Review: Basics of Drug Development in Rheumatology

Mina‐Osorio, Paola

doi:10.1002/art.39253

Cited by 9 publications

(6 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…considerations that must be accounted for. Furthermore, in the context of RA, autoimmune conditions that are present in humans do not develop in the same way as in animals, and have to be induced therapeutically with a short disease lifetime [73]. Finally, clinical trials or human studies give the optimal biologically relevant setting, however, the information that can be obtained from patients is limited.…”

Section: Parameter Estimation and Availability Of Datamentioning

confidence: 99%

“…Initially, biological mechanisms to target within RA must be firstly identified. To find these targets in vitro [90] and in vivo models can be used, with in vivo models then used to further validate these targets [73,101]. After initial drug development, in vivo studies can be used to assess the pharmacodynamic and pharmacokinetics of the proposed drug in response to RA [73].…”

Section: Parameter Estimation and Availability Of Datamentioning

confidence: 99%

See 1 more Smart Citation

Quantitative Predictive Modelling Approaches to Understanding Rheumatoid Arthritis: A Brief Review

Macfarlane

Chaplain

Eftimie

2019

Cells

View full text Add to dashboard Cite

Rheumatoid arthritis is a chronic autoimmune disease that is a major public health challenge. The disease is characterised by inflammation of synovial joints and cartilage erosion, which lead to chronic pain, poor life quality and, in some cases, mortality. Understanding the biological mechanisms behind the progression of the disease, as well as developing new methods for quantitative predictions of disease progression in the presence/absence of various therapies is important for the success of therapeutic approaches. The aim of this study is to review various quantitative predictive modelling approaches for understanding rheumatoid arthritis. To this end, we start by briefly discussing the biology of this disease and some current treatment approaches, as well as emphasising some of the open problems in the field. Then, we review various mathematical mechanistic models derived to address some of these open problems. We discuss models that investigate the biological mechanisms behind the progression of the disease, as well as pharmacokinetic and pharmacodynamic models for various drug therapies. Furthermore, we highlight models aimed at optimising the costs of the treatments while taking into consideration the evolution of the disease and potential complications.

show abstract

Section: Parameter Estimation and Availability Of Datamentioning

confidence: 99%

Section: Parameter Estimation and Availability Of Datamentioning

confidence: 99%

Quantitative Predictive Modelling Approaches to Understanding Rheumatoid Arthritis: A Brief Review

Macfarlane

Chaplain

Eftimie

2019

Cells

View full text Add to dashboard Cite

show abstract

“…However, from all drugs evaluated in clinical development every year, only 15% of them are approved or even considered safe [1]. In this respect, there are several limitations associated with drug discovery, such as the identification of a specific target as a relevant biomarker, adverse effects not previously identified in early stages of long-term treatments, and heterogeneity of patients and its implication in drug effectiveness; all these especially relevant in rheumatic diseases [2]. In light of these issues, drug repositioning emerges as a new field in the drug industry.…”

Section: Introduction: Drug Repositioning and Current Strategiesmentioning

confidence: 99%

Genomic opportunities for drug repositioning in systemic seropositive rheumatic diseases

Casares-Marfil

Martı́n

Acosta‐Herrera

2020

Expert Review of Clinical Immunology

View full text Add to dashboard Cite

“…The development of immunosuppressive drugs and target-based drugs has expanded our therapeutic armamentarium in the treatment of inflammatory and autoimmune diseases ( Mina-Osorio, 2015 ; Romão and Fonseca, 2019 ). Despite these advances, glucocorticoids (GCs) remain the most reliable agents as an initial treatment in the acute phase of the disease and the maintenance therapy for preventing disease relapse GCs are a double-edged sword because long-term use can induce adverse events, including cardiovascular disease, osteoporosis, cataracts and muscle atrophy, in addition to the risk of serious infections ( Fardet et al, 2015 ; Hardy et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Identification of Compounds With Glucocorticoid Sparing Effects on Suppression of Chemokine and Cytokine Production by Rheumatoid Arthritis Fibroblast-Like Synoviocytes

et al. 2020

View full text Add to dashboard Cite

In recent years target based drug discovery has expanded our therapeutic armamentarium in the treatment of inflammatory and autoimmune diseases. Despite these advances and adverse effects, glucocorticoids remain reliable agents that are used in many of these diseases. The anti-inflammatory mechanisms of glucocorticoids include the suppression of transcription factor activity like nuclear factor kappa B (NF-κB). By reanalyzing data from two prior high throughput screens (HTS) that utilized a NF-κB reporter construct in THP-1 cells, we identified 1824 small molecule synthetic compounds that demonstrated NF-κB suppressive activities similar to the glucocorticoids included in the original >134,000 compound libraries. These 1824 compounds were then rescreened for attenuating NF-κB activity at 5 and 16 h after LPS stimuli in the NF-κB THP-1 reporter cells. After a “Top X” selection approach 122 hit compounds were further tested for toxicity and suppression of LPS induced CXCL8 release in THP-1 cells. Excluding cytotoxic compounds, the remaining active compounds were grouped into chemotype families using Tanimoto based clustering. Promising representatives from clustered chemotype groups were commercially purchased for further testing. Amongst these index compounds a lead chemotype: 1H-pyrazolo [3,4 d] pyrimidin-4-amine, effectively suppressed CXCL8, and TNF production by THP-1 cells when stimulated with LPS, TNF or IL-1ß. Extending these studies to primary cells, these lead compounds also reduced IL-6 and CXCL8 production by TNF stimulated fibroblast-like synoviocytes (FLS) from rheumatoid arthritis (RA) patients. Importantly a lead 1H-pyrazolo [3,4 d] pyrimidin-4-amine compound demonstrated synergistic effects with dexamethasone when co-administered to TNF stimulated THP-1 cells and RA FLS in suppressing chemokine production. In summary, a cell based HTS approach identified lead compounds that reduced NF-κB activity and chemokine secretion induced by potent immunologic stimuli, and one lead compound that acted synergistically with dexamethasone as an anti-inflammatory agent showing a dose-sparing effect.

show abstract

Review: Basics of Drug Development in Rheumatology

Cited by 9 publications

References 51 publications

Quantitative Predictive Modelling Approaches to Understanding Rheumatoid Arthritis: A Brief Review

Quantitative Predictive Modelling Approaches to Understanding Rheumatoid Arthritis: A Brief Review

Genomic opportunities for drug repositioning in systemic seropositive rheumatic diseases

Identification of Compounds With Glucocorticoid Sparing Effects on Suppression of Chemokine and Cytokine Production by Rheumatoid Arthritis Fibroblast-Like Synoviocytes

Contact Info

Product

Resources

About