Quality by design driven development and optimization of teriflunomide loaded nanoliposomes for treatment of rheumatoid arthritis: An in vitro and in vivo assessments

2019 ◽  
Vol 51 ◽  
pp. 383-396 ◽  
Author(s):  
Asiya Mahtab ◽  
Md. Rizwanullah ◽  
Shweta Pandey ◽  
Ankita Leekha ◽  
Syed Arman Rabbani ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Quality By Design

Comparison of In Vitro and In Vivo Effects of Infliximab on Cytokine Production in Proliferating CD4+ T Cells in Patients with Rheumatoid Arthritis

2015 ◽  
Vol 1 (2) ◽  
pp. 122-128
Author(s):  
Syuichi Koarada ◽  
Yuri Sadanaga ◽  
Natsumi Nagao ◽  
Satoko Tashiro ◽  
Rie Suematsu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Cd4 T Cells ◽  
Cytokine Production

scholarly journals Secreted KIAA1199 promotes the progression of rheumatoid arthritis by mediating hyaluronic acid degradation in an ANXA1-dependent manner

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wei Zhang ◽  
Guoyu Yin ◽  
Heping Zhao ◽  
Hanzhi Ling ◽  
Zhen Xie ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Hyaluronic Acid ◽  
Dependent Manner ◽  
Collagen Induced Arthritis ◽  
Intracellular Degradation ◽  
Main Pathway ◽  
First Time

AbstractIn inflamed joints, enhanced hyaluronic acid (HA) degradation is closely related to the pathogenesis of rheumatoid arthritis (RA). KIAA1199 has been identified as a hyaladherin that mediates the intracellular degradation of HA, but its extracellular function remains unclear. In this study, we found that the serum and synovial levels of secreted KIAA1199 (sKIAA1199) and low-molecular-weight HA (LMW-HA, MW < 100 kDa) in RA patients were significantly increased, and the positive correlation between them was shown for the first time. Of note, treatment with anti-KIAA1199 mAb effectively alleviated the severity of arthritis and reduced serum LMW-HA levels and cytokine secretion in collagen-induced arthritis (CIA) mice. In vitro, sKIAA1199 was shown to mediate exogenous HA degradation by attaching to the cell membrane of RA fibroblast-like synoviosytes (RA FLS). Furthermore, the HA-degrading activity of sKIAA1199 depended largely on its adhesion to the membrane, which was achieved by its G8 domain binding to ANXA1. In vivo, kiaa1199-KO mice exhibited greater resistance to collagen-induced arthritis. Interestingly, this resistance could be partially reversed by intra-articular injection of vectors encoding full-length KIAA1199 instead of G8-deleted KIAA119 mutant, which further confirmed the indispensable role of G8 domain in KIAA1199 involvement in RA pathological processes. Mechanically, the activation of NF-κB by interleukin-6 (IL-6) through PI3K/Akt signaling is suggested to be the main pathway to induce KIAA1199 expression in RA FLS. In conclusion, our study supported the contribution of sKIAA1199 to RA pathogenesis, providing a new therapeutic target for RA by blocking sKIAA1199-mediated HA degradation.

Lipidated Methotrexate Microbubbles: A Promising Rheumatoid Arthritis Theranostic Medicine Manipulated via Ultrasonic Irradiation

2021 ◽  
Vol 17 (7) ◽  
pp. 1293-1304
Author(s):  
Zhuofei Zhao ◽  
Xiaona Lin ◽  
Lulu Zhang ◽  
Xia Liu ◽  
Qingwen Wang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
De Novo ◽  
Low Ph ◽  
Curative Effect ◽  
Inflammatory Microenvironment ◽  
Raw 264.7 Cell ◽  
Infection Focus ◽  
Raw 264.7 Cell Line

De novo designed lipidated methotrexate was synthesized and self-assembled into microbubbles for targeted rheumatoid arthritis theranostic treatment. Controlled lipidatedmethotrexate delivery was achieved by ultrasound-targetedmicrobubble destruction technique. Methotrexate was dissociated inflammatory microenvironment of synovial cavity, owing to representive low pH and enriched leucocyte esterase. We first manipulated methotrexate controlled release with RAW 264.7 cell line in vitro and further verified with rheumatoid arthritis rabbits in vivo. Results showed that lipidated methotrexate microbubbles precisely affected infection focus and significantly enhanced rheumatoid arthritis curative effect comparing with dissociative methotrexate. This study indicates that lipidated methotrexate microbubbles might be considered as a promising rheumatoid arthritis theranostics medicine.

In-silico Molecular Docking of Coumarin and Naphthalene Derivatives from Pyrenacantha volubilis with the Pathological Mediators of Rheumatoid Arthritis

2021 ◽  
pp. 5121-5125
Author(s):  
Anjali P ◽  
Vimalavathini R
Keyword(s):  
Rheumatoid Arthritis ◽  
Symptomatic Relief ◽  
In Vivo Studies ◽  
Gas Chromatography Mass Spectrometry ◽  
Therapeutic Drugs ◽  
Herbal Plants ◽  
In Silico Molecular Docking ◽  
Inflammatory Autoimmune Disease

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease which mainly targets synovial membrane during its disease pathogenesis. Available therapeutic drugs for the treatment of RA provide only symptomatic relief and are associated with severe side effects. Herbal plants comprise many active biological compounds that cure the disease with minimal adverse effects. Pyrenacantha volubilis is a climber and member of Icacinaceae family. Gas chromatography- mass spectrometry (GC-MS) analysis of ethanolic extracts of leaves of Pyrenacantha volubilis (EEPV) reveals the presence of 2-isopropyl-5-methylcyclohexyl 3-(1-(4- chlorophenyl)-3-oxobutyl)-coumarin-4-yl carbonate and 1-naphthalenepropanol, alpha-ethyldecahydro-5- (hydroxymethyl)-alpha,5,8A-trimethyl-2-methyl phytoconstitutents. Hence these compounds were docked with various pathological mediators of RA using Autodock 4.2. The docking results unveils that these compounds had better binding energy against inflammatory, oxidative stress and receptor for advanced glycation end products (RAGE) mediators that plays a pivotal role in the progression of RA. However, this study warrants further in- vitro and in-vivo studies to be carried out to establish the anti-inflammatory and anti-arthritic activity of selected phytoconstitutents.

scholarly journals Tofacitinib Suppresses Several JAK-STAT Pathways in Rheumatoid Arthritis In Vivo and Baseline Signaling Profile Associates With Treatment Response

2021 ◽  
Vol 12 ◽  
Author(s):  
Maaria Palmroth ◽  
Krista Kuuliala ◽  
Ritva Peltomaa ◽  
Anniina Virtanen ◽  
Antti Kuuliala ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Treatment Response ◽  
Peripheral Blood ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Stat3 Phosphorylation ◽  
Stat Pathway

ObjectiveCurrent knowledge on the actions of tofacitinib on cytokine signaling pathways in rheumatoid arthritis (RA) is based on in vitro studies. Our study is the first to examine the effects of tofacitinib treatment on Janus kinase (JAK) - signal transducer and activator of transcription (STAT) pathways in vivo in patients with RA.MethodsSixteen patients with active RA, despite treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), received tofacitinib 5 mg twice daily for three months. Levels of constitutive and cytokine-induced phosphorylated STATs in peripheral blood monocytes, T cells and B cells were measured by flow cytometry at baseline and three-month visits. mRNA expression of JAKs, STATs and suppressors of cytokine signaling (SOCS) were measured from peripheral blood mononuclear cells (PBMCs) by quantitative PCR. Association of baseline signaling profile with treatment response was also investigated.ResultsTofacitinib, in csDMARDs background, decreased median disease activity score (DAS28) from 4.4 to 2.6 (p &lt; 0.001). Tofacitinib treatment significantly decreased cytokine-induced phosphorylation of all JAK-STAT pathways studied. However, the magnitude of the inhibitory effect depended on the cytokine and cell type studied, varying from 10% to 73% inhibition following 3-month treatment with tofacitinib. In general, strongest inhibition by tofacitinib was observed with STAT phosphorylations induced by cytokines signaling through the common-γ-chain cytokine receptor in T cells, while lowest inhibition was demonstrated for IL-10 -induced STAT3 phosphorylation in monocytes. Constitutive STAT1, STAT3, STAT4 and STAT5 phosphorylation in monocytes and/or T cells was also downregulated by tofacitinib. Tofacitinib treatment downregulated the expression of several JAK-STAT pathway components in PBMCs, SOCSs showing the strongest downregulation. Baseline STAT phosphorylation levels in T cells and monocytes and SOCS3 expression in PBMCs correlated with treatment response.ConclusionsTofacitinib suppresses multiple JAK-STAT pathways in cytokine and cell population specific manner in RA patients in vivo. Besides directly inhibiting JAK activation, tofacitinib downregulates the expression of JAK-STAT pathway components. This may modulate the effects of tofacitinib on JAK-STAT pathway activation in vivo and explain some of the differential findings between the current study and previous in vitro studies. Finally, baseline immunological markers associate with the treatment response to tofacitinib.

scholarly journals QUALITY BY DESIGN (QBD) AS A TOOL FOR THE OPTIMIZATION OF INDOMETHACIN FREEZE-DRIED SUBLINGUAL TABLETS: IN VITRO AND IN VIVO EVALUATION

2021 ◽  
pp. 160-171
Author(s):  
MERVAT SHAFIK IBRAHIM ◽  
NIHAL MOHAMED ELMAHDY ELSAYYAD ◽  
ABEER SALAMA ◽  
SHEREEN H. NOSHI
Keyword(s):  
Response Surface ◽  
Quality By Design ◽  
Drug Dissolution ◽  
Disintegration Time ◽  
Optimization Study ◽  
Freeze Dried ◽  
Screening Study ◽  
Wetting Time

Objective: This study aims to prepare and optimize indomethacin freeze-dried sublingual tablets (IND-FDST) by utilizing a quality by design (QbD) approach to achieve rapid drug dissolution and simultaneously bypassing the GIT for better patient tolerability. Methods: A screening study was utilized to determine the most significant factors which the quality attributes, namely disintegration time and % friability. Then an optimization study was conducted using a full response surface design to determine the optimized formula by varying the amount of the matrix-forming polymer (gelatin) and super disintegrant (croscarmellose sodium (CCS)). The variables' effect on the % friability, disintegration time, wetting time, and amount of drug release after 10 min (%Q10) was studied. The optimized formula was tested for compatibility, morphology as well as stability studies under accelerated conditions in addition to the in vivo pharmacodynamics in rats. QbD was adopted by utilizing a screening study to identify the significant formulation factors followed by a response surface optimization study to determine the optimized IND-FDST formulation. Results: Optimized IND-FDST comprised of gelatin/CCS combination in a ratio of 1:1 possessed adequate %friability (0.73±0.03%), disintegration time (25.40±1.21 seconds), wetting time (3.49±0.68 seconds), and % Q10 (100.99±5.29%) as well as good stability under accelerated conditions. IND-FDST also showed significant inhibition of edema, tumour necrosis factor-alpha, and interleukin-6 release in vivo compared to the oral market product by 70%, 42%, and 65%, respectively. Conclusion: QbD presents a successful approach in the optimization of a successful IND-FDST formula that showed superior in vivo and in vitro characteristics.

scholarly journals Design and Characterization of Combinational Domperidone-Famotidine Floating Drug Delivery System - In vitro and In vivo studies

2021 ◽  
Vol 62 (2) ◽  
pp. 144-162
Author(s):  
Mounika Chidurala ◽  
Raveendra Reddy J
Keyword(s):  
Drug Release ◽  
Oral Administration ◽  
Quality By Design ◽  
Release Kinetics ◽  
Cost Effective ◽  
Fickian Diffusion ◽  
In Vivo Studies ◽  
Pharmacokinetic Studies

Introduction: The drawbacks assosiated with oral administration of drugscan be controlled or minimized by gastro retentive formulations that remain buoyant within the stomach for an extended time by providing prolonged gastric retention and releasethe drug in an exceedingly extended manner thereby improving bioavailability. The current research was to develop and optimize Domperidone and Famotidine floating tablets with extended release by Quality by Design approach. Method: Based on QTPP (Quality Target Product Profile), CQAs (Critical Quality Attributes)wereidentified. Risk analysis by the evaluation of formulation and process parameters showed that optimizing the levels of polymers could reduce high risk to achieve the target profile. A 23factor experimental design with midpoints was selected for statistical analysis and optimization. Results: HPMC K100 and Carbopol 934P had a positive effect while ethyl cellulose demonstrated a negative effect on the selected responses. Drug release kinetics followed the first-order release with Higuchi diffusion and Fickian diffusion. Optimized formula satisfying all the required parameters was selected and evaluated. The predicted response values were in close agreement with experimental response values. Abdominal X-ray imaging after oral administration of the tablets on a healthy rabbit’s stomach confirmed the extended floating behavior with shorter lag time. In vivo, pharmacokinetic studies in rabbits revealed that the optimized formulation exhibited prolonged drug release with enhanced Cmax, tmax, AUCo-t, and t1/2 of an optimized product when compared to the marketed product. Conclusions: It has been concluded that the application of Quality by Design in the formulation and optimization reduced the number of trials to produce a cost-effective formula.

Quality by Design enabled anti-hypertensive Floating drug delivery system by Risk assessment and Design of Experiment (DoE) – In vitro – In vivo correlation studies

2021 ◽  
Vol 16 ◽  
Author(s):  
Mounika Chidurala ◽  
Raveendra Reddy J
Keyword(s):  
Drug Release ◽  
Risk Analysis ◽  
Quality By Design ◽  
Release Kinetics ◽  
Cost Effective ◽  
Fickian Diffusion ◽  
In Vivo Studies ◽  
Pharmacokinetic Studies

Background: The present research aimed to develop and optimize extended-release floating tablets of Sacubitril and Valsartan through Quality by Design (QbD) approach. Risk analysis by formulation assessment and process parameters showed that optimizing the levels of the polymer will minimize high risk to meet the target profile. A two (2) level three (3) full factorial experimental design along with midpoints was carefully chosen for optimization and statistical analysis. Based on the literature, the independent and dependent variables were selected. Results: HPMC K100, Carbopol 934P had a positive effect, whereas Ethylcellulose had a negative effect on Floating time, drug release at 2 h, drug release at 12 h and, 50% responses. Drug release kinetics followed the first-order release with Higuchi and Fickian diffusion. Contour and overlay plots were utilized for an assortment of design space and optimized formula. ANOVA results of all the factors exhibited significance at p<0.05. Abdominal X-ray imaging of the optimized tablets on healthy rabbit’s stomach confirmed the floating behavior for more than 12 h. In vivo pharmacokinetic studies in rabbits showed that the optimized formulation exhibited prolonged and extended drug release with improved Cmax, tmax, AUCo-t, and t1/2 of test product when compared to marketed product. IVIVC model was developed by using dissolution data of in vitro and pharmacokinetics data of in-vivo by de-convolution method (Wagner-Nelson method). Conclusion: The Quality by Design implementation in the formulation and optimization abridged the number of trials to produce a cost-effective formula. In vivo studies confirmed that the formula was successfully developed with extended floating time (12 h) and drug release by risk analysis and experimental designs. Level A correlation was observed which confirmed a good correlation between in vitro and in vivo data.

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