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Ultraviolet (UV) light is known to induce the generation of free radicals in biological tissues such as skin. Of these free radicals, the O2-. and particularly the.OH radical can induce cellular damage including lipid peroxidation. Thus, the use of antioxidants to prevent such damage induced by UV irradiation has received much attention recently. One such antioxidant, which has the potential to be incorporated into sunscreens, is the pineal secretory product melatonin. One of the concerns of using melatonin in sunscreens is its photostability. In the present study, we investigated the photostability of melatonin subjected to UV irradiation. In addition, we used liquid chromatography mass spectrometry (LC-MS) to identify the degradants and we also assessed the ability of the degradants to inhibit O2-. generation as well as lipid peroxidation in rat brain homogenate. The results show that UV irradiation of melatonin (0.1 mg/mL) using a 400-W lamp for 2 hr caused a significant decline of melatonin to 18% of its original concentration after 20 min, with the decline continuing until the melatonin concentration reaches zero at 120 min. The LC-MS results show that the degradants of melatonin are 6-hydroxymelatonin and N1-acetyl-N2-formyl-5-methoxykynurenamine (AFMK). These degradants were able to provide equipotent activity against potassium cyanide (KCN)-induced superoxide generation compared to non-irradiated melatonin. Thus, the study shows that although melatonin is rapidly degraded by UV irradiation, the degradants retain antioxidant activity, making melatonin a likely candidate for inclusion in sunscreens.  相似文献   
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Purpose

Novel therapies to treat chronic obstructive pulmonary disease are highly desirable. The safety, tolerability, and pharmacokinetic (PK) parameters of nemiralisib, a phosphoinositide 3-kinase δ inhibitor, administered via the Ellipta dry powder inhaler (GlaxoSmithKline, Research Triangle Park, North Carolina) was evaluated, including an assessment of oral bioavailability.

Methods

This single-center, 3-part, placebo-controlled trial in 22 healthy subjects evaluated single (100 and 200 μg) and repeat (200 μg for 10 days) doses of inhaled nemiralisib in parts A (n?=?12) and B (n?=?12) (double-blind) and single doses of inhaled nemiralisib (200 µg) with and without charcoal block in Part C (n?=?6) (open-label, 2-period, crossover). There was a minimum 14-day washout period between dosing days.

Findings

21 subjects completed the study, mean age was similar in the three parts (A: 49 years; B: 44 years; C: 55 years). After single doses of nemiralisib, observed plasma Cmax dropped rapidly, followed by a slower elimination phase. Near-dose proportionality was observed: mean (95% CI) plasma Cmax and AUC0–24 values were 174.3 pg/mL (96.9–313.3) and 694.6 pg·h/mL (503.5–958.2) for 100 μg and 398.9 pg/mL (318.3–500.1) and 1699.6 pg·h/mL (1273.3–2268.7) for 200 μg, respectively. Repeat dosing for 10 days showed exposures ~2- to 4-fold higher than on the single dose (peak, trough, and AUC0–24 levels), achieving steady-state by day 6. Mean AUC0–24 was 2193.6 pg·h/mL and 1645.3 pg·h/mL in the absence/presence of charcoal. Two non–drug-related adverse events were observed; neither was serious or resulted in withdrawal.

Implications

Inhalation of nemiralisib was well tolerated in these healthy subjects. Plasma pharmacokinetic variables were well defined, and charcoal block data indicate that ~23% of the total systemic exposure after inhalation from Ellipta was attributable to orally absorbed drug. ClinicalTrials.gov identifier: NCT02691325.  相似文献   
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Limited data are available on the longitudinal occurrence of syndemic factors among women at risk for HIV infection in the USA and how these factors relate to sexual risk over time. HVTN 906 was a longitudinal study enrolling 799 HIV-uninfected women in three cities. Assessments were done at baseline, 6, 12, and 18 months to assess syndemic factors (low education, low income, unemployment, lack of health insurance, housing instability, substance use, heavy alcohol use, partner violence, incarceration) and sexual risk outcomes. For each sexual risk outcome, a GEE model was fit with syndemic factors or syndemic score (defined as sum of binary syndemics, ranging from 0 to 9), visit, study site, age and race/ethnicity as predictors to examine the multivariable association between syndemic factors and outcomes over time. Odds of unprotected sex while drunk or high were significantly higher when women reported lack of health insurance, substance and heavy alcohol use and partner violence. Housing instability, substance and heavy alcohol use, partner violence and recent incarceration were associated with higher odds of having multiple sexual partners. Odds of sex exchange were significantly higher in the presence of unemployment, housing instability, low education, lack of health insurance, substance and heavy alcohol use, partner violence and incarceration. Housing instability, substance and heavy alcohol use, and partner violence were significantly associated with higher odds of unprotected anal sex. Odds of having a recent STI were significantly higher when women reported housing instability and partner violence. There were significantly higher odds of the reporting of any risk outcomes during follow-up with higher syndemic score. This study highlights a group of women experiencing multiple poor social and health outcomes who need to be the focus of comprehensive interventions.  相似文献   
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Ecotoxicology - To characterize environmental risks linked to former uranium mines in the Limousin region of France, a study was conducted on fish health effects from uranium releases. Two private...  相似文献   
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Journal of Thrombosis and Thrombolysis - To study whether a diagnosis of cancer affects the clinical presentation and outcomes of patients with pulmonary embolism (PE). A retrospective analysis was...  相似文献   
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