Global trends and differences in the burden of alcohol use disorders attributable to childhood sexual abuse by sex, age, and socio-demographic index: Findings from the Global Burden of Disease Study 2019.

BACKGROUND: Childhood sexual abuse (CSA) is a severe global problem associated with alcohol use disorder (AUD). Previous studies have confirmed this relationship; however, there is a lack of research on the disease burden of AUD attributable to CSA. OBJECTIVE: To analyze global spatiotemporal trends and differences in the disease burden of AUD attributable to CSA and its relationship with age, sex, and the sociodemographic index (SDI). PARTICIPANTS AND SETTING: Data from the Global Burden of Disease 2019 Public Database. METHODS: Summary exposure value (SEV) was used to evaluate CSA. Disability-adjusted life year (DALY), years lived with disability (YLD), years of life lost (YLL), and their annual rates of change were used to evaluate disease burden. Cluster analysis based on Ward's method was used to examine the global burden associated with age, sex, and SDI. A 95 % uncertainty intervals (UI), excluding 0, was considered statistically significant. RESULTS: In 2019, 1.63 million (95 % UI 0.23-3.90 million) DALYs of AUD were caused by CSA and the age-standardized rates (ASRs) of DALY was 19.77 (95 % UI 2.78-47.46) globally. Annual rates of change in DALY of people over 65 years of age increased from 1990 to 2019 in all regions except the High-middle SDI regions. The ASRs of DALY of females in High SDI regions, were always at a much higher level than other SDI regions, and showed an upward trend from 1990 to 2019 (DALY 1990: 20.38 [95 % UI 2.87-47.77], 2019: 23.61 [95 % UI 3.55-54.94]). CONCLUSIONS: Substantial geographical differences were observed in the burden of AUD attributable to CSA. The level of CSA exposure was inconsistent with the related burden of AUD in different regions according to the sociodemographic index. The burden of disease increased in the elderly population and in females in high sociodemographic index regions.

Differentiating the association between age of alcohol use initiation and conditional suicidal behaviors among adolescents.

INTRODUCTION: Suicide and early alcohol use initiation are public health concerns. Previous studies have explored the associations between age of alcohol use initiation and suicidal behaviors, which progresses from ideation to action. Distinguishing between the various associations can help gain a deeper understanding of suicidal behaviors and aid in developing social suicide prevention strategies. METHODS: The study utilized the Youth Risk Behavior Survey to investigate this association. A total of 17 209 students were finally included in the study. Conditional suicidal behaviors included no suicidal behavior (NS), suicidal ideation without a plan or attempt (SINPA), suicide plan without an attempt (SPNA) and suicide attempt (SA). RESULTS: Among 17 209 students, the prevalence of suicidal ideation, suicide plan, and suicide attempt were 21.4%, 17.3%, and 11.1%, respectively. Moreover, 15.2% of the students used alcohol before age 13, whereas 31.7% of students used alcohol at age 13 or older. Compared to NS, students using alcohol showed significant associations with SA (OR = 2.34, p < .001; OR = 1.29, p < .01), SPNA (OR = 1.68, p < .001; OR = 1.19, p < .05) and SINPA (OR = 1.55, p < .001; OR = 1.40, p < .001). Comparing with SINPA and SNPA, students using alcohol before age 13 were associated with SA (OR = 1.61, p < .001; OR = 1.46, p < .001), whereas those using alcohol at or after the age 13 were not associated with SA (OR = 0.98, p > .05; OR = 1.09, p > .05). DISCUSSION: This study demonstrated that early alcohol use initiation was significantly associated with suicide attempts among students with suicidal ideations or plans.

Global, regional and national burdens of bipolar disorders in adolescents and young adults: a trend analysis from 1990 to 2019.

Background: Bipolar disorder is identified as a cause of severe damage to the physical, psychological and social functioning of adolescents and young adults. Aims: The aim of this study is to ascertain the trends in the burden of bipolar disorder among individuals aged 10-24 years at global, regional and national levels from 1990 to 2019. Methods: The data analysed in this study were from the Global Burden of Diseases 2019. The numbers, rates per 100 000 population, average annual percentage changes (AAPCs) of incidence, prevalence and years lived with disability (YLDs) of bipolar disorder are reported at the global, regional and national levels among individuals aged 10-24 years. Global trends by age, sex and Social Development Index (SDI) were further analysed. Results: Globally, the incidence of bipolar disorder among adolescents and young adults increased from 79.21 per 100 000 population (95% uncertainty interval (UI): 58.13 to 105.15) in 1990 to 84.97 per 100 000 population (95% UI: 61.73 to 113.46) in 2019, AAPC 0.24 (95% confidence interval (CI): 0.22 to 0.26). In the past three decades, there has been an increase in incidence, prevalence and YLDs in both males and females. The largest increase in incidence between 1990 and 2019 was observed in those aged 20-24 years old (from 51.76 per 100 000 population (95% UI: 26.81 to 87.20) in 1990 to 58.37 per 100 000 population (95% UI: 30.39 to 98.55) in 2019; AAPC 0.42 (95% CI: 0.38 to 0.47)). By the SDI quintile, the largest increase in incidence was observed in the middle SDI; however, the high SDI countries had the highest incidence. Regionally, the largest increase in incidence was observed in southern Latin America. At the national level, the most pronounced increase in the incidence was in Greenland. Conclusions: The global increase in incidence among adolescents and young adults between 1990 and 2019 indicates that strategies to improve their mental health still need to be emphasised.

Quantitative determination of proxalutamide in rat plasma and tissues using liquid chromatography/tandem mass spectrometry.

RATIONALE: Proxalutamide is a novel drug for the treatment of prostate cancer. However, to date, there are almost no reports on the pharmacokinetics of proxalutamide in vivo. This study developed a liquid chromatography/tandem mass spectrometry (LC/MS/MS) method to determine the concentrations of proxalutamide in biological samples for pharmacokinetic studies. METHODS: Chromatographic separation was achieved on a Kromasil 100-5C8 column followed by gradient elution using a Shimadzu HPLC system. MS was performed in positive ion electrospray ionization mode using a SCIEX API 4000 triple quadrupole system. A simple and rapid one-step protein precipitation method was used for sample processing, and a low sample volume of 10 µL was used for processing and analysis. RESULTS: The method was validated to show good selectivity, sensitivity, precision, and accuracy. Good linearity (r2 > 0.99) was observed for rat plasma (range: 2-5000 ng/mL) and rat tissue homogenates (range: 2-2000 ng/mL). The extraction recovery was above 98%, and no significant matrix effect was observed. This method was successfully applied to investigate the pharmacokinetics and tissue distribution of proxalutamide in rats. CONCLUSIONS: A rapid and sensitive LC/MS/MS method was developed and validated to determine the quantity of proxalutamide in rat plasma and tissue homogenates and to further study the pharmacokinetic parameters of proxalutamide in a rat model. The results showed that proxalutamide had good oral bioavailability and wide tissue distribution in vivo.

Characterization of isochlorogenic acid A metabolites in rats using high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry.

Isochlorogenic acid A is widely present in fruits, vegetables and herbal medicines, and is characterized by anti-inflammatory, hepatoprotective and antiviral properties. However, little is known about its metabolic fate and pharmacokinetic properties. This study is thus designed to investigate the metabolic fate of isochlorogenic acid A. An analytical method based on high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (HPLC/Q-TOF MS) was established to characterize the metabolites of isochlorogenic acid A in the plasma, urine and feces of rats. A total of 32 metabolites were identified. The metabolic pathways mainly include hydrolyzation, dehydroxylation, hydrogenation and conjugation with methyl, glucuronic acid, glycine, sulfate, glutathione and cysteine. Moreover, the pharmacokinetic profiles of all the circulating metabolites were investigated. M11 resulting from hydrolyzation, dehydroxylation and hydrogenation was the dominant circulating metabolite after the intragastric administration of isochlorogenic acid A. The results obtained will be useful for further study of elucidating potential bioactive metabolites which can provide better explanation of the pharmacological and/or toxicological effects of this compound.

Integrated identification, qualification and quantification strategy for pharmacokinetic profile study of Guizhi Fuling capsule in healthy volunteers.

Guizhi Fuling capsule (GZFL), a traditional Chinese medicine formulation, is widely used in China to relieve pain from dysmenorrhea and is now in a Phase II clinical trial in the USA. Due to the low exposure of the five main medicative ingredients (amygdalin, cinnamic acid, gallic acid, paeoniflorin and paeonol) of GZFL in human, a strategy was built to qualitatively and quantitatively identify the possible metabolites of GZFL and to describe the pharmacokinetic profiles of GZFL in human. In this strategy, LC-Q-TOF/MS was used to identify and structurally elucidate the possible metabolites of GZFL in vivo; and a time-based metabolite-confirming step (TBMCs) was used to confirm uncertain metabolites. The simultaneously quantitation results by LC-MS/MS showed low exposure of the five medicative ingredients. According to the strategy we built, a total of 36 metabolites were found and structurally elucidated. The simultaneously semi-quantitative analysis by LC-MS/MS showed that obvious time-concentration curves could be established for 12 of the metabolites, and most of them showed a relatively higher exposure. This study provides a better understanding of the metabolic processes of GZFL in human.

Identification and characterization of in vivo metabolites of asulacrine using advanced mass spectrophotometry technique in combination with improved data mining strategy.

Asulacrine (ASL) is a broad-spectrum, antitumor drug whose data are promising for the treatment of breast and lung cancers; however, a high incidence of phlebitis hampered its further development. Phlebitis is associated with generation of reactive species. Asulacrine donates electrons and produces oxidative stress in chemical reactions. It was expected that ASL would actively metabolize to oxidized products through reactive intermediates and produce more products in vivo than reported and thus cause phlebitis. A comprehensive study was planned to investigate in vivo metabolism of ASL, using high-resolution mass spectrometry LC/IT-TOF MS in positive mode. Metabolites were detected by different software by applying annotated detection strategy. The possible metabolites and their product ions were simultaneously detected by segmented data acquisition to get accurate mass values. Segmented data acquisition improved signal-to-noise (S/N) ratio, which was helpful to detect metabolites and their fragments even when present in trace amounts. A total of 21 metabolites were detected in gender-based biological fluids and characterized by comparing their accurate mass values, fragmentation patterns, and relative retention times with that of ASL. Among previously reported glucuronosylation metabolites, some oxidation, hydroxylation, carboxylation, demethylation, hydrogenation, glutamination, and acetylcysteine conjugation were detected for the first time. Twenty metabolites were tentatively identified by using the annotated strategy for data acquisition and post-data mining.

A comprehensive assay for nine major cytochrome P450 enzymes activities with 16 probe reactions on human liver microsomes by a single LC/MS/MS run to support reliable in vitro inhibitory drug-drug interaction evaluation.

1. A comprehensive method for the simultaneous characterization of xenobiotic compound inhibition of nine major CYP enzymes in human liver microsomes was established by using 16 CYP-catalyzed reactions of 14 probe substrates with three cocktail incubation sets and a single LC/MS/MS analysis. 2. The three cocktail subgroups were developed to minimize the effects of organic solvents, polyunsaturated fatty acids and mutual substrate interactions: Group I was composed of tolbutamide (CYP2C9), S-mephenytoin (CYP2C19), testosterone (CYP3A4), dextromethorphan (CYP2D6); Group II was composed of nifedipine (CYP3A4), midazolam (CYP3A4), coumarin (CYP2A6), bupropion (CYP2B6), diclofenac (CYP2C9); Group III was composed of phenacetin (CYP1A2), chlorzoxazone (CYP2E1), omeprazole (CYP2C19 and CYP3A4), paclitaxel (CYP2C8), (+)-bufuralol (CYP2D6). In the case of CYP2C9, CYP2C19, CYP2D6 and CYP3A4, multiple probe substrates were used due to the phenomenon of multiple substrate-binding pockets and substrate-dependent inhibition. All probe metabolites were simultaneously analyzed with a polarity switching mode in a single LC/MS/MS run. 3. This method was validated against the single probe substrate assay using 12 well-characterized CYP inhibitors and two new entities (GT0918, MDV3100). The IC50 values of each inhibitor in the cocktail agreed well with that of the individual probe drug as well as with values reported in previous literatures.

Guanfu base A, an antiarrhythmic alkaloid of Aconitum coreanum, Is a CYP2D6 inhibitor of human, monkey, and dog isoforms.

Guanfu base A (GFA) is a novel heterocyclic antiarrhythmic drug isolated from Aconitum coreanum (Lèvl.) rapaics and is currently in a phase IV clinical trial in China. However, no study has investigated the influence of GFA on cytochrome P450 (P450) drug metabolism. We characterized the potency and specificity of GFA CYP2D inhibition based on dextromethorphan O-demethylation, a CYP2D6 probe substrate of activity in human, mouse, rat, dog, and monkey liver microsomes. In addition, (+)-bufuralol 1'-hydroxylation was used as a CYP2D6 probe for the recombinant form (rCYP2D6), 2D1 (rCYP2D1), and 2D2 (rCYP2D2) activities. Results show that GFA is a potent noncompetitive inhibitor of CYP2D6, with inhibition constant Ki = 1.20 ± 0.33 µM in human liver microsomes (HLMs) and Ki = 0.37 ± 0.16 µM for the human recombinant form (rCYP2D6). GFA is also a potent competitive inhibitor of CYP2D in monkey (Ki = 0.38 ± 0.12 µM) and dog (Ki = 2.4 ± 1.3 µM) microsomes. However, GFA has no inhibitory activity on mouse or rat CYP2Ds. GFA did not exhibit any inhibition activity on human recombinant CYP1A2, 2A6, 2C8, 2C19, 3A4, or 3A5, but showed slight inhibition of 2B6 and 2E1. Preincubation of HLMs and rCYP2D6 resulted in the inactivation of the enzyme, which was attenuated by GFA or quinidine. Beagle dogs treated intravenously with dextromethorphan (2 mg/ml) after pretreatment with GFA injection showed reduced CYP2D metabolic activity, with the Cmax of dextrorphan being one-third that of the saline-treated group and area under the plasma concentration-time curve half that of the saline-treated group. This study suggests that GFA is a specific CYP2D6 inhibitor that might play a role in CYP2D6 medicated drug-drug interaction.

[Application and development of in vitro metabolism study at early drug discovery stage].

Drug metabolism studies, including in vivo and in vitro metabolism studies, are significant in the design of candidate compounds and screening of lead compounds at drug discovery/development stages. Compared with in vivo metabolism studies, in vitro metabolism studies have the advantages of rapidity, simplicity, without consumption of large amounts of samples and animals. Moreover, it is convenient for researchers to observe the selective interaction between compound and target. Therefore, in vitro metabolism studies are appropriate for high throughput screening of compounds which are lack of metabolism information and have been widely used during drug discovery stages. This article briefly introduced the application of in vitro drug metabolism studies based on the metabolic stability, reaction phenotyping and metabolic drug-drug interactions, aiming to raise valuable evaluation strategies for innovative drug discovery in China.

Quantitative determination of diterpenoid alkaloid Fuziline by hydrophilic interaction liquid chromatography (HILIC)-electrospray ionization mass spectrometry and its application to pharmacokinetic study in rats.

A rapid, sensitive and specific hydrophilic interaction liquid chromatography coupled to electrospray ionization mass spectrometric (HILIC-MS) method for the quantification of Fuziline (15α-Hydroxyneoline) in rat plasma was developed and validated. After liquid-liquid extraction with ethyl acetate, Fuziline and Guanfu base A (internal standard) were separated with HILIC Chrom Matrix HP amide column (5µm, 10cm×3.0mm I.D.) with isocratic elution at a flow-rate of 0.2mL/min. The analytes were detected by using an electrospray positive ionization mass spectrometry in the selected ion monitoring (SIM) mode. A good linear relationship was obtained in the concentration ranging from 1 to 1000ng/mL (R(2)=0.999) with the lower limit of quantification (LLOQ) at 1ng/mL and limit of detection (LOD) at 0.5ng/mL. The average recoveries of Fuziline in plasma at the concentrations of 2, 50, 1000ng/mL ranged from 68.2 to 69.9%. Intra- and inter-batch relative standard deviations ranged from 1.5 to 3.3% and 2.6 to 8.3%, respectively. Fuziline was stable under different sample storage and processing conditions except three-cycle freeze-thaw treatment at 2ng/mL. This method was successfully applied to the pharmacokinetic studies in Sprague-Dawley rats. The absolute bioavailability of Fuziline after oral administration 4mg/kg Fuziline in rats was 21.1±7.0%, with clearance rate at 1745.6±818.1mL/kg/h, and half-life at about 6.3±2.6h.