Management, Local Unit Practice, and a Review of the Literature.

Arterial complications following traumatic knee injury are relatively rare but mandate timely recognition and treatment to avoid significant comorbidity and medicolegal ramifications. In this report we describe a case of acute thrombotic occlusion of the popliteal artery occurring after knee dislocation, successfully repaired by intimal fixation and a limited venous patch reconstruction. We present a review of local practice in screening vascular injuries following knee dislocation, aligned with a review of the literature and considerations for practice.

Hybrid endovascular repair of aneurysmal right-sided aortic arch and Kommerell's diverticulum using a two-vessel branched stent graft: Case report and review of literature.

Right-sided aortic arches are rare, affecting approximately 0.1% of the population. They are a result of abnormal development of the primitive aortic arches and may present later in life with later life with aneurysmal expansion of the aberrant left subclavian artery 'Kommerell's diverticulum'. These can be challenging to treat effectively. We report a rare case presenting with mild dysphagia and right-sided aneurysmal aortic arch with aneurysmal aberrant left-sided. The patient underwent hybrid endovascular repair incorporating bilateral carotid-subclavian bypasses and dual-arch-branch endograft placement to the left and right common carotid arteries. Although endovascular approaches have been described, there are no reports of branched endografts in this scenario. Right-sided aneurysmal aortic arch and the aneurysmal aberrant left subclavian artery are rare and represent a significant therapeutic challenge. Endovascular repair in conjunction with extra-anatomical bypass utilising a custom-made branched thoracic endograft is feasible.

Patient Compliance with Surveillance Following Elective Endovascular Aneurysm Repair.

PURPOSE: Integral to maintaining good outcomes post-endovascular aneurysm repair (EVAR) is a robust surveillance protocol. A significant proportion of patients fail to comply with surveillance, exposing themselves to complications. We examine EVAR surveillance in Wessex (UK), exploring factors that may predict poor compliance. METHODS: Retrospective analysis of 179 consecutive elective EVAR cases [2008-2013] was performed. 167 patients were male, with the age range of 50-95. Surveillance was conducted centrally (tertiary referral trauma centre) and at four spoke units. Surveillance compliance and predictors of non-compliance including age, gender, co-morbid status, residential location and socioeconomic status were analysed for univariate significance. RESULTS: Fifty patients (27.9 %) were non-compliant with surveillance; 14 (8.1 %) had no imaging post-EVAR. At 1 year, 56.1 % (of 123 patients) were compliant. At years 2 and 3, 41.5 and 41.2 % (of 65 and 34 patients, respectively) were compliant. Four years post-EVAR, only one of eight attended surveillance (12.5 %). There were no statistically significant differences in age (p = 0.77), co-morbid status or gender (p = 0.64). Distance to central unit (p = 0.67) and surveillance site (p = 0.56) was non-significant. While there was a trend towards compliance in upper-middle-class socioeconomic groups (ABC1 vs. C1C2D), correlating with >50 % of non-compliant patients living within <10 mile radius of the central unit, overall predictive value was not significant (p = 0.82). CONCLUSIONS: Compliance with surveillance post-EVAR is poor. No independent predictor of non-compliance has been confirmed, but socioeconomic status appears to be relevant. There is a worrying drop-off in attendance beyond the first year. This study highlights a problem that needs to be addressed urgently, if we are to maintain good outcomes post-EVAR.

Bioequivalence of oxycodone hydrochoride extended release tablets to marketed reference products OxyContin® in Canada and US.

INTRODUCTION: Oxycodone is a semisynthetic opioid agonist used for the relief of moderate to severe pain. A new generic oxycodone hydrochloride (HCl) extended release (ER) tablet is currently being developed by Ranbaxy Pharmaceutical Inc., New Brunswick, NJ, USA. OBJECTIVE: To assess relative bioavailability of a new generic (test) formulation of oxycodone hydrochloride (HCl) extended release (ER) tablets with that of marketed reference products, OxyContin®, in Canada and USA, in healthy adult subjects under fasting and fed conditions. METHODS: Five studies were conducted in all, three of which were designed to comply with the regulatory criteria for marketing a new generic formulation of OxyContin® in Canada and the remaining two to comply with regulatory criteria for marketing a new generic formulation of OxyContin® in the USA. Each study was a balanced, randomized two-period, two-treatment, two-sequence, crossover design. A single oral dose of test or reference product was given in Period 1, followed by a 7-day washout period, after which subjects received the alternative product in Period 2. In order to block the pharmacological effects of oxycodone, subjects were administered naltrexone HCl (1 × 50 mg tablet) 12 hours prior to oxycodone HCl administration, concurrent with oxycodone HCl administration, and 12 hours after oxycodone HCl administration. Throughout the confinement portion of the study, adverse events were closely monitored. Serial blood samples were collected, following which oxycodone in plasma was estimated using a validated analytical procedure. RESULTS: Oxycodone was well tolerated by subjects in both periods of each study under both fed and fasted conditions. No serious adverse events were observed. The ratios of geometric means for AUC0-t and Cmax and the affiliated 90% confidence intervals for AUC were within acceptance range recommended by Health Canada. These criteria were met for both the raw data as well as data corrected for measured drug content (potency). The ratios of geometric means and the 90% confidence intervals for AUC0-t, AUC0-∞ and Cmax were within acceptance range recommended by United States Food and Drug Administration (FDA). CONCLUSIONS: Results demonstrate that the test formulation of oxycodone HCl ER tablets is bioequivalent to marketed OxyContin® reference formulations in Canada and USA, when administered both under fasted and fed conditions. Additionally, oxycodone HCl ER tablets were well tolerated as a single oral dose when administered to healthy adult subjects under fasted and fed conditions.

Single-dose bioequivalence of 105-mg fenofibric acid tablets versus 145-mg fenofibrate tablets under fasting and fed conditions: a report of two phase I, open-label, single-dose, randomized, crossover clinical trials.

BACKGROUND: Fenofibrate is used to treat primary hypercholesterolemia, mixed lipidemia, and hypertriglyceridemia in adults who do not respond to nonpharmacologic measures. Fenofibrate is a prodrug that is rapidly and completely hydrolyzed to fenofibric acid, the active moiety. A new orally administered agent, fenofibric acid, was developed as an alternative to fenofibrate. OBJECTIVE: Two separate studies were conducted to evaluate the bioequivalence of fenofibric acid relative to fenofibrate under fasted and fed (standard breakfast) conditions, characterize the pharmacokinetic profile, and assess the safety and tolerability of fenofibric acid. METHODS: In study 1 (fasted), during each study period, volunteers received a single 105-mg dose of fenofibric acid or single 145-mg dose of fenofibrate (depending on their randomization scheme) after an overnight fast (a minimum fast of 10 hours). A 7-day washout period followed the first treatment period, after which the volunteers received the alternate treatment. Study 2 followed a similar dosing scheme and differed only in that volunteers received their single dose after being fed a standard meal (575 calories, of which 36% were contributed by fat). Serial blood samples in both studies were collected up to 72 hours after drug administration. The pharmacokinetic parameters of interest for assessing bioequivalence were AUC(0-t), AUC(0-∞), C(max), and T(max). The criterion for a lack of difference between products was a 90% CI between 0.80 and 1.25 for the fenofibric acid:fenofibrate ratios for AUC(0-t), AUC(0-∞), and C(max.) Tolerability was assessed by adverse events (AEs), laboratory parameters, vital signs, and physical examinations. RESULTS: Volunteers in study 1 (fasted; n = 54) were aged 18 to 43 years; 19 (35%) were men and 35 (65%) were women; mean weight was 155.2 pounds (range, 103.0-267.0 pounds); and 48 (89%) were white, 1 (2%) was black, and 5 (9%) were white/American Indian/Alaskan native/Asian. Volunteers in study 2 (fed; n = 54) were aged 18 to 43 years; 27 (50%) were men and 27 (50%) were women; mean weight was 161.9 pounds (range, 112.0-225.0 pounds); and 51 (94%) were white (including 2 Hispanic) and 3 (6%) were black. The 90% CIs about the ratio of the fenofibric acid geometric mean to the fenofibrate geometric mean were within the 80% and 125% limits for the pharmacokinetic parameters C(max), AUC(0-t), and AUC(0-∞) of the ln-transformed data in both study 1 (fasted) and study 2. In study 1 (fasted), 14 volunteers (26%) experienced a total of 29 AEs; the most common nonlaboratory AEs were dizziness (6%) and headache (4%). In study 2, 12 volunteers (22%) experienced a total of 19 AEs; the most common nonlaboratory AEs were headache (17%) and dry throat (4%). AEs were generally mild or moderate in intensity. CONCLUSIONS: In these 2 single-dose studies, these healthy volunteers administered a single oral dose of 105-mg fenofibric acid met the US Food and Drug Administration regulatory criteria for assuming bioequivalence to a single oral dose of 145-mg fenofibrate tablets with respect to the rate and extent of fenofibric acid absorption in both fed and fasted states. Fenofibric acid at the dose studied was well tolerated in this population.

A single-blinded, randomized pilot study evaluating the aroma of Lavandula augustifolia as a treatment for mild insomnia.

BACKGROUND: Insomnia is the most common of all sleep complaints and is under-researched. The current treatments of choice are conventional hypnotics agents, but these have potential for serious adverse reactions. Uncontrolled and anecdotal evidence suggests that lavender oil is an effective treatment for insomnia, but this has not been formally investigated. OBJECTIVES: The aims of this study were to evaluate the proposed trial methodology and the efficacy of Lavandula augustifolia (lavender) on insomnia. INTERVENTIONS: INTERVENTIONS consisted of Lavandula augustifolia (treatment) and sweet almond oil as placebo/control. The aroma was supplied via an Aromastream device (Tisserand Aromatherapy, Sussex, UK). DESIGN: This was a pilot study with randomized, single-blind, cross-over design (baseline, two treatment periods, and a washout period, each of 1 week duration). SUBJECTS AND SETTING: Volunteers with defined insomnia treated on a domiciliary basis participated in the study. OUTCOME MEASURES: Outcomes were assessed with the following: Pittsburgh Sleep Quality Index (PSQI) indicating insomnia (score > 5 at entry); Borkovec and Nau (B&N) Questionnaire evaluating treatment credibility; and Holistic Complementary and Alternative Medicine Questionnaire (HCAMQ) assessing attitudes to CAM and health beliefs. RESULTS: Ten (10) volunteers (5 male and 5 female) were entered and completed the 4 week study. Lavender created an improvement of -2.5 points in PSQI (p = 0.07, 95% CI - 4.95 to - 0.4). Each intervention was equally credible and belief in CAM did not predict outcome. Women and younger volunteers with a milder insomnia improved more than others. No period or carry-over effect was observed. CONCLUSION: The methodology for this pilot study appeared to be appropriate. Outcomes favor lavender, and a larger trial is required to draw definitive conclusions.

Characterization of the expression of inducible nitric oxide synthase in rat and human liver during hemorrhagic shock.

It has been previously shown that the inducible nitric oxide (NO) synthase (iNOS; NOS-2) is elevated after hemorrhage, and that iNOS-derived NO participates in the upregulation of inflammation as well as lung and liver injury postresuscitation from shock. The purpose of this study was to elucidate the time course of iNOS mRNA expression, as well as the cellular and subcellular localization of iNOS protein in the liver posthemorrhage in rats subjected to varying durations of hemorrhagic shock (HS; mean arterial blood pressure [MAP] = 40 mmHg) with or without resuscitation. Expression of iNOS mRNA in rat liver by real-time reverse transcriptase (RT)-PCR demonstrated iNOS upregulation in shocked animals as compared with their sham counterparts as early as 60 min after the initiation of hemorrhage. By 1 h of HS, iNOS protein was detectable in rat liver by immunofluorescence, and this expression increased with time. Immunofluorescence localized iNOS primarily to the hepatocytes, and in particular to hepatocytes in the centrilobular regions. This analysis, confirmed by immunoelectron microscopy, revealed that iNOS colocalizes with catalase, a peroxisomal marker. Furthermore, we determined that iNOS mRNA is detectable by RT-PCR in liver biopsies from human subjects with HS (MAP < 90 mmHg) associated with trauma (n = 18). In contrast, none of the seven nontrauma surgical patients studied had detectable iNOS mRNA in their livers. Collectively, these results suggest that hepatic iNOS expression, associated with peroxisomal localization, is an early molecular response to HS in experimental animals and possibly in human patients with trauma with HS.