Progress of triazole antifungal agent posaconazole in individualized therapy.

WHAT IS KNOWN AND OBJECTIVE: Posaconazole is the second-generation triazole antifungal agent with widespread clinical application. Posaconazole exposure is influenced by various factors such as drug interactions, disease state and diet, resulting in a high interindividual variability in many patients and failure to ensure therapeutic efficacy. Therefore, it is necessary to conduct individualized therapy on posaconazole to ensure the efficacy and safety of treatment. METHODS: Articles were identified through PubMed using the keywords such as "posaconazole," "therapeutic drug monitoring" and "Population pharmacokinetics" from 1 January 2001 to 30 April 2022. RESULTS AND DISCUSSION: In this paper, we review the individualized treatment studies of posaconazole from the three aspects of therapeutic drug monitoring, population pharmacokinetic study and Monte Carlo simulation to provide reference for in-depth individualized posaconazole dosing studies. WHAT IS NEW AND CONCLUSION: This review suggests that therapeutic drug monitoring should be performed in patients taking posaconazole to adjust the dosage and assess the efficacy and cost-effectiveness of posaconazole under different clinical conditions and different dosing regimens through Monte Carlo simulations. In the future, a more detailed delineation and comprehensive examination of posaconazole PPK for specific populations requires further study.

Modeling and insights into the structural basis of chemical acute aquatic toxicity.

It has become a top global regulatory priority to prevent and control pollution from the release of synthetic chemicals, which continues to affect the aquatic communities. In the past decades, computational tools were largely used to significantly reduce the budget and time cost of chemical acute aquatic toxicity assessment. But the structural basis of toxic compounds was rarely analyzed. In the present study, we collected 1438, 485 and 961 chemicals with acute toxicity data records for three representative aquatic species, including Tetrahymena pyriformis, Daphnia magna, and Fathead minnow, respectively. A series of artificial intelligence models were developed using OCHEM tools. For each aquatic toxicity endpoint, a consensus model was developed based on the top performed individual models. The consensus models provided good performance on external validation sets with total accuracy values 96.88 %, 90.63 %, and 84.90 % for Tetrahymena pyriformis toxicity (TPT), Daphnia magna toxicity (DMT), and Fathead minnow toxicity (FMT), respectively. The models can be freely accessed via https://ochem.eu/article/146910. Moreover, the analysis of physical-chemical properties suggested that several key molecular properties of aquatic toxic compounds were significantly different with those of non-toxic compounds. Thus, these descriptors may be associated to chemical acute aquatic toxicity, and may be useful for the understand of chemical aquatic toxicity. Besides, in this study, the structural alerts for aquatic toxicity were detected using f-score and frequency ratio analysis of predefined substructures. A total of 112, 58 and 33 structural alerts were identified responsible for TPT, DMT, and FMT, respectively. These structural alerts could provide useful information for the mechanisms of chemical aquatic toxicity and visual alerts for environmental assessment. All the structural alerts were integrated in the web-server SApredictor (www.sapredictor.cn).

In silico prediction of chemical-induced hematotoxicity with machine learning and deep learning methods.

Chemical-induced hematotoxicity is an important concern in the drug discovery, since it can often be fatal when it happens. It is quite useful for us to give special attention to chemicals which can cause hematotoxicity. In the present study, we focused on in silico prediction of chemical-induced hematotoxicity with machine learning (ML) and deep learning (DL) methods. We collected a large data set contained 632 hematotoxic chemicals and 1525 approved drugs without hematotoxicity. Computational models were built using several different machine learning and deep learning algorithms integrated on the Online Chemical Modeling Environment (OCHEM). Based on the three best individual models, a consensus model was developed. It yielded the prediction accuracy of 0.83 and balanced accuracy of 0.77 on external validation. The consensus model and the best individual model developed with random forest regression and classification algorithm (RFR) and QNPR descriptors were made available at https://ochem.eu/article/135149 , respectively. The relevance of 8 commonly used molecular properties and chemical-induced hematotoxicity was also investigated. Several molecular properties have an obvious differentiating effect on chemical-induced hematotoxicity. Besides, 12 structural alerts responsible for chemical hematotoxicity were identified using frequency analysis of substructures from Klekota-Roth fingerprint. These results should provide meaningful knowledge and useful tools for hematotoxicity evaluation in drug discovery and environmental risk assessment.

Intranasal Delivery of Botulinum Neurotoxin A Protects against Hippocampal Neuron Death in the Lithium-Pilocarpine Rat Model.

Botulinum neurotoxins (BoNTs) block the release of a series of neurotransmitters, which are pivotal for neuron action. Intrahippocampal administration of BoNTs inhibits glutamate release, protects neurons against cell death, and attenuates epileptic seizures. Compared with intrahippocampal administration, intranasal delivery is less invasive and more practical for chronic drug administration. To assess whether intranasal administration is feasible, we examined the role of botulinum neurotoxin A (BoNT/A) in hippocampal neuronal injury after status epilepticus (SE) induced by pilocarpine. Our data showed BoNT/A could bypass the blood-brain barrier (BBB) and entered the olfactory bulb and hippocampal neurons. In addition, SE could result in up-regulation of pro-apoptotic proteins (Caspase-3, Bax), down-regulation of anti-apoptotic protein Bcl-2 and neuronal death in hippocampus. BoNT/A could suppress the expression of Caspase-3 and Bax, attenuate the decrease of Bcl-2, and inhibit hippocampal neuron death induced by SE. Meanwhile, there was no significant difference in cognitive behavior between the BoNT/A-pretreated rats and normal rats. Thus, we provided a more convenient and less invasive route for taking advantage of BoNT/A in the field of anti-epilepsy.

Rhodium-Catalyzed Synthesis of 4-Bromo-1,2-dihydroisoquinolines: Access to Bromonium Ylides by the Intramolecular Reaction of a Benzyl Bromide and an α-Imino Carbene.

Highly functionalized 4-bromo-1,2-dihydroisoquinolines were synthesized from readily available 4-(2-(bromomethyl)phenyl)-1-sulfonyl-1,2,3-triazoles. A bromonium ylide is proposed as the key intermediate, which can be formed by the intramolecular nucleophilic attack of the benzyl bromide on the α-imino rhodium carbene formed in the presence of the rhodium catalyst.

Synthesis of ß-Amino-α,ß-unsaturated Ketone Derivatives via Sequential Rhodium-Catalyzed Sulfur Ylide Formation/Rearrangement.

In the presence of a Rh(II) catalyst and ß-(methylthio)-α,ß-unsaturated ketones, 1-sulfonyl-1,2,3-triazoles can be converted into functionalized ß-amino-α,ß-unsaturated ketones via formation of α-imino rhodium carbene/sulfur ylide and subsequent rearrangement. The products decompose to useful 2-methylthiopyrrole derivatives conveniently in high yield.

Corrigendum to "Discovery and identification of quality markers of Sparganii Rhizoma based on zebrafish thrombosis model" [Chin. Herb. Med. 13 (2021) 389-395].

[This corrects the article DOI: 10.1016/j.chmed.2021.04.015.].

SApredictor: An Expert System for Screening Chemicals Against Structural Alerts.

The rapid and accurate evaluation of chemical toxicity is of great significance for estimation of chemical safety. In the past decades, a great number of excellent computational models have been developed for chemical toxicity prediction. But most machine learning models tend to be "black box", which bring about poor interpretability. In the present study, we focused on the identification and collection of structural alerts (SAs) responsible for a series of important toxicity endpoints. Then, we carried out effective storage of these structural alerts and developed a web-server named SApredictor (www.sapredictor.cn) for screening chemicals against structural alerts. People can quickly estimate the toxicity of chemicals with SApredictor, and the specific key substructures which cause the chemical toxicity will be intuitively displayed to provide valuable information for the structural optimization by medicinal chemists.

In Silico Prediction and Insights Into the Structural Basis of Drug Induced Nephrotoxicity.

Drug induced nephrotoxicity is a major clinical challenge, and it is always associated with higher costs for the pharmaceutical industry and due to detection during the late stages of drug development. It is desirable for improving the health outcomes for patients to distinguish nephrotoxic structures at an early stage of drug development. In this study, we focused on in silico prediction and insights into the structural basis of drug induced nephrotoxicity, based on reliable data on human nephrotoxicity. We collected 565 diverse chemical structures, including 287 nephrotoxic drugs on humans in the real world, and 278 non-nephrotoxic approved drugs. Several different machine learning and deep learning algorithms were employed for in silico model building. Then, a consensus model was developed based on three best individual models (RFR_QNPR, XGBOOST_QNPR, and CNF). The consensus model performed much better than individual models on internal validation and it achieved prediction accuracy of 86.24% external validation. The results of analysis of molecular properties differences between nephrotoxic and non-nephrotoxic structures indicated that several key molecular properties differ significantly, including molecular weight (MW), molecular polar surface area (MPSA), AlogP, number of hydrogen bond acceptors (nHBA), molecular solubility (LogS), the number of rotatable bonds (nRotB), and the number of aromatic rings (nAR). These molecular properties may be able to play an important part in the identification of nephrotoxic chemicals. Finally, 87 structural alerts for chemical nephrotoxicity were mined with f-score and positive rate analysis of substructures from Klekota-Roth fingerprint (KRFP). These structural alerts can well identify nephrotoxic drug structures in the data set. The in silico models and the structural alerts could be freely accessed via https://ochem.eu/article/140251 and http://www.sapredictor.cn, respectively. We hope the results should provide useful tools for early nephrotoxicity estimation in drug development.

Discovery and identification of quality markers of Sparganii Rhizoma based on zebrafish thrombosis model.

Objective: The aim of the present study was to determine the quality marker (Q-Markers) of Sparganii Rhizoma against thrombus through an integration of investigations on its antithrombotic effect, content determination and spectrum-effect correlation analysis. Methods: Based on the concept of Q-Marker, Sparganii Rhizoma was investigated for the identification of chemical component. The pharmacological effects on arachidonic acid-induced thrombosis in zebrafish were also investigated. The material basis in ethanol extract was determined by HPLC-UV. Furthermore, the potential Q-Markers were analyzed and predicted according to the effect-chemical correlation analysis. Finally, the anti-thrombotic Q-Markers were verified through the anti-thrombotic test of monomer components. Results: The model of thrombosis zebrafish was established with larvae exposed to 100 µmol/L arachidonic acid for 1 h. Nine ingredients in Sparganii Rhizoma were identified as 5-hydroxymethylfurfural, vanillic acid, ferulic acid, p-hydroxybenzaldehyde, p-hydroxybenzoic acid, vanillin, protocatechuic acid, p-coumaric acid and isoferulic acid. According to the determination effect of zebrafish thrombosis model and HPLC content analysis results, all the other contents present positive correlation except 5-hydroxymethylfurfural, and the P values of three representative potential Q-Markers (ferulic acid, protocatechuic acid and p-coumaric acid) were 0.002, 0.001 and 0.026, respectively. Conclusion: Sparganii Rhizoma showed a dose-dependent effect on the recovery of reducing cardiac red blood cell on zebrafish model. Three phenolic acids (ferulic acid, protocatechuic acid and p-coumaric acid) were proved to possess the anti-thrombotic effects which could be regarded as the potential Q-Markers for quality assessment of Sparganii Rhizoma.

Antifungal effects and potential mechanisms of lonidamine in combination with fluconazole against Candida albicans.

OBJECTIVES: The resistance of Candida albicans (C. albicans) to classical antifungals has been increasing significantly and poses great challenges to clinical treatment. The objective of this research is to evaluate whether the combination of lonidamine (LND) and fluconazole (FLC) have synergistic antifungal activity against C. albicans and to explore the underlying synergistic mechanisms against FLC-resistant C. albicans. METHODS: The antifungal effect on resistant planktonic C. albicans and preformed biofilms were performed by broth microdilution assay and XTT reduction assay. The influence on hyphal growth, cellular ROS level, metacaspase activity and drug transporters were investigated by morphogenesis observation, DCFH-DA, FITC-VAD-FMK and rhodamine6G assay, respectively. RESULTS: LND in combination with FLC exhibited synergistic antifungal effects against resistant planktonic C. albicans and preformed biofilms of C. albicans in the early stages (performed at 4 h and 8 h). The synergistic mechanisms associated with the inhibition of the hyphal growth and the activation of metacaspase, but were not related to mediate cellular ROS level or drug uptake and efflux in resistant C. albicans. CONCLUSION: LND combined with FLC exhibited synergistic antifungal activity against resistant C. albicans, and the synergistic mechanisms were related to anti-biofilms and reduce virulence factors. EXPERT OPINION: The emergence of fluconazole-resistant Candida albicans strains poses great challenges to clinical treatment. Drug combination of non-antifungals and fluconazole has attracted a lot of attention to overcome Candida albicans drug resistance.

Alterations of oral microbiota in patients with panic disorder.

The main characteristics of panic disorder (PD) include recurrent panic attacks and persistent worry, accompanied by other physical and cognitive symptoms. While recent studies have revealed that gut bacteria play an important role in anxiety and depression, little is known about the relationship between oral microbiota and PD. Therefore, the objective of this study was to explore a possible correlation between oral microbiota and PD. We conducted 16S rRNA sequencing to compare differences in the oral microbiota of patients with PD (n = 26) and healthy controls (n = 40). Patients with PD exhibited higher alpha diversity (abundance and evenness) in their oral microbiota than healthy controls, while analysis of beta diversity revealed that the two groups differed in microbial community composition. Moreover, the relative abundance of 61 genera differed between them. Overall, PD resulted in distinct oral microbial profiles that could be potential diagnostic markers and therapeutic targets.

CYP3A5 Genotype-Dependent Drug-Drug Interaction Between Tacrolimus and Nifedipine in Chinese Renal Transplant Patients.

Purpose: The drug-drug interactions (DDIs) of tacrolimus greatly contributed to pharmacokinetic variability. Nifedipine, frequently prescribed for hypertension, is a competitive CYP3A5 inhibitor which can inhibit tacrolimus metabolism. The objective of this study was to investigate whether CYP3A5 genotype could influence tacrolimus-nifedipine DDI in Chinese renal transplant patients. Method: All renal transplant patients were divided into CYP3A5*3/*3 homozygotes (group I) and CYP3A5*1 allele carriers (CYP3A5*1/*1 + CYP3A5*1/*3) (group II). Each group was subdivided into patients taking tacrolimus co-administered with nifedipine (CONF) and that administrated with tacrolimus alone (Controls). Tacrolimus trough concentrations (C0) were measured using high performance liquid chromatography. A retrospective analysis compared tacrolimus dose (D)-corrected trough concentrations (C0) (C0/D) between CONF and Controls in group I and II, respectively. At the same time, a multivariate line regression analysis was made to evaluate the effect of variates on C0/D. Results: In this study, a significant DDI between tacrolimus and nifedipine with respect to the CYP3A5*3 polymorphism was confirmed. In group I (n = 43), the C0/D of CONF was significantly higher than in Controls [225.2 ± 66.3 vs. 155.1 ± 34.6 ng/ml/(mg/kg); p = 0.002]. However, this difference was not detected in group II (n = 27) (p = 0.216). The co-administrated nifedipine and CYP3A5*3/*3 homozygotes significantly increased tacrolimus concentrations in multivariate line regression analysis. Discussion: A CYP3A5 genotype-dependent DDI was found between tacrolimus and nifedipine. Therefore, personalized therapy accounting for CYP3A5 genotype detection as well as therapeutic drug monitoring are necessary for renal transplant patients when treating with tacrolimus and nifedipine.

A case-control study of the determinants for cervicocerebral artery dissection.

BACKGROUND: Cervicocerebral artery dissection (CAD) is a major cause of ischemic stroke in young adults. There are many existing studies on determinants for CAD; however, they are still not totally defined. We conduct the study to further investigate the determinants for CAD based on ischemic stroke patients. METHODS: 81 ischemic stroke patients with CAD were enrolled in the CAD stroke group and 84 ischemic stroke patients without CAD were enrolled in the non-CAD stroke group. Their clinical data, such as age, gender, vascular risk factors, headache and neck pain and clinical laboratory data, were collected to analyze the differences between the two groups. RESULTS: A total of 165 ischemic stroke patients were included. The mean age of CAD stroke group was (51.6 ± 12.4) years, and (55.5 ± 8.1) years in non-CAD stroke group, with a statistically significant difference (P = 0.017). The average level of triglycerides in CAD stroke group was (1.3 ± 0.7) mmol/L, and (1.7 ± 1.1) mmol/L in non-CAD stroke group, with a statistically significant difference (P = 0.012). There were 42.0% (34/81) of headache and neck pain in CAD stroke group and 22.6% (19/84) in non-CAD stroke group, with a statistically significant difference (P = 0.008). The key findings with significant difference were stratified and multivariate logistic regression analysis showed that age < 50 years old (OR 2.98, 95% CI 1.43-6.21, P = 0.004), triglycerides < 1.6 mmol/L (OR 3.51, 95% CI 1.69-7.27, P = 0.001) and headache and neck pain (OR 2.94, 95% CI 1.39-6.20, P = 0.005) showed a positive correlation with CAD. CONCLUSION: In the process of diagnosis and treatment of ischemic stroke, for patients with age < 50 years old, headache and neck pain and triglycerides < 1.6 mmol/L, the cervicocerebral artery dissection should be considered, and vascular imaging examination needs to be performed in time.

Characteristics and relative factors of headache caused by cervicocerebral artery dissection.

OBJECTIVE: To analyze the characteristics and relative factors of headache and neck pain due to cervicocerebral artery dissection (CAD). METHODS: A total of 146 consecutive patients with CAD in Zhengzhou, China (2010-2017) were observed and registered prospectively. There were 60 (60/146) cases who complained of headache and neck pain, and we analyzed the characteristics of pain according to their clinical features. For the 130 (130/146) patients with complete clinical laboratory data, they were divided into two groups according to pain, and the relative factors of pain were analyzed. RESULTS: The headache and neck pain in 60 CAD patients was mostly acute onset (98.3%), 70.6% (12/17) of patients with anterior circulation dissection and 88.4% (38/43) of patients with posterior circulation dissection complained of moderate to severe pain. 41.2% (7/17) of patients with anterior circulation dissection had temporal pain, while 46.5% (20/43) of the patients with posterior circulation dissection had occipital pain. There were 23.5% (4/17) and 32.6% (14/43) of patients with anterior and posterior circulation dissection complained of throbbing pain, respectively, 23.5% (4/17) and 20.9% (9/43) of patients with anterior and posterior circulation dissection complained of pulsating pain. The pain could occur in the ipsilateral (40.0%), bilateral (52.7%), or contralateral (7.3%) sites of the dissection. In the 130 patients, there were 56 cases (43.1%) in the pain group, and 74 cases (56.9%) in the non-pain group. Multivariate logistic regression analysis showed that female gender (OR 4.01, 95% CI 1.63-9.85, P = 0.002), posterior circulation (OR 3.18, 95% CI 1.39-7.28, P = 0.006), history of headache (OR 4.72, 95% CI 1.08-20.52, P = 0.039), and low-density lipoprotein less than 1.8 mmol/L (OR 2.90, 95% CI 1.15-7.34, P = 0.025) were risk factors of the occurrence of the pain related to CAD. CONCLUSION: The headache and neck pain caused by CAD is a moderate to severe pain occurring suddenly. The pain nature may be diverse but mostly like throbbing and pulsating. When the dissected artery is located in the posterior circulation, the pain is mostly in the occipital region, and mostly in the temporal region when the dissected artery is located in the anterior circulation. The pain can occur in ipsilateral, bilateral, or contralateral of the dissection. In addition, several factors might contribute to the occurrence of headache and neck pain.

Synthesis of 5-Iodo-1,2,3,4-tetrahydropyridines by Rhodium-Catalyzed Tandem Nucleophilic Attacks Involving 1-Sulfonyl-1,2,3-triazoles and Iodides.

Sodium iodide is used for the first time as a nucleophile to trap an α-imino rhodium carbene, which triggers a tandem process involving intermolecular nucleophilic attack and intramolecular SN2 reaction. A series of 5-iodo-1,2,3,4-tetrahydropyridines are obtained in high yield, and the synthetic utility of the products is demonstrated in cross-coupling reactions and the construction of biorelated polycyclic compounds.