Journal of Pharmaceutical Analysis - 华体会 iOS下载

Challenges for cysteamine stabilization, quantification, and biological effects improvement

Carla Atallah, Catherine Charcosset, Hélène Greige-Gerges — 2022-01-24

Carla Atallah, Catherine Charcosset, Hélène Greige-Gerges The aminothiol cysteamine, derived from coenzyme A degradation in mammalian cells, presents several biological applications. However, the bitter taste and sickening odor, chemical instability, hygroscopicity, and poor pharmacokinetic profile of cysteamine limit its efficacy. The use of encapsulation systems is a good methodology to overcome these undesirable properties and improve the pharmacokinetic behavior of cysteamine. Besides, the conjugation of cysteamine to the surface of nanoparticles is generally proposed to improve the intra-oral delivery of cyclodextrin-drug inclusion complexes, as well as to enhance the colorimetric detection of compounds by a gold nanoparticle aggregation method. On the other hand, the detection and quantification of cysteamine is a challenging mission due to the lack of a chromophore in its structure and its susceptibility to oxidation before or during the analysis. Derivatization agents are therefore applied for the quantification of this molecule. To our knowledge, the derivatization techniques and the encapsulation systems used for cysteamine delivery were not reviewed previously. Thus, this review aims to compile all the data on these methods as well as to provide an overview of the various biological applications of cysteamine focusing on its skin application. Journal of Pharmaceutical Analysis. 2020 10(6): 499-516.

The current status of anti-GPCR drugs against different cancers

Sana Usman, Maria Khawer, Shazia Rafique, Zara Naz, Komal Saleem — 2022-01-24

Sana Usman, Maria Khawer, Shazia Rafique, Zara Naz, Komal Saleem G protein coupled receptors (GPCRs) have emerged as the most potential target for a number of drug discovery programs ranging from control of blood pressure, diabetes, cure for genetic diseases to treatment of cancer. A panel of different ligands including hormones, peptides, ions and small molecules is responsible for activation of these receptors. Molecular genetics has identified key GPCRs, whose mutations or altered expressions are linked with tumorgenicity. In this review, we discussed recent advances regarding the involvement of GPCRs in the development of cancers and approaches to manipulating the mechanism behind GPCRs involved tumor growth and metastasis to treat different types of human cancer. This review provides an insight into the current scenario of GPCR-targeted therapy, progress to date and the challenges in the development of anticancer drugs. Journal of Pharmaceutical Analysis. 2020 10(6): 517-521.

Three-dimensional aspects of formulation excipients in drug discovery: a critical assessment on orphan excipients, matrix effects and drug interactions

2022-01-24

Vijayabhaskar Veeravalli, Hanumanth Srikanth Cheruvu, Pratima Srivastava, Lakshmi Mohan Vamsi Madgula Formulation/pharmaceutical excipients play a major role in formulating drug candidates, with the objectives of ease of administration, targeted delivery and complete availability. Many excipients used in pharmaceutical formulations are orphanized in preclinical drug discovery. These orphan excipients could enhance formulatability of highly lipophilic compounds. Additionally, they are safe in preclinical species when used below the LD₅₀ values. However, when the excipients are used in formulating compounds with diverse physico-chemical properties, they pose challenges by modulating study results through their bioanalytical matrix effects. Excipients invariably present in study samples and not in the calibration curve standards cause over-/under- estimation of exposures. Thus, the mechanism by which excipients cause matrix effects and strategies to nullify these effects needs to be revisited. Furthermore, formulation excipients cause drug interactions by moderating the pathways of drug metabolizing enzymes and drug transport proteins. Although it is not possible to get rid of excipient driven interactions, it is always advised to be aware of these interactions and apply the knowledge to draw meaningful conclusions from study results. In this review, we will comprehensively discuss a) orphan excipients that have wider applications in preclinical formulations, b) bioanalytical matrix effects and possible approaches to mitigating these effects, and c) excipient driven drug interactions and strategies to alleviate the impacts of drug interactions. Journal of Pharmaceutical Analysis. 2020 10(6): 522-531.

Use of subcutaneous tocilizumab to prepare intravenous solutions for COVID-19 emergency shortage: Comparative analytical study of physicochemical quality attributes

2022-01-24

Natalia Navas, Jesús Hermosilla, Anabel Torrente-López, José Hernández-Jiménez, Jose Cabeza, Raquel Pérez-Robles, Antonio Salmerón-García COVID-19, a disease caused by the novel coronavirus SARS-CoV-2, has produced a serious emergency for global public health, placing enormous stress on national health systems in many countries. Several studies suggest that cytokine storms (interleukins) may play an important role in severe cases of COVID-19. Neutralizing key inflammatory factors in cytokine release syndrome (CRS) could therefore be of great value in reducing the mortality rate. Tocilizumab (TCZ) in its intravenous (IV) form of administration -RoActemra® 20 mg/mL (Roche)-is indicated for treatment of severe CRS patients. Preliminary investigations have concluded that inhibition of IL-6 with TCZ appears to be efficacious and safe, with several ongoing clinical trials. This has led to a huge increase in demand for IV TCZ for treating severe COVID-19 patients in hospitals, which has resulted in drug shortages. Here, we present a comparability study assessing the main critical physicochemical attributes of TCZ solutions used for infusion, at 6 mg/mL and 4 mg/mL, prepared from RoActemra® 20 mg/mL (IV form) and from RoActemra® 162 mg (0.9 mL solution pre-filled syringe, subcutaneous(SC) form), to evaluate the use of the latter for preparing clinical solutions required for IV administration, so that in a situation of shortage of the IV medicine, the SC form could be used to prepare the solutions for IV delivery of TCZ. It is important to remember that during the current pandemic all the medicines are used off-label, since none of them has yet been approved for the treatment of COVID-19. Journal of Pharmaceutical Analysis. 2020 10(6): 532-545.

Discovery of human coronaviruses pan-papain-like protease inhibitors using computational approaches

2022-01-24

Mubarak A. Alamri, Muhammad Tahir ul Qamar, Muhammad Usman Mirza, Safar M. Alqahtani, Matheus Froeyen, Ling-Ling Chen The papain-like protease (PL^pro) is vital for the replication of coronaviruses (CoVs), as well as for escaping innate-immune responses of the host. Hence, it has emerged as an attractive antiviral drug-target. In this study, computational approaches were employed, mainly the structure-based virtual screening coupled with all-atom molecular dynamics (MD) simulations to computationally identify specific inhibitors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PL^pro, which can be further developed as potential pan-PL^pro based broad-spectrum antiviral drugs. The sequence, structure, and functional conserveness of most deadly human CoVs PL^pro were explored, and it was revealed that functionally important catalytic triad residues are well conserved among SARS-CoV, SARS-CoV-2, and middle east respiratory syndrome coronavirus (MERS-CoV). The subsequent screening of a focused protease inhibitors database composed of ∼7,000 compounds resulted in the identification of three candidate compounds, ADM_13083841, LMG_15521745, and SYN_15517940. These three compounds established conserved interactions which were further explored through MD simulations, free energy calculations, and residual energy contribution estimated by MM-PB(GB)SA method. All these compounds showed stable conformation and interacted well with the active residues of SARS-CoV-2 PL^pro, and showed consistent interaction profile with SARS-CoV PL^pro and MERS-CoV PL^pro as well. Conclusively, the reported SARS-CoV-2 PL^pro specific compounds could serve as seeds for developing potent pan-PL^pro based broad-spectrum antiviral drugs against deadly human coronaviruses. Moreover, the presented information related to binding site residual energy contribution could lead to further optimization of these compounds. Journal of Pharmaceutical Analysis. 2020 10(6): 546-559.

Vancomycin pretreatment attenuates acetaminophen-induced liver injury through 2-hydroxybutyric acid

2022-01-24

Ningning Zheng, Yu Gu, Ying Hong, Lili Sheng, Linlin Chen, Feng Zhang, Jie Hou, Weidong Zhang, Zean Zhang, Wei Jia, Houkai Li Liver injury caused by acetaminophen (AP) overdose is a leading public health problem. Although AP-induced liver injury is well recognized as the formation of N-acetyl-p-benzoquinone (NAPQI), a toxic metabolite of AP, resulting in cell damage, emerging evidence indicates that AP-induced liver injury is also associated with gut microbiota. However, the gut microbiota-involved mechanism remains largely unknown. In our study, we found that vancomycin (Vac) pretreatment (100 mg/kg, twice a day for 4 days) attenuated AP-induced liver injury, altered the composition of gut microbiota, and changed serum metabolic profile. Moreover, we identified Vac pretreatment elevated cecum and serum 2-hydroxybutyric acid (2-HB), which ameliorated AP-induced cell damage and liver injury in mice by reducing AP bioavailability and elevating GSH levels. Our current results revealed the novel role of 2-HB in protecting AP-induced liver injury and add new evidence for gut microbiota in affecting AP toxicity. Journal of Pharmaceutical Analysis. 2020 10(6): 560-570.

Isoflavones' effects on pharmacokinetic profiles of main iridoids from Gardeniae Fructus in rats

2022-01-24

Ruirui Chang, Jialin Liu, Yusha Luo, Taohong Huang, Qiang Li, Jun Wen, Weidong Chen, Tingting Zhou Gardeniae Fructus (GF) and Semen Sojae Praeparatum (SSP) are both medicine food homologies and widely used in Chinese clinical prescriptions together. The research investigated the pharmacokinetics of four iridoids in normal rats and isolfavones-fed rats, which were administered with isolfavones from SSP for 7, 14, 21 and 28 consecutive days. A validated LC-MS/MS method was developed for determining shanzhiside, genipin-1-gentiobioside, geniposide and their metabolite genipin in rat plasma. Plasma samples were pretreated by solid-phase extraction using paeoniflorin as the internal standard. The chromatographic separation was performed on a Waters Atlantis T3 (4.6 mm × 150 mm, 3 μm) column using a gradient mobile phase consisting of acetonitril and water (containing 0.06% acetic acid). The mass detection was under the multiple reaction monitoring (MRM) mode via polarity switching between negative and positive ionization modes. The calibration curves exhibited good linearity (r > 0.997) for all components. The lower limit of quantitation was in the range of 1–10 ng/mL. The intra-day and inter-day precisions (RSD) at three different levels were both less than 12.2% and the accuracies (RE) ranged from −10.1% to 16.4%. The extraction recovery of them ranged from 53.8% to 99.7%. Pharmacokinetic results indicated the bioavailability of three iridoid glycosides and the metabolite, genipin in normal rats was higher than that in rats exposed to isoflavones. With the longer time of administration of isoflavones, plasma concentrations of iridoids decreased, while genipin sulfate, the phase Ⅱ metabolite of genposide and genipin-1-gentiobioside, appeared the rising exposure. The pharmacokinetic profiles of main iridoids from GF were altered by isoflavones. Journal of Pharmaceutical Analysis. 2020 10(6): 571-580.

Metabonomic analysis of plasma biochemical changes in pyrexia rats after treatment with Gegenqinlian decoction, aspirin and itraconazole by UHPLC-FT-ICR-MS

Ting Liu, Ruiyun Li, Yue Cui, Zhiguo Yu, Yunli Zhao — 2022-01-24

Ting Liu, Ruiyun Li, Yue Cui, Zhiguo Yu, Yunli Zhao A metabonomic approach involving an ultrahigh-performance liquid chromatography combined with Fourier transform ion cyclotron resonance mass spectrometry (UHPLC-FT-ICR-MS) was used to investigate the changes in the endogenous metabolites in the plasma of rats with yeast-induced pyrexia treated with Gegenqinlian decoction (GQLD), aspirin and itraconazole. The differences in the small molecule profiles of treatment using traditional Chinese medicine, etiological treatment and symptomatic treatment were elucidated. Thirty-six plasma metabolites were identified or putatively identified, and the effects of the three medicines on the thirty-six metabolites were studied. Their metabolic pathways indicated that GQLD, aspirin and itraconazole ameliorated the rats with yeast-induced pyrexia predominantly by regulating the metabolisms of phospholipid, sphingolipid, fatty acid oxidation, fatty acid amides, amino acid and glycerolipid in vivo. The pharmacodynamics and metabonomic results showed that the three medicines exhibited the therapeutic effects on pyrexia by regulating the perturbations of multiple metabolisms. The study provided a scientific basis for an in-depth understanding of the therapeutic effects of GQLD, aspirin and itraconazole on rats with yeast-induced pyrexia. Journal of Pharmaceutical Analysis. 2020 10(6): 581-587.

Comparative analysis of constitutes and metabolites for traditional Chinese medicine using IDA and SWATH data acquisition modes on LC-Q-TOF MS

2022-01-24

Dian Kang, Qingqing Ding, Yangfan Xu, Xiaoxi Yin, Huimin Guo, Tengjie Yu, He Wang, Wenshuo Xu, Guangji Wang, Yan Liang Identification of components and metabolites of traditional Chinese medicines (TCMs) employing liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-Q-TOF MS) techniques with information-dependent acquisition (IDA) approaches is increasingly frequent. A current drawback of IDA-MS is that the complexity of a sample might prevent important compounds from being triggered in IDA settings. Sequential window acquisition of all theoretical fragment-ion spectra (SWATH) is a data-independent acquisition (DIA) method where the instrument deterministically fragments all precursor ions within the predefined m/z range in a systematic and unbiased fashion. Herein, the superiority of SWATH on the detection of TCMs’ components was firstly investigated by comparing the detection efficiency of SWATH-MS and IDA-MS data acquisition modes, and sanguisorbin extract was used as a mode TCM. After optimizing the setting parameters of SWATH, rolling collision energy (CE) and variable Q1 isolation windows were found to be more efficient for sanguisorbin identification than the fixed CE and fixed Q1 isolation window. More importantly, the qualitative efficiency of SWATH-MS on sanguisorbins was found significantly higher than that of IDA-MS data acquisition. In IDA mode, 18 kinds of sanguisorbins were detected in sanguisorbin extract. A total of 47 sanguisorbins were detected when SWATH-MS was used under rolling CE and flexible Q1 isolation window modes. Besides, 26 metabolites of sanguisorbins were identified in rat plasma, and their metabolic pathways could be deduced as decarbonylation, oxidization, reduction, methylation, and glucuronidation according to their fragmental ions acquired in SWATH-MS mode. Thus, SWATH-MS data acquisition could provide more comprehensive information for the component and metabolite identification for TCMs than IDA-MS. Journal of Pharmaceutical Analysis. 2020 10(6): 588-596.

Offline two-dimensional liquid chromatography coupled with ion mobility-quadrupole time-of-flight mass spectrometry enabling four-dimensional separation and characterization of the multicomponents from white ginseng and red ginseng

2022-01-24

Tiantian Zuo, Chunxia Zhang, Weiwei Li, Hongda Wang, Ying Hu, Wenzhi Yang, Li Jia, Xiaoyan Wang, Xiumei Gao, Dean Guo Inherent complexity of plant metabolites necessitates the use of multi-dimensional information to accomplish comprehensive profiling and confirmative identification. A dimension-enhanced strategy, by offline two-dimensional liquid chromatography/ion mobility-quadrupole time-of-flight mass spectrometry (2D-LC/IM-QTOF-MS) enabling four-dimensional separations (2D-LC, IM, and MS), is proposed. In combination with in-house database-driven automated peak annotation, this strategy was utilized to characterize ginsenosides simultaneously from white ginseng (WG) and red ginseng (RG). An offline 2D-LC system configuring an Xbridge Amide column and an HSS T3 column showed orthogonality 0.76 in the resolution of ginsenosides. Ginsenoside analysis was performed by data-independent high-definition MS^E (HDMS^E) in the negative ESI mode on a Vion™ IMS-QTOF hybrid high-resolution mass spectrometer, which could better resolve ginsenosides than MS^E and directly give the CCS information. An in-house ginsenoside database recording 504 known ginsenosides and 58 reference compounds, was established to assist the identification of ginsenosides. Streamlined workflows, by applying UNIFI™ to automatedly annotate the HDMS^E data, were proposed. We could separate and characterize 323 ginsenosides (including 286 from WG and 306 from RG), and 125 thereof may have not been isolated from the Panax genus. The established 2D-LC/IM-QTOF-HDMS^E approach could also act as a magnifier to probe differentiated components between WG and RG. Compared with conventional approaches, this dimension-enhanced strategy could better resolve coeluting herbal components and more efficiently, more reliably identify the multicomponents, which, we believe, offers more possibilities for the systematic exposure and confirmative identification of plant metabolites. Journal of Pharmaceutical Analysis. 2020 10(6): 597-609.

Single-run reversed-phase HPLC method for determining sertraline content, enantiomeric purity, and related substances in drug substance and finished product

2022-01-24

Alessia Rosetti, Rosella Ferretti, Leo Zanitti, Adriano Casulli, Claudio Villani, Roberto Cirilli A direct enantio-, diastereo-, and chemo-selective high-performance liquid chromatographic method was developed for determining the content, enantiomeric purity, and related substances of the chiral antidepressant drug sertraline HCl in a single chromatographic run. The separation was achieved on a chiral stationary phase based on amylose tris(3-chloro-5-methylphenylcarbamate) under reversed-phase conditions. The method was optimized by evaluating the influence of the temperature and mobile phase composition on the retention and selectivity. The application of the single-run approach allowed to baseline resolve all investigated species in less than 15 min, without using buffers or tandem-coupled columns. The chromatographic method was validated according to the guidelines of the Official Medicines Control Laboratory and applied to control the content of sertraline HCl and related chiral substances in a generic antidepressant formulation. Journal of Pharmaceutical Analysis. 2020 10(6): 610-616.

Development of a UHPLC-MS/MS method for the quantification of ilaprazole enantiomers in rat plasma and its pharmacokinetic application

Fengting Ou, Ying Zhou, Jinxiu Lei, Su Zeng, Fuhai Wu, Ning Zhang, Lushan Yu — 2022-01-24

Fengting Ou, Ying Zhou, Jinxiu Lei, Su Zeng, Fuhai Wu, Ning Zhang, Lushan Yu In Korea and China, ilaprazole is a widely used proton pump inhibitor in the treatment of gastric ulcers. In this study, a specific and sensitive LC-MS/MS method has been developed and validated for the quantification of ilaprazole enantiomers in the rat plasma, using R-lansoprazole as the internal standard. The enantioseparation was achieved on a CHIRALPAK AS-RH column (4.6 mm × 150 mm, i.d. 5 μm), with a mobile phase composed of 10 mM ammonium acetate aqueous solution and acetonitrile (60:40, V/V), at a flow-rate of 0.5 mL/min. The method was validated over the concentration range of 0.5–300 ng/mL for both, R- and S -ilaprazole. The lower limit of quantification was 0.5 ng/mL for both enantiomers. The relative standard deviation (RSD) of intra- and inter-day precision of R-ilaprazole and S-ilaprazole was less than 10.9%, and the relative error accuracy (RE) ranged from −0.5%–2.0%. Finally, the method was successfully evaluated in rats in a stereoselective pharmacokinetic study of the ilaprazole racemate. Journal of Pharmaceutical Analysis. 2020 10(6): 617-623.