Design, synthesis and characterization of a novel multicomponent salt of bexarotene with metformin and application in ameliorating psoriasis with T2DM.

Psoriasis is a common systemic inflammatory skin disorder affecting over 60 million people globally. Some patients with psoriasis are associated with a higher risk of type 2 diabetes mellitus (T2DM). Psoriasis and T2DM occur concurrently in some patients; however, there is no effective drug for the treatment of psoriasis with T2DM. Bexarotene (BEX) is a specific RXR agonist and an antineoplastic agent indicated by the FDA for cutaneous T-cell lymphoma (CTLA). Metformin (MET) is the first-line treatment for T2DM. To develop novel effective drugs for the treatment of psoriasis with T2DM, multicomponent salts containing MET and BEX were designed and synthesized based on the drug-drug combination strategy. MET-BEX (1:1) and MET-BEX-H2O (1:1:1) were obtained and structurally characterized. The in vitro evaluation results showed that the hygroscopicity of MET was significantly optimized by the salt formation strategy, while the solubility of BEX was improved, which laid the foundation for improving the bioavailability of BEX in vivo. In a mouse model of imiquimod-induced psoriasis with T2DM, MET-BEX ameliorated imiquimod-induced psoriasis morphological features and systematic inflammation and improved glucolipid metabolism. These results showed that the multicomponent drug combination strategy in this study optimized the physicochemical properties of MET and BEX simultaneously, providing a promising candidate therapy for psoriasis with T2DM.

Versatile Solid Modifications of Multicomponent Pharmaceutical Salts: Novel Metformin-Rhein Salts Based on Advantage Complementary Strategy Design.

This study aimed to develop an effective treatment for diabetes and diabetic complications, based on the advantage complementary strategy of drug-drug salt, by designing and synthesizing the multicomponent molecular salts containing metformin (MET) and rhein (RHE). Finally, the salts of MET-RHE (1:1), MET-RHE-H2O (1:1:1), MET-RHE-ethanol-H2O (1:1:1:1), and MET-RHE-acetonitrile (2:2:1) were obtained, indicating the polymorphism of salts formed by MET and RHE. The structures were analyzed by the combination of characterization experiments and theoretical calculation, and the formation mechanism of polymorphism was discussed. The obtained results of in vitro evaluation showed that MET-RHE had a similar hygroscopicity with metformin hydrochloride (MET·HCl), and the solubility of the component of RHE increased by approximately 93 times, which laid a foundation for improving the bioavailability of MET and RHE in vivo. The evaluation of hypoglycemic activity in mice (C57BL/6N) indicated that MET-RHE exhibited better hypoglycemic activity than the parent drugs and the physical mixtures of MET and RHE. The above findings demonstrate that this study achieved the complementary advantages of MET and RHE through the multicomponent pharmaceutical salification technique, and provides new possibilities for the treatment of diabetic complications.

The relevant research of adverse childhood experiences and "risky drinking" in children of alcoholics in China.

OBJECTIVE: To determine whether adverse childhood experiences (ACEs) of children of alcoholics (COA) in male were associated with their current "risky drinking". METHODS: This case-control study used the Alcohol Use Disorder Identification Test (AUDIT, cutoff is 7) to divide the participants into two groups, a "risky drinking" group (N = 53) and a "non-risky drinking" group (N = 97). Demographic data, Adverse Childhood Experiences-International Questionnaire (ACE-IQ), the Hamilton Anxiety Rating Scale (HAMA), the Hamilton Depression Rating Scale (HAMD) and the Mini-International Neuropsychiatric Interview (MINI) were used for assessment. The specific relationships between ACEs and "risky drinking" were explored. RESULTS: Respondents ranged in age from 29.70 ± 6.72 years; 74.5% were females; 94.7% were of Han nationality; 56.7% had a level of education above high school; 12% had no formal or stable job. There was difference in attitude to self-drinking between two groups (P < 0.001). The "risky drinking" group was more likely to have experienced a major depressive episode (P < 0.05), nonalcohol psychoactive substance use disorder (P < 0.01) and bulimia nervosa (P < 0.05), and they also experienced more physical abuse (P < 0.05), community violence (P < 0.001) and collective violence (P < 0.01). In a single factor logistic regression, physical abuse, community violence and collective violence were associated with a two to 11- fold increase in "risky drinking" in the adult COA, and in multiple factor logistic regression, community violence showed a graded relationship with "risky drinking". CONCLUSION: The childhood adverse experiences contribute to "risky drinking" in COA. This finding in the Chinese context have significant implications for prevention not only in China but in other cultures. There must be greater awareness of the role of ACEs in the perpetuation of alcoholism.

Can Fluoxetine Combined with Cognitive Behavioral Therapy Reduce the Suicide and Non-Suicidal Self-Injury Incidence and Recurrence Rate in Depressed Adolescents Compared with Fluoxetine Alone? A Meta-Analysis.

Objective: The efficacy of medication and psychotherapy for adolescent depression is controversial, so we conducted a meta-analysis to evaluate the efficacy of combination therapy. Methods: We followed the PRISMA checklist in completing the meta-analysis. Relevant literature was searched in PubMed, Web of Science and Embase, Chinese databases CNKI and WanFang Data. We included the literature on the comparison of the fluoxetine plus psychotherapy or cognitive-behavioral therapy (CBT) and each treatment alone for adolescent depression published in 1980-2021. All statistical analyses were performed using Stata software. Results: After careful review, a total of 489 relevant articles were retrieved, and 13 studies were finally included. In comparison with the control group (fluoxetine alone), fluoxetine plus CBT achieved higher response rate (RR=1.12, 95% CI: 1.04, 1.21), lower incidence of adverse Reactions (RR=0.62,95% CI:0.40,0.96), lower proportion of suicide or self-injury (RR=0.94,95% CI:0.74,1.20), and lower one-year recurrence rate (RR=0.27, 95% CI: 0.16, 0.45). Before treatment, there were no significant differences in Hamilton Depression Scale score (HAMD), Children's Depression Rating Scale Revised (CDRS-R) score, and Clinical Global Impression (CGI) Severity score. After treatment, HAMD score (SMD=-1.01, 95% CI:-1.39,-0.63), CDRS-R score (SMD= -0.10,95% CI:-0.26,-0.07), and CGI score (SMD = -0.22, 95% CI: -0.54, -0.10) were significantly lower in the combined treatment group than in the control group. Conclusion: Adolescents simultaneously treated with fluoxetine and CBT had significantly reduced incidence of depressive symptoms, suicide or NSSI, adverse reactions, and one-year recurrence of symptoms, than adolescents treated with fluoxetine alone. This indicates fluoxetine plus CBT may be superior to fluoxetine alone for the clinical treatment of adolescent depression.

Recent Advances on the Biological Study of Pharmaceutical Cocrystals.

As a low-risk, low-cost, but high-reward route, cocrystallization of drugs with appropriate coformers is applied to improve the physiochemical and biopharmaceutical properties of drugs. Currently, most researchers concentrate their efforts on the preparation, characterization, and improvement of physicochemical properties of pharmaceutical cocrystals. On the contrary, the biological study of pharmaceutical cocrystals has not attracted wide attention of researchers. In this review, we have focused on recent advances reporting the biological studies of pharmaceutical cocrystals. The covered areas consist of the solubility and permeability, the pharmacokinetics study, metabolism and distribution, pharmacodynamics research, and the toxicological evaluation of pharmaceutical cocrystals. Besides, discussions have been made on the in vivo-in vitro correlations for pharmaceutical cocrystals, the enhancement of efficiency and reduction of toxicity for pharmaceutical cocrystals, and the interaction between APIs and coformers in pharmaceutical cocrystals and marketed pharmaceutical cocrystals as well as their biological studies. At the same time, some problems such as the amount of animal samples, the number and distribution of blood sampling points, investigation on the pharmacokinetics of physical mixtures containing APIs and coformers, and the consideration of species differences should be taken into account. Although pharmaceutical cocrystals face some challenges in clarifying the characteristics of metabolism and distribution, revealing potential pharmacological mechanism, and evaluating safety, cocrystal engineering is still considered a green and promising approach to developing valuable new drugs.

A new cocrystal of isoniazid-quercetin with hepatoprotective effect: The design, structure, and in vitro/in vivo performance evaluation.

With the purpose of overcoming the serious hepatotoxicity of antituberculosis drug isoniazid (INH), a cocrystallization strategy based on complementary advantages was implemented by choosing the hepatoprotective nutraceutical quercetin (QCT) as the cocrystal former. The strategy plays the solubility advantage of INH to improve the bioavailability of the insoluble QCT, thereby significantly enhancing the QCT's hepatoprotective effects. The optimized protective effects of QCT, in turn, feed back to INH to reduce its hepatotoxicity. Along this line, a novel INH-QCT cocrystal was successfully prepared and structurally characterized. The systematic evaluation results of the in vitro/in vivo revealed that, due to the advantage of INH's solubility, the dissolution efficiency of QCT from the cocrystal was increased 51.67-fold compared with that of coarse quercetin, and the oral bioavailability of the cocrystal in rats was enhanced by 28.91 times. As a result, the INH-QCT cocrystal almost removed INH induced serious hepatotoxicity, which has been demonstrated by the hepatotoxicity studies in rats. These findings present new opportunities for the advantageous solid forms of low-toxic antituberculosis drugs, and open new avenues against toxic side effects of drugs through the cocrystallization mean.

2-(2-Eth-oxy-2-oxoacetamido)-benzoic acid.

The title compound, C11H11NO5, has a nearly planar geometry. In the crystal, the mol-ecules are assembled into chains parallel to the [11] direction by O-H⋯O and C-H⋯O hydrogen bonds.

Bacterial Community Associated with Healthy and Diseased Pacific White Shrimp (Litopenaeus vannamei) Larvae and Rearing Water across Different Growth Stages.

Bacterial communities are called another "organ" for aquatic animals and their important influence on the health of host has drawn increasing attention. Thus, it is important to study the relationships between aquatic animals and bacterial communities. Here, bacterial communities associated with Litopenaeus vannamei larvae at different healthy statuses (diseased and healthy) and growth stages (i.e., zoea, mysis, and early postlarvae periods) were examined using 454-pyrosequencing of the 16S rRNA gene. Bacterial communities with significant difference were observed between healthy and diseased rearing water, and several bacterial groups, such as genera Nautella and Kordiimonas could also distinguish healthy and diseased shrimp. Rhodobacteraceae was widely distributed in rearing water at all growth stages but there were several stage-specific groups, indicating that bacterial members in rearing water assembled into distinct communities throughout the larval development. However, Gammaproteobacteria, mainly family Enterobacteriaceae, was the most abundant group (accounting for more than 85%) in shrimp larvae at all growth stages. This study compared bacterial communities associated with healthy and diseased L. vannamei larvae and rearing water, and identified several health- and growth stage-specific bacterial groups, which might be provided as indicators for monitoring the healthy status of shrimp larvae in hatchery.

Aquimarina hainanensis sp. nov., isolated from diseased Pacific white shrimp Litopenaeus vannamei larvae.

One novel Gram-stain-negative, long rod-shaped, non-spore-forming, non-motile, non-flagellated and strictly aerobic strain, designated M124T, was isolated from diseased Pacific white shrimp Litopenaeus vannamei larvae. Growth occurred at 16-37 °C (optimum 28 °C), in the presence of 2-5 % (w/v) NaCl (optimum 3 %) and at pH 7-8 (optimum pH 7). Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain M124T belonged to the genus Aquimarina and showed highest sequence similarity to Aquimarina penaei P3-1T (96.4 %). The dominant fatty acids of the isolate were iso-C15 : 0 and iso-C17 : 0 3-OH. The major polar lipids comprised phosphatidylethanolamine, one unknown aminolipid, three unknown phospholipids, two unknown glycolipids and one unknown polar lipid. The major respiratory quinone was menaquinone 6 (MK-6). The DNA G+C content of strain M124T was 33.7 mol%. Based on the polyphasic analyses in this study, strain M124T is considered to represent a novel species of the genus Aquimarina, for which the name Aquimarina hainanensis sp. nov. is proposed. The type strain is M124T ( = KCTC 42423T = MCCC 1K00498T).