ResearchPad - Pharmaceutical Science https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Avidin-biotin technology to synthesize multi-arm nano-construct for drug delivery]]> https://www.researchpad.co/article/elastic_article_5891 Image, graphical abstract

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<![CDATA[Pipeline for the removal of hardware related artifacts and background noise for Raman spectroscopy]]> https://www.researchpad.co/article/N62784fe2-635a-4b82-912b-cad3436d7cd3 Image, graphical abstract

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<![CDATA[A novel method for the collection of highly developmental murine immature oocytes]]> https://www.researchpad.co/article/N2cfb2892-63b5-43ce-982e-b341a580758c Image, graphical abstract

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<![CDATA[Data on metabolic stability, aqueous solubility and CYP inhibition of novel triazole-based nicotinamide phosphoribosyltransferase (NAMPT) inhibitors]]> https://www.researchpad.co/article/N60ba1e8b-af71-45b3-ab92-d5cb2dc5e5e0

In the related research article, entitled “Identification of novel triazole-based nicotinamide phosphoribosyltransferase (NAMPT) inhibitors endowed with antiproliferative and antiinflammatory activity” [1], we reported the in vitro hepatic metabolism data for compounds 30c, 48b, and 31b (here named as E5, A6, and T1), in comparison with the reference compounds GPP78 and FK866 [1–3]. In this article, we retrieved the available data about the hepatic microsomal stability and metabolites structural characterization of the entire library of triazole-based NAMPT inhibitors, also implementing the given information with data regarding aqueous solubility and CYP inhibition. Compounds are divided in subclasses based on the hydrolytic resistant groups replacing the amide function of GPP78 [1, 2].

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<![CDATA[Data of ureagenesis from ammonia, glutamine and alanine, and mitochondrial aquaporin-8 expression in thioacetamide-treated hepatocytes]]> https://www.researchpad.co/article/N31bbd1ba-207b-4380-9fa0-013b26ff2dd3

We present data about the synthesis of urea from different substrates, i.e., free ammonia, glutamine and alanine in primary cultured rat hepatocytes treated or untreated with the model hepatotoxic agent thioacetamide (TAA). We also provide data about the expression of mitochondrial aquaporin-8 (mtAQP8), a hepatocyte channel protein which facilitates ammonia diffusion into mitochondria to supply the urea cycle. Ammonia-derived ureagenesis was significantly inhibited by about 30% while that from the both amino acids resulted unaffected in TAA-treated hepatocytes. Protein expression of mtAQP8 was decreased by about 80% after TAA treatment. These data can be useful for the understanding of the mechanisms of drug-induced hepatic dysfunction.

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<![CDATA[Data on the stability of darunavir/cobicistat suspension after tablet manipulation]]> https://www.researchpad.co/article/Nb07c557b-e791-4fd2-8ef9-697b722fc19b

The COVID-19 outbreak is now one of the most critical crises to manage for most of the national healthcare systems in the world. In the absence of authorised pharmacological treatments, many antiretrovirals, including darunavir/cobicistat fixed combination, are used off-label in the hospital wards as life-treating medicines for COVID-19 patients. Unfortunately, for most of them, the drug products available on the market are not designed to be administered by a nasogastric tube to inpatients of intensive care units. Therefore, their manipulation, even if it can strongly affect the product quality, is necessary for the preparation of suspension to meet patients’ need. In this situation, it is urgent to provide data and guidance to support hospital pharmacists and clinicians in their activity. The data in this article indicate that darunavir/cobicistat suspensions compounded by pharmacists using as active ingredient a commercially available tablet can be stable at least for one week.

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<![CDATA[Secondary prevention of acute coronary syndrome with antiplatelet agents in real life: A high-dimensional propensity score matched cohort study in the French National claims database]]> https://www.researchpad.co/article/N40eff8b8-f258-43ec-82a3-f4c81c576861

Graphical abstract

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<![CDATA[The method simulating spontaneous pain in patients with nociplastic pain using rats with fibromyalgia-like condition]]> https://www.researchpad.co/article/N7b23d9d7-4da4-4ec5-a86b-1cd7d92bc21e

The method shown in this article simulates spontaneous pain in patients with nociplastic pain using rats; the measurement with this method could be related to better translation of analgesic efficacies of therapeutic compounds between rats and humans. Nociplastic pain occurs in various disorders including fibromyalgia. Because the pain in patients occurs without an external stimulus, we assessed spontaneous pain in rats. The grimace scale, a methodology for rating facial expression, has been used for measuring spontaneous pain in animals. However, the responses in animals have been rather short-lived, and the scale has never been applied to animals exhibiting nociplastic pain. Here, we apply the rat grimace scale (RGS) to the reserpine-induced fibromyalgia-like rat, which induces nociplastic pain. The ratings of the orbital tightening, nose/cheek flattening, and changes in characteristics of ears and whiskers by three raters, who were blinded to the treatment allocated to rats, demonstrated substantial, long-lasting change in facial expression of rats. In this article, reference images for raters, and sample images used for rater training are provided. All raters independently indicated that the RGS score is significantly elevated with this methodology in reserpine-induced fibromyalgia-like rats.

  • The grimace scale, a method for rating facial expression, is applied to the reserpine-induced fibromyalgia-like rat, which manifests nociplastic pain.

  • Facial expression change in the reserpine-induced fibromyalgia-like rat is substantial and long-lasting.

  • Elevation of the RGS score in the reserpine-induced fibromyalgia-like rat may simulate spontaneous pain in patients with nociplastic pain.

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<![CDATA[Data on GC-MS analysis, in vitro anti-oxidant and anti-microbial activity of the Catharanthus roseus and Moringa oleifera leaf extracts]]> https://www.researchpad.co/article/N6a38c90d-0037-4102-b25f-966a2cdd83eb

The article reports data on chemical profiling by gas chromatography-mass spectrometry (GC-MS) of aqueous and methanolic leaf extracts of Madagascar periwinkle (Catharanthus roseus) and drumstick tree (Moringa oleifera) and on their antioxidant and antibacterial effects against three clinical human pathogens. In total 105 compounds were tentatively identified; in which 65 in Catharanthus roseus and 40 in Moringa oleifera compounds. A large number of peaks with good area percentage was found in methanolic extract of Catharanthus roseus with core chemical constituents such as trans-squalene, n-hexadecanoic acid, Eicosyl acetate, stearin, 1H-Benz(G)indole-3-carboxylic acid. The corresponding constituents from Moringa oleifera include 9-Octadecenoic acid (z)-, Heptadecanoic acid and phytol acetate. The highest scavenging activity (87.7% at 200 μg/mL) was shown by DPPH aqueous leaf extract of C. roseus. Moreover, the methanolic scavenging of both plant extracts was in the order of FRAP>DPPH>NO> H2O2 with lowest antioxidant activity (51.4% at 200 μg/mL) exposed by Catharanthus roseus in comparison of all cases. Good antibacterial action was examined against three different organisms (E.coli, B. subtilis and S. aureus) of aqueous infusion of Catharanthus roseus.

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<![CDATA[A method to dissolve 3-MCPD mono- and di-esters in aqueous cell culture media]]> https://www.researchpad.co/article/N845aa6e8-ad45-4619-a30e-ca25563e4888

Graphical abstract

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<![CDATA[Protocol for evaluating the abilities of diverse nitroaromatic prodrug metabolites to exit a model Gram negative bacterial vector]]> https://www.researchpad.co/article/N3dad3f2d-00d1-4f45-af16-275f5285761b

Graphical abstract

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<![CDATA[The cytochrome P450 isoenzyme and some new opportunities for the prediction of negative drug interaction in vivo]]> https://www.researchpad.co/article/5b59b9f1463d7e79e6a1004f

Cytochrome (CYP) 450 isoenzymes are the basic enzymes involved in Phase I biotransformation. The most important role in biotransformation belongs to CYP3A4, CYP2D6, CYP2C9, CYP2C19 and CYP1A2. Inhibition and induction of CYP isoenzymes caused by drugs are important and clinically relevant pharmacokinetic mechanisms of drug interaction. Investigation of the activity of CYP isoenzymes by using phenotyping methods (such as the determination of the concentration of specific substrates and metabolites in biological fluids) during drug administration provides the prediction of negative side effects caused by drug interaction. In clinical practice, the process of phenotyping of CYP isoenzymes and some endogenous substrates in the ratio of cortisol to 6β-hydroxycortisol in urine for the evaluation of CYP3A4 activity has been deemed to be a quite promising, safe and minimally invasive method for patients nowadays.

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<![CDATA[A Decision Support Tool Facilitating Medicine Design for Optimal Acceptability in The Older Population]]> https://www.researchpad.co/article/5b59793f463d7e5ce270da2e

Purpose

Medicine acceptability, which is of the utmost importance for vulnerable patients’ adherence, is driven by both user and product characteristics. Herein, a novel multivariate approach integrating the many aspects of acceptability is used to discriminate positively and negatively accepted medicines in the older population.

Methods

An observational study was carried out in eight hospitals and eight nursing homes to collect a large set of real-life data on medicines uses in older patients (≥65 years). Mapping and clustering explored these multiple observational measures and summarised the main information into an intelligible reference framework. Resampling statistics were used to validate the model’s reliability.

Results

A three-dimensional map and two clusters defining acceptability profiles, as positive or negative, emerged from the 1079 evaluations. Factors of interest (medicines, user features…) were positioned on the map at the barycentre of their evaluations and assigned to an acceptability profile. Focusing on patients’ ability to swallow, we have highlighted the tool’s efficacy in demonstrating the impact of user features on medicine acceptability.

Conclusions

This multivariate approach provides a relevant judgement criterion for this multi-dimensional concept. Facilitating the choice of the most appropriate dosage form to achieve optimal acceptability in a targeted population, this tool is of real potential to improve clinical decisions.

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<![CDATA[Combination of Garcinia cambogia Extract and Pear Pomace Extract Additively Suppresses Adipogenesis and Enhances Lipolysis in 3T3-L1 Cells]]> https://www.researchpad.co/article/5b591ff2463d7e56f0caf901

Background:

Inhibition of adipogenesis has been a therapeutic target for reducing obesity and obesity-related disorders such as diabetes, hypertension, atherosclerosis, and cancer. For decades, anti-adipogenic potential of many herbal extracts has been investigated. One example is Garcinia cambogia extract (GE) containing (-)-hydroxycitric acid as an active ingredient. GE is currently marketed as a weight loss supplement, used alone or with other ingredients. Pear pomace extract (PE), another natural product, has been also shown to have anti-adipogenic activity in a recent report.

Objective:

It was tested if the mixture of PE and GE (MIX) would produce more effective anti-adipogenic activity than PE or GE alone.

Materials and Methods:

Differentiation of 3T3-L1 preadipocyte was induced by adding insulin, dexamethasone, and isobutylmethylxanthine and lipid accumulation was measured by Oil Red O staining. Cellular markers for adipogenesis and lipolysis such as CCAAT/enhancer binding protein (C/EBP-α), peroxisome proliferator-activated receptor gamma (PPAR-γ), fatty acid synthase (FAS), and hormone-sensitive lipase (HSL) was measured using immunocytochemistry.

Results:

MIX, compared to PE or GE alone, showed greater inhibition of lipid accumulation. Furthermore, MIX reduced the expression of adipogenesis-related factors C/EBP-α, PPAR-γ, and FAS more than PE or GE alone did. In contrast, the expression of HSL the enzyme required for lipolysis was further enhanced in MIX-treated adipocytes compared to the PE or GE alone treated groups.

Conclusions:

Anti-adipogenic effect of PE and GE appears synergistic, and the MIX may be a useful therapeutic combination for the treatment of obesity and obesity-related diseases.

SUMMARY

  • PE and GE efficiently inhibited adipocyte differentiation by suppressing the expression of adipogenic transcription factor CEBP-α and PPAR-γ.

  • PE and GE significantly decreased the expression of adipogenic enzyme FAS.

  • PE and GE increased the expression of lipid degrading enzyme HSL.

  • Mixture of PE and GE exhibited additive or moderately synergistic effect on adipocyte differentiation and lipid accumulation.

Abbreviations used: CEBP-a: CCAT/enhancer binding protein alpha, CI: Combination Index, FAS: Fatty acid synthase, GE: Garcinia cambogia extract, HSL: Hormone sensitive lipase, PE: Pear pomace extract, PPAR-γ: Peroxisome proliferator-activated receptor gamma.

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<![CDATA[PEGylated crushed gold shell-radiolabeled core nanoballs for in vivo tumor imaging with dual positron emission tomography and Cerenkov luminescent imaging]]> https://www.researchpad.co/article/5b58ec17463d7e5414116038

Background

Radioactive isotope-labeled gold nanomaterials have potential biomedical applications. Here, we report the synthesis and characterization of PEGylated crushed gold shell-radioactive iodide-124-labeled gold core nanoballs (PEG-124I-Au@AuCBs) for in vivo tumor imaging applications through combined positron emission tomography and Cerenkov luminescent imaging (PET/CLI).

Results

PEG-124I-Au@AuCBs showed high stability and sensitivity in various pH solutions, serum, and in vivo conditions and were not toxic to tested cells. Combined PET/CLI clearly revealed tumor lesions at 1 h after injection of particles, and both signals remained visible in tumor lesions at 24 h, consistent with the biodistribution results.

Conclusion

Taken together, the data provided strong evidence for the application of PEG-124I-Au@AuCBs as promising imaging agents in nuclear medicine imaging of various biological systems, particularly in cancer diagnosis.

Electronic supplementary material

The online version of this article (10.1186/s12951-018-0366-x) contains supplementary material, which is available to authorized users.

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<![CDATA[Development and Validation of an UPLC-MS/MS Method for Pharmacokinetic Comparison of Five Alkaloids from JinQi Jiangtang Tablets and Its Monarch Drug Coptidis Rhizoma]]> https://www.researchpad.co/article/5b4cd630463d7e0fba429dfa

JinQi Jiangtang (JQJT) tablets, a Chinese patent medicine approved by the State Food and Drug Administration, are composed of Coptidis Rhizoma, Astragali Radix, and Lonicerae Japonicae Flos, and have a significant effect on diabetes. Coptidis Rhizoma is monarch drug in the prescription. The aim of the present study was to investigate and compare the pharmacokinetics of multiple ingredients from JQJT tablets and Coptidis Rhizoma extract (CRE) following oral administration in rats. Five alkaloids: coptisine chloride, epiberberine chloride, berberine chloride, jatrorrhizine chloride, and palmatine chloride, were simultaneously determined in rat plasma using established and validated ultra-high performance liquid chromatography mass spectrometry (UPLC-MS/MS). Significant pharmacokinetic differences were observed for the five alkaloids after a single administration of CRE and JQJT tablets. Compared with CRE, the Cmax values of palmatine chloride and jatrorrhizine chloride were decreased significantly, the AUC0–t values of four alkaloids (all except jatrorrhizine chloride) were notably decreased, and the mean residence times of all five alkaloids were significantly decreased after administration of JQJT tablets. The results indicated that the absorption characteristics of the five alkaloids from Coptidis Rhizoma would be influenced by the compatibility of Astragali Radix or Lonicerae Japonicae Flos from JQJT tablets, such that absorption was inhibited and elimination was accelerated. In conclusion, the developed strategy was suitable for the comparison of five alkaloids from JinQi Jiangtang tablets and its monarch drug, which could be valuable for compatibility studies of traditional Chinese medicines.

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<![CDATA[Endolysosomal Cation Channels and Cancer—A Link with Great Potential]]> https://www.researchpad.co/article/5b4cd5af463d7e0fba429df8

The endolysosomal system (ES) consists of lysosomes; early, late, and recycling endosomes; and autophagosomes. It is a key regulator not only of macromolecule degradation and recycling, plasma membrane repair, homeostasis, and lipid storage, but also of antigen presentation, immune defense, cell motility, cell death signaling, tumor growth, and cancer progression. In addition, it plays a critical role in autophagy, and the autophagy-lysosome pathway is intimately associated with the hallmarks of cancer, such as escaping cell death pathways, evading immune surveillance, and deregulating metabolism. The function of endolysosomes is critically dependent on both soluble and endolysosomal membrane proteins such as ion channels and transporters. Cation channels found in the ES include members of the TRP (transient receptor potential) channel superfamily, namely TRPML channels (mucolipins) as well as two-pore channels (TPCs). In recent studies, these channels have been found to play crucial roles in endolysosomal trafficking, lysosomal exocytosis, and autophagy. Mutation or loss of these channel proteins can impact multiple endolysosomal trafficking pathways. A role for TPCs in cancer cell migration and metastasis, linked to distinct defects in endolysosomal trafficking such as integrin trafficking, has been recently established. In this review, we give an overview on the function of lysosomes in cancer with a particular focus on the roles which TPCs and TRPML channels play in the ES and how this can affect cancer cells.

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<![CDATA[Sevoflurane post-conditioning attenuates traumatic brain injury-induced neuronal apoptosis by promoting autophagy via the PI3K/AKT signaling pathway]]> https://www.researchpad.co/article/5b4c85ae463d7e0cf681797c

Background

Sevoflurane post-conditioning exerts nerve-protective effects through inhibiting caspase-dependent neuronal apoptosis after a traumatic brain injury (TBI). Autophagy that is induced by the endoplasmic reticulum stress plays an important role in the secondary neurological dysfunction after a TBI. However, the relationship between autophagy and caspase-dependent apoptosis as well as the underlying nerve protection mechanism that occurs with sevoflurane post-conditioning following a TBI remains unclear.

Methods

The Feeney TBI model was used to induce brain injury in rats. Evaluation of the modified neurological severity scores, measurement of brain water content, Nissl staining, and terminal deoxynucleotidyl transferase dUTP nick end labeling assay were used to determine the neuroprotective effects of the sevoflurane post-conditioning. Both immunofluorescence and Western blot analyses were used to detect the expression of autophagy-related proteins microtubule-associated protein 1 light chain 3-II and Beclin-1, pro-apoptotic factors, as well as the activation of the phosphatidylinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway within the lesioned cortex.

Results

Autophagy and neuronal apoptosis were activated in the lesioned cortex following the TBI. Sevoflurane post-conditioning enhanced early autophagy, suppressed neuronal apoptosis, and alleviated brain edema, which improved nerve function after a TBI (all P < 0.05). Sevoflurane post-conditioning induced the activation of PI3K/AKT signaling after the TBI (P < 0.05). The neuroprotective effects of sevoflurane post-conditioning were reversed through the autophagy inhibitor 3-methyladenine treatment.

Conclusion

Neuronal apoptosis and the activation of autophagy were involved in the secondary neurological injury following a TBI. Sevoflurane post-conditioning weakened the TBI-induced neuronal apoptosis by regulating autophagy via PI3K/AKT signaling.

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<![CDATA[Benralizumab in the treatment of severe asthma: design, development and potential place in therapy]]> https://www.researchpad.co/article/5bfb917fd5eed0c484af96f5

Asthma is a widespread and heterogeneous inflammatory disease of the airways, which is characterized by several different phenotypes and endotypes. In particular, eosinophilic airway inflammation is a common pathologic trait of both allergic and nonallergic asthma. The key cytokine responsible for maturation, activation, recruitment, and survival of eosinophils is interleukin (IL)-5, which is mainly produced by T helper 2 (Th2) lymphocytes and group 2 innate lymphoid cells. Therefore, for uncontrolled patients with severe eosinophilic asthma, who are not fully responsive to corticosteroids, IL-5 represents a very important molecular target for add-on biological therapies. Among these new treatments, anti-IL-5 monoclonal antibodies such as mepolizumab and reslizumab have been developed and clinically evaluated. Furthermore, benralizumab is currently the only available biologic drug that specifically binds to the IL-5 receptor, thus preventing the interaction with its ligand and the consequent pro-inflammatory effects. The effectiveness of benralizumab in improving severe eosinophilic asthma has been well-documented by many randomized controlled trials.

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<![CDATA[Vitexin protects dopaminergic neurons in MPTP-induced Parkinson&rsquo;s disease through PI3K/Akt signaling pathway]]> https://www.researchpad.co/article/5bfb30d1d5eed0c48496364e

Parkinson’s disease (PD) is a progressive neurodegenerative disease which is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc).

Methods

In this study, the neuroprotective effect of vitexin (Vit), a flavonoid compound isolated from Crataegus pinnatifida Bunge was examined in PD models both in vitro and in vivo.

Results

On SH-SY5Y cells, methyl-4-phenylpyridine (MPP+) treatment suppressed cell viability, induced apoptosis, and increased Bax/Bcl-2 ratio and caspase-3 activity. However, Vit improved these parameters induced by MPP+ treatment significantly. Further study disclosed that Vit enhanced the phosphorylation of PI3K and Akt which was downregulated by MPP+ in SH-SY5Y cells, the effect of which could be blocked by PI3K inhibitor LY294002 and activated by PI3K activator IGF-1. Moreover, results from the pole test and traction test suggested that Vit pretreatment prevented bradykinesia and alleviated the initial lesions caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in MPTP-treated mouse PD model. Vit also enhanced the activation of PI3K and Akt and suppressed the ratio of Bax/Bcl-2 and caspase-3 activity in MPTP-treated mice.

Conclusion

Taken together, this study demonstrated that Vit protected dopaminergic neurons against MPP+/MPTP-induced neurotoxicity through the activation of PI3K/Akt signaling pathway. Our findings may facilitate the clinical application of Vit in the therapy of PD.

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