scholarly journals Interaction of Rifampin and Darunavir-Ritonavir or Darunavir-Cobicistat In Vitro

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Owain Roberts ◽  
Saye Khoo ◽  
Andrew Owen ◽  
Marco Siccardi
Keyword(s):  
High Performance ◽  
Linear Regression Analysis ◽  
Intrinsic Clearance ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Content Type ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Dosing Regimens

ABSTRACT Treatment of HIV-infected patients coinfected with Mycobacterium tuberculosis is challenging due to drug-drug interactions (DDIs) between antiretrovirals (ARVs) and antituberculosis (anti-TB) drugs. The aim of this study was to quantify the effect of cobicistat (COBI) or ritonavir (RTV) in modulating DDIs between darunavir (DRV) and rifampin (RIF) in a human hepatocyte-based in vitro model. Human primary hepatocyte cultures were incubated with RIF alone or in combination with either COBI or RTV for 3 days, followed by coincubation with DRV for 1 h. The resultant DRV concentrations were quantified by high-performance liquid chromatography with UV detection, and the apparent intrinsic clearance (CLint.app.) of DRV was calculated. Both RTV and COBI lowered the RIF-induced increases in CLint.app. in a concentration-dependent manner. Linear regression analysis showed that log10 RTV and log10 COBI concentrations were associated with the percent inhibition of RIF-induced elevations in DRV CLint.app., where β was equal to −234 (95% confidence interval [CI] = −275 to −193; P < 0.0001) and −73 (95% CI = −89 to −57; P < 0.0001), respectively. RTV was more effective in lowering 10 μM RIF-induced elevations in DRV CLint.app. (half-maximal [50%] inhibitory concentration [IC50] = 0.025 μM) than COBI (IC50 = 0.223 μM). Incubation of either RTV or COBI in combination with RIF was sufficient to overcome RIF-induced elevations in DRV CLint.app., with RTV being more potent than COBI. These data provide the first in vitro experimental insight into DDIs between RIF and COBI-boosted or RTV-boosted DRV and will be useful to inform physiologically based pharmacokinetic (PBPK) models to aid in optimizing dosing regimens for the treatment of patients coinfected with HIV and M. tuberculosis.

scholarly journals In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

2020 ◽  
Vol 71 (15) ◽  
pp. 732-739 ◽  
Author(s):  
Xueting Yao ◽  
Fei Ye ◽  
Miao Zhang ◽  
Cheng Cui ◽  
Baoying Huang ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Safety Profile ◽  
Late Phase ◽  
Vero Cells ◽  
Lung Fluid ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Autoimmune Conditions ◽  
Dosing Regimens

Abstract Background The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first broke out in 2019 and subsequently spread worldwide. Chloroquine has been sporadically used in treating SARS-CoV-2 infection. Hydroxychloroquine shares the same mechanism of action as chloroquine, but its more tolerable safety profile makes it the preferred drug to treat malaria and autoimmune conditions. We propose that the immunomodulatory effect of hydroxychloroquine also may be useful in controlling the cytokine storm that occurs late phase in critically ill patients with SARS-CoV-2. Currently, there is no evidence to support the use of hydroxychloroquine in SARS-CoV-2 infection. Methods The pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2–infected Vero cells. Physiologically based pharmacokinetic (PBPK) models were implemented for both drugs separately by integrating their in vitro data. Using the PBPK models, hydroxychloroquine concentrations in lung fluid were simulated under 5 different dosing regimens to explore the most effective regimen while considering the drug’s safety profile. Results Hydroxychloroquine (EC50 = 0.72 μM) was found to be more potent than chloroquine (EC50 = 5.47 μM) in vitro. Based on PBPK models results, a loading dose of 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days is recommended for SARS-CoV-2 infection, as it reached 3 times the potency of chloroquine phosphate when given 500 mg twice daily 5 days in advance. Conclusions Hydroxychloroquine was found to be more potent than chloroquine to inhibit SARS-CoV-2 in vitro.

scholarly journals Structural Characterization and Antioxidative Activity of Low-Molecular-Weights Beta-1,3-Glucan from the Residue of ExtractedGanoderma lucidumFruiting Bodies

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Pai-Feng Kao ◽  
Shwu-Huey Wang ◽  
Wei-Ting Hung ◽  
Yu-Han Liao ◽  
Chun-Mao Lin ◽  
...  
Keyword(s):  
Cell Death ◽  
High Performance ◽  
Anion Exchange Chromatography ◽  
Exchange Chromatography ◽  
Water Soluble ◽  
Dependent Manner ◽  
Ros Production ◽  
Fruiting Bodies ◽  
Concentration Dependent Manner

The major cell wall constituent ofGanoderma lucidum(G. lucidum) isβ-1,3-glucan. This study examined the polysaccharide from the residues of alkaline-extracted fruiting bodies using high-performance anion-exchange chromatography (HPAEC), and it employed nuclear magnetic resonance (NMR) and mass spectrometry (MS) to confirm the structures. We have successfully isolated low-molecular-weightβ-1,3-glucan (LMG), in high yields, from the waste residue of extracted fruiting bodies ofG. lucidum. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay evaluated the capability of LMG to suppress H2O2-induced cell death in RAW264.7 cells, identifying that LMG protected cells from H2O2-induced damage. LMG treatment decreased H2O2-induced intracellular reactive oxygen species (ROS) production. LMG also influenced sphingomyelinase (SMase) activity, stimulated by cell death to induce ceramide formation, and then increase cell ROS production. Estimation of the activities of neutral and acid SMasesin vitroshowed that LMG suppressed the activities of both neutral and acid SMases in a concentration-dependent manner. These results suggest that LMG, a water-solubleβ-1,3-glucan recycled from extracted residue ofG. lucidum, possesses antioxidant capability against H2O2-induced cell death by attenuating intracellular ROS and inhibiting SMase activity.

scholarly journals LuxR Homologue SmcR Is Essential for Vibrio vulnificus Pathogenesis and Biofilm Detachment, and Its Expression is Induced by Host Cells

2013 ◽  
Vol 81 (10) ◽  
pp. 3721-3730 ◽  
Author(s):  
Seung Min Kim ◽  
Jin Hwan Park ◽  
Hyun Sung Lee ◽  
Won Bin Kim ◽  
Jung Min Ryu ◽  
...  
Keyword(s):  
Quorum Sensing ◽  
Vibrio Vulnificus ◽  
Cell Communication ◽  
Cellular Level ◽  
Host Cells ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Content Type ◽  
Biofilm Detachment

ABSTRACTQuorum sensing is a cell-to-cell communication system known to control many bacterial processes. In the present study, the functions of quorum sensing in the pathogenesis ofVibrio vulnificus, a food-borne pathogen, were assessed by evaluating the virulence of a mutant deficient in SmcR, a quorum-sensing regulator and homologue of LuxR. When biofilms were used as an inoculum, thesmcRmutant was impaired in virulence and colonization capacity in the infection of mice. The lack of SmcR also resulted in decreased histopathological damage in mouse jejunum tissue. These results indicated that SmcR is essential forV. vulnificuspathogenesis. Moreover, thesmcRmutant exhibited significantly reduced biofilm detachment. Upon exposure to INT-407 host cells, the wild type, but not thesmcRmutant, revealed accelerated biofilm detachment. The INT-407 cells increasedsmcRexpression by activating the expression of LuxS, an autoinducer-2 synthase, indicating that host cells manipulate the cellular level of SmcR through the quorum-sensing signaling ofV. vulnificus. A whole-genome microarray analysis revealed that the genes primarily involved in biofilm detachment and formation are up- and downregulated by SmcR, respectively. Among the SmcR-regulated genes,vvpEencoding an elastolytic protease was the most upregulated, and the purified VvpE appeared to dissolve established biofilms directly in a concentration-dependent mannerin vitro. These results suggest that the host cell-induced SmcR enhances the detachment ofV. vulnificusbiofilms entering the host intestine and thereby may promote the dispersal of the pathogen to new colonization loci, which is crucial for pathogenesis.

scholarly journals A Cysteine Protease Inhibitor Rescues Mice from a Lethal Cryptosporidium parvum Infection

2013 ◽  
Vol 57 (12) ◽  
pp. 6063-6073 ◽  
Author(s):  
Momar Ndao ◽  
Milli Nath-Chowdhury ◽  
Mohammed Sajid ◽  
Victoria Marcus ◽  
Susan T. Mashiyama ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Cryptosporidium Parvum ◽  
Cysteine Protease ◽  
Intestinal Inflammation ◽  
Cysteine Protease Inhibitor ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Content Type ◽  
Mammalian Cell Lines

ABSTRACTCryptosporidiosis, caused by the protozoan parasiteCryptosporidium parvum, can stunt infant growth and can be lethal in immunocompromised individuals. The most widely used drugs for treating cryptosporidiosis are nitazoxanide and paromomycin, although both exhibit limited efficacy. To investigate an alternative approach to therapy, we demonstrate that the clan CA cysteine protease inhibitorN-methyl piperazine-Phe-homoPhe-vinylsulfone phenyl (K11777) inhibitsC. parvumgrowth in mammalian cell lines in a concentration-dependent manner. Further, using the C57BL/6 gamma interferon receptor knockout (IFN-γR-KO) mouse model, which is highly susceptible toC. parvum, oral or intraperitoneal treatment with K11777 for 10 days rescued mice from otherwise lethal infections. Histologic examination of untreated mice showed intestinal inflammation, villous blunting, and abundant intracellular parasite stages. In contrast, K11777-treated mice (210 mg/kg of body weight/day) showed only minimal inflammation and no epithelial changes. Three putative protease targets (termed cryptopains 1 to 3, or CpaCATL-1, -2, and -3) were identified in theC. parvumgenome, but only two are transcribed in infected mammals. A homology model predicted that K11777 would bind to cryptopain 1. Recombinant enzymatically active cryptopain 1 was successfully targeted by K11777 in a competition assay with a labeled active-site-directed probe. K11777 exhibited no toxicityin vitroandin vivo, and surviving animals remained free of parasites 3 weeks after treatment. The discovery that a cysteine protease inhibitor provides potent anticryptosporidial activity in an animal model of infection encourages the investigation and development of this biocide class as a new, and urgently needed, chemotherapy for cryptosporidiosis.

scholarly journals Phytochemical Composition and In Vitro Biological Activity of Iris spp. (Iridaceae): A New Source of Bioactive Constituents for the Inhibition of Oral Bacterial Biofilms

Antibiotics ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 403 ◽  
Author(s):  
Lan Hoang ◽  
František Beneš ◽  
Marie Fenclová ◽  
Olga Kronusová ◽  
Viviana Švarcová ◽  
...  
Keyword(s):  
Quorum Sensing ◽  
Biofilm Formation ◽  
High Performance ◽  
Human Fibroblasts ◽  
Antibiofilm Activity ◽  
Dependent Manner ◽  
Bioactive Constituents ◽  
Concentration Dependent Manner ◽  
Oral Biofilms

The inhibition and eradication of oral biofilms is increasingly focused on the use of plant extracts as mouthwashes and toothpastes adjuvants. Here, we report on the chemical composition and the antibiofilm activity of 15 methanolic extracts of Iris species against both mono-(Pseudomonas aeruginosa, Staphylococcus aureus) and multi-species oral biofilms (Streptococcus gordonii, Veillonella parvula, Fusobacterium nucleatum subsp. nucleatum, and Actinomyces naeslundii). The phytochemical profiles of Iris pallida s.l., Iris versicolor L., Iris lactea Pall., Iris carthaliniae Fomin, and Iris germanica were determined by ultra-high performance liquid chromatography-high-resolution tandem mass spectroscopy (UHPLC-HRMS/MS) analysis, and a total of 180 compounds were identified among Iris species with (iso)flavonoid dominancy. I. pallida, I. versicolor, and I. germanica inhibited both the quorum sensing and adhesion during biofilm formation in a concentration-dependent manner. However, the extracts were less active against maturated biofilms. Of the five tested species, Iris pallida s.l. was the most effective at both inhibiting biofilm formation and disrupting existing biofilms, and the leaf extract exhibited the strongest inhibitory effect compared to the root and rhizome extracts. The cytotoxicity of the extracts was excluded in human fibroblasts. The inhibition of bacterial adhesion significantly correlated with myristic acid content, and quorum sensing inhibition correlated with the 7-β-hydroxystigmast-4-en-3-one content. These findings could be useful for establishing an effective tool for the control of oral biofilms and thus dental diseases.

scholarly journals Chemical Profile, Antioxidant, Anti-Proliferative, Anticoagulant and Mutagenic Effects of a Hydroalcoholic Extract of Tuscan Rosmarinus officinalis

Plants ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 97
Author(s):  
Stefania Lamponi ◽  
Maria Camilla Baratto ◽  
Elisabetta Miraldi ◽  
Giulia Baini ◽  
Marco Biagi
Keyword(s):  
High Performance ◽  
Biological Activities ◽  
Ethanolic Extract ◽  
Metabolic Activation ◽  
Rosmarinus Officinalis ◽  
Breast Adenocarcinoma ◽  
Dependent Manner ◽  
Chemical Profile ◽  
Concentration Dependent Manner

This study aimed to characterize the chemical profile of an ethanolic extract of Tuscan Rosmarinus officinalis (Roex) and to determine its in vitro bioactivity. The content of phenolic and flavonoid compounds, hydroxycinnamic acids and triterpenoids was determined, and high-performance liquid chromatography-diode array detection (HPLC-DAD) analysis revealed that rosmarinic acid and other hydroxycinnamic derivatives were the main constituents of the extract. Roex demonstrated to have both antioxidant activity and the capability to scavenge hydrogen peroxide in a concentration dependent manner. Moreover, NIH3T3 mouse fibroblasts and human breast adenocarcinoma cells MDA-MB-231 viability was influenced by the extract with an IC50 of 2.4 × 10−1 mg/mL and 4.8 × 10−1 mg/mL, respectively. The addition of Roex to the culture medium of both the above cell lines, resulted also in the reduction of cell death after H2O2 pre-treatment. The Ames test demonstrated that Roex was not genotoxic towards both TA98 and TA100 strains, with and without S9 metabolic activation. The extract, by inactivating thrombin, showed to also have an anti-coagulating effect at low concentration values. All these biological activities exerted by Roex are tightly correlated to its phytochemical profile, rich in bioactive compounds.

Chickpea (Cicer arietinum L.) Lectin Exhibit Inhibition of ACE-I, α-amylase and α-glucosidase Activity

2019 ◽  
Vol 26 (7) ◽  
pp. 494-501 ◽  
Author(s):  
Sameer Suresh Bhagyawant ◽  
Dakshita Tanaji Narvekar ◽  
Neha Gupta ◽  
Amita Bhadkaria ◽  
Ajay Kumar Gautam ◽  
...  
Keyword(s):  
Biological Effects ◽  
Exchange Chromatography ◽  
Health Concern ◽  
Carbohydrate Binding ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Ic50 Values ◽  
Chickpea Lectin

Background: Diabetes and hypertension are the major health concern and alleged to be of epidemic proportions. This has made it a numero uno subject at various levels of investigation. Glucosidase inhibitor provides the reasonable option in treatment of Diabetes Mellitus (DM) as it specifically targets post prandial hyperglycemia. The Angiotensin Converting Enzyme (ACE) plays an important role in hypertension. Therefore, inhibition of ACE in treatment of elevated blood pressure attracts special interest of the scientific community. Chickpea is a food legume and seeds contain carbohydrate binding protein- a lectin. Some of the biological properties of this lectin hitherto been elucidated. Methods: Purified by ion exchange chromatography, chickpea lectin was tested for its in vitro antioxidant, ACE-I inhibitory and anti-diabetic characteristic. Results: Lectin shows a characteristic improvement over the synthetic drugs like acarbose (oral anti-diabetic drug) and captopril (standard antihypertensive drug) when, their IC50 values are compared. Lectin significantly inhibited α-glucosidase and α-amylase in a concentration dependent manner with IC50 values of 85.41 ± 1.21 ҝg/ml and 65.05 ± 1.2 µg/ml compared to acarbose having IC50 70.20 ± 0.47 value of µg/ml and 50.52 ± 1.01 µg/ml respectively. β-Carotene bleaching assay showed antioxidant activity of lectin (72.3%) to be as active as Butylated Hydroxylanisole (BHA). In addition, lectin demonstrated inhibition against ACE-I with IC50 value of 57.43 ± 1.20 µg/ml compared to captopril. Conclusion: Lectin demonstrated its antioxidant character, ACE-I inhibition and significantly inhibitory for α-glucosidase and α-amylase seems to qualify as an anti-hyperglycemic therapeutic molecule. The biological effects of chickpea lectin display potential for reducing the parameters of medically debilitating conditions. These characteristics however needs to be established under in vivo systems too viz. animals through to humans.

Improved Method for Obtaining of Arctigenin from Arctium Lappa L. and its Antiproliferative Effect on Human Hepatocarcinoma HepG2 Cells

2020 ◽  
Vol 16 (3) ◽  
pp. 358-362
Author(s):  
Renan S. Teixeira ◽  
Paulo H.D. Carvalho ◽  
Jair A.K. Aguiar ◽  
Valquíria P. Medeiros ◽  
Ademar A. Da Silva Filho ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Crude Extract ◽  
Hepg2 Cells ◽  
Liver Carcinoma ◽  
Adhesion Assay ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Arctium Lappa ◽  
Nih 3T3

Background: Arctigenin is a lignan found in Arctium lappa L. (Asteraceae) that displays anti-inflammatory activities. Previous studies showed that the crude extract of A. Lappa has antitumor activity in human liver carcinoma, lung and stomach cancer cells. The aim of this study was to obtain arctigenin from A. lappa L., as well as to evaluate its antiproliferative effects in cells of liver carcinoma (HepG2) and fibroblasts (NIH/3T3). Methods: Arctigenin was obtained from the hydrolysis of arctiin, which was isolated from the crude extract of A. lappa. The effects of arctigenin and arctiin on HepG2 cell viability and cell adhesion were analyzed by MTT method. Adhesion assay was also carried out to evaluate the antitumor activity. Results: Our results showed that the analytical process to obtain arctigenin was fast and easy. In vitro experiments showed that arctigenin (107-269 μM) decreased HepG2 cells viability and did not cause cytotoxicity on NIH/3T3 cells. Arctigenin (27-269 μM) demonstrated anti-adhesion in HepG2 cells in a concentration-dependent manner, when compared with control. Conclusion: These results suggest a promising pharmacological activity for arctigenin as an antiproliferative compound.

scholarly journals In VitroAnalyses of the Effects of Heparin and Parabens on Candida albicans Biofilms and Planktonic Cells

2011 ◽  
Vol 56 (1) ◽  
pp. 148-153 ◽  
Author(s):  
Marisa H. Miceli ◽  
Stella M. Bernardo ◽  
T. S. Neil Ku ◽  
Carla Walraven ◽  
Samuel A. Lee
Keyword(s):  
Candida Albicans ◽  
Metabolic Activity ◽  
Biofilm Formation ◽  
High Dose ◽  
Dependent Manner ◽  
Planktonic Cells ◽  
Content Type ◽  
Heparin Sodium ◽  
The Individual

ABSTRACTInfections and thromboses are the most common complications associated with central venous catheters. Suggested strategies for prevention and management of these complications include the use of heparin-coated catheters, heparin locks, and antimicrobial lock therapy. However, the effects of heparin onCandida albicansbiofilms and planktonic cells have not been previously studied. Therefore, we sought to determine thein vitroeffect of a heparin sodium preparation (HP) on biofilms and planktonic cells ofC. albicans. Because HP contains two preservatives, methyl paraben (MP) and propyl paraben (PP), these compounds and heparin sodium without preservatives (Pure-H) were also tested individually. The metabolic activity of the mature biofilm after treatment was assessed using XTT [2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide] reduction and microscopy. Pure-H, MP, and PP caused up to 75, 85, and 60% reductions of metabolic activity of the mature preformedC. albicansbiofilms, respectively. Maximal efficacy against the mature biofilm was observed with HP (up to 90%) compared to the individual compounds (P< 0.0001). Pure-H, MP, and PP each inhibitedC. albicansbiofilm formation up to 90%. A complete inhibition of biofilm formation was observed with HP at 5,000 U/ml and higher. When tested against planktonic cells, each compound inhibited growth in a dose-dependent manner. These data indicated that HP, MP, PP, and Pure-H havein vitroantifungal activity againstC. albicansmature biofilms, formation of biofilms, and planktonic cells. Investigation of high-dose heparin-based strategies (e.g., heparin locks) in combination with traditional antifungal agents for the treatment and/or prevention ofC. albicansbiofilms is warranted.

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