Comparative Assessment of the New PDE7 Inhibitor – GRMS-55 and Lisofylline in Animal Models of Immune-Related Disorders: A PK/PD Modeling Approach

Abstract Purpose This study aimed to assess the activity of two phosphodiesterase (PDE) inhibitors, namely GRMS-55 and racemic lisofylline ((±)-LSF)) in vitro and in animal models of immune-mediated disorders. Methods Inhibition of human recombinant (hr)PDEs and TNF-alpha release from LPS-stimulated whole rat blood by the studied compounds were assessed in vitro. LPS-induced endotoxemia, concanavalin A (ConA)-induced hepatitis, and collagen-induced arthritis (CIA) animal models were used for in vivo evaluation. The potency of the investigated compounds was evaluated using PK/PD and PK/PD/disease progression modeling. Results GRMS-55 is a potent hrPDE7A and hrPDE1B inhibitor, while (±)-LSF most strongly inhibits hrPDE3A and hrPDE4B. GRMS-55 decreased TNF-alpha levels in vivo and CIA progression with IC50 of 1.06 and 0.26 mg/L, while (±)-LSF with IC50 of 5.80 and 1.06 mg/L, respectively. Moreover, GRMS-55 significantly ameliorated symptoms of ConA-induced hepatitis. Conclusions PDE4B but not PDE4D inhibition appears to be mainly engaged in anti-inflammatory activity of the studied compounds. GRMS-55 and (±)-LSF seem to be promising candidates for future studies on the treatment of immune-related diseases. The developed PK/PD models may be used to assess the anti-inflammatory and anti-arthritic potency of new compounds for the treatment of rheumatoid arthritis and other inflammatory disorders.

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Phytochemical Analysis of Anti-Inflammatory and Antioxidant Effects of Mahonia aquifolium Flower and Fruit Extracts

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/2879793 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 13

Author(s):

Andra-Diana Andreicut ◽

Alina Elena Pârvu ◽

Augustin Cătălin Mot ◽

Marcel Pârvu ◽

Eva Fischer Fodor ◽

...

Keyword(s):

Oxidative Stress ◽

Antioxidant Activity ◽

Stress Index ◽

Tnf Alpha ◽

Phytochemical Analysis ◽

Anti Inflammatory ◽

Mahonia Aquifolium ◽

Antioxidant Effects

Oxidative stress and inflammation are interlinked processes. The aim of the study was to perform a phytochemical analysis and to evaluate the antioxidant and anti-inflammatory activities of ethanolic Mahonia aquifolium flower (MF), green fruit (MGF), and ripe fruit (MRF) extracts. Plant extract chemical composition was evaluated by HLPC. A DPPH test was used for the in vitro antioxidant activity. The in vivo antioxidant effects and the anti-inflammatory potential were tested on a rat turpentine oil-induced inflammation, by measuring serum nitric oxide (NOx) and TNF-alpha, total oxidative status (TOS), total antioxidant reactivity (TAR), oxidative stress index (OSI), 3-nitrothyrosine (3NT), malondialdehyde (MDA), and total thiols (SH). Extracts were administrated orally in three dilutions (100%, 50%, and 25%) for seven days prior to inflammation. The effects were compared to diclofenac. The HPLC polyphenol and alkaloid analysis revealed chlorogenic acid as the most abundant compound. All extracts had a good in vitro antioxidant activity, decreased NOx, TOS, and 3NT, and increased SH. TNF-alpha was reduced, and TAR increased only by MF and MGF. MDA was not influenced. Our findings suggest that M. aquifolium has anti-inflammatory and antioxidant effects that support the use in primary prevention of the inflammatory processes.

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The effects of PDE inhibitors on multiple sclerosis: a review of in vitro and in vivo models

Current Pharmaceutical Design ◽

10.2174/1381612827666210303142356 ◽

2021 ◽

Vol 27 ◽

Author(s):

Alexandra Ainatzoglou ◽

Eleni Stamoula ◽

Ioannis Dardalas ◽

Spyridon Siafis ◽

Georgios Papazisis

Keyword(s):

Multiple Sclerosis ◽

Animal Models ◽

In Vivo Studies ◽

Pde4 Inhibitor ◽

Neuroprotective Effects ◽

In Vivo Models ◽

Pde Inhibitors ◽

Ms Therapy

Background: Multiple sclerosis (MS) is a chronic inflammatory and immune-mediated disease, whose current therapeutic means are mostly effective in the relapsing-remitting form of MS, where inflammation is still prominent, but fall short of preventing long term impairment. However, apart from inflammation-mediated demyelination, autoimmune mechanisms play a major role in MS pathophysiology, constituting a promising pharmacological target. Phosphodiesterase (PDE) inhibitors have been approved for clinical use in psoriasis and have undergone trials suggesting their neuroprotective effects, rendering them eligible as an option for accessory MS therapy. Objective: In this review, we discuss the potential role of PDE inhibitors as a complementary MS therapy. Methods: We conducted a literature search through which we screened and comparatively assessed papers on the effects of PDE inhibitor use, both in vitro and in animal models of MS, taking into account a number of inclusion and exclusion criteria. Results: In vitro studies indicated that PDE inhibitors promote remyelination and axonal sustenance, while curbing inflammatory cell infiltration, hindering oligodendrocyte and neuronal loss and suppressing cytokine production. In vivo studies underlined that these agents alleviate symptoms and reduce disease scores in MS animal models. Conclusion: PDE inhibitors proved to be effective in addressing various aspects of MS pathogenesis both in vitro and in vivo models. Given the latest clinical trials proving that the PDE4 inhibitor Ibudilast exerts neuroprotective effects in patients with progressive MS, research on this field should be intensified and selective PDE4 inhibitors with enhanced safety features should be seriously considered as prospective complementary MS therapy.

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The effect of antidepressants on inflammatory markers in animal models of depression

European Psychiatry ◽

10.1016/s0924-9338(11)73794-4 ◽

2011 ◽

Vol 26 (S2) ◽

pp. 2091-2091

Author(s):

A. Harkin ◽

T.J. Connor

Keyword(s):

Animal Models ◽

Inflammatory Cytokines ◽

Glial Cells ◽

Inflammatory Cytokine ◽

Animal Models Of Depression ◽

In Vitro Exposure ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

Considering the evidence that pro-inflammatory cytokines play a causal role in depressive illness, the ability of antidepressants to induce anti-inflammatory effects is a subject of considerable interest. In an in vivo context we observe that antidepressants that enhance noradrenaline availability are the most effective anti-inflammatory agents; a fact consistent with the established anti-inflammatory actions of noradrenaline. Specifically, we have observed that noradrenaline reuptake inhibitors (NRIs) inhibit microglial activation and inhibit expression of pro-inflammatory cytokines (IL-1beta and TNF-alpha), iNOS, and inflammatory chemokines (IP-10 and RANTES) in rat brain following a systemic inflammatory challenge. These in vivo anti-inflammatory actions of NRIs are mimicked by in vitro exposure of primary glial cells to noradrenaline, but not by in vitro exposure of glial cells to the drugs themselves. These data suggest that NRIs promote an anti-inflammatory environment in rat brain in vivo by increasing noradrenaline availability at glial cells. We have also observed that even in the absence of any overt inflammation, chronic treatment with the NRI reboxetine promotes an anti-inflammatory phenotype in the CNS characterised by reduced expression of pro-inflammatory cytokine IFN-gamma, and increased expression of the anti-inflammatory cytokine IL-10. Current experiments are focused on the activation of the inflammatory response system in animal models of depression secondary to inflammation. The models are used subsequently to assess the anti-inflammatory effects of antidepressants in vivo.

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Nemszteroid gyulladáscsökkentők okozta adverz reakciók differenciáldiagnosztikája. In vitro és in vivo módszerek

Orvosi Hetilap ◽

10.1556/650.2018.31170 ◽

2018 ◽

Vol 159 (38) ◽

pp. 1556-1566

Author(s):

József Mátyás Baló-Banga ◽

Katalin Schweitzer

Keyword(s):

Plasma Membranes ◽

Mononuclear Cells ◽

In Vitro Tests ◽

Immune Mediated ◽

Release Assay ◽

Inflammatory Drugs ◽

Anti Inflammatory ◽

Cox 1

Abstract: Introduction: According to the present knowledge, the effect of non-steroidal anti-inflammatory drugs (NSAIDs) depends on the inhibitory ratio of cyclooxigenase (COX)-1 to COX-2 in the plasma membranes. In addition to cardiovascular and gastrointestinal side effects, there are adverse symptoms which can be divided into cross-intolerance (non-immune mediated) and single or multiple hypersensitive (immune mediated) reactions. Due to clinical phenotypes and to in vivo aspirin reactivity, adverse effects could be further classified. Aim: The aim of these studies was a comparison of hit ratios obtained by a humoral serum test measuring specific immunglobulin E (IgE) against a rapid cellular test measuring interleukin (IL)-6 release from sensitized mononuclear cells due to various suspect NSAID after symptoms within one year. Retrospective case studies were performed in in- and out-patients of our teaching hospital in Budapest, between 2003 and 2013. Method: Specific anti-NSAID IgE levels were determined by ELISA in 55 cases. The other matching group of patients consisted of 51 patients and 9 tolerant persons. Their separated cells’ supernatants were checked for IL-6 release incubated for 20 minutes by NSAID dilutions including intraassay controls by two-step ELISA assay. Both groups have been stratified according to “new” clinical classification. Results: Results have disclosed no significant differences among the distribution of clinical symptoms between the two groups. In both groups, 9 non-steroidal anti-inflammatory drugs were tested representing all frequently used compounds with COX-1 inhibitory potential. The overall positivity rate was nearly double (65.4% against 36.9%) within the group using IL-6 release assay against that with specific IgE as the diagnostic tool. In certain cases, non-drug components of commercial preparations prompted IL-6 release as well which was paralleled by in vivo test results. Positive in vitro tests were obtained in both groups with clinically cross-intolerant as well as single or multiple sensitized cases. Conclusion: The rates of single or multiple sensitized cases exceeded in both groups that of cross-intolerant patients. In some phenotypes belonging to the latter categories, IgE type antibodies against acetylsalicylic acid could be detected as well. IL-6 release assay was the more sensitive test. In addition to pure drugs, other ingredients of medicines could also be responsible for adverse events. Orv Hetil. 2018; 159(38): 1556–1566.

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Catunaregam spinosa (Thunb.) Tirveng: A Review of Traditional Uses, Phytochemistry, Pharmacological Activities, and Toxicological Aspects

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/3257732 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Deepak Timalsina ◽

Hari Prasad Devkota ◽

Deepti Bhusal ◽

Khaga Raj Sharma

Keyword(s):

Animal Models ◽

South Asian ◽

Scientific Information ◽

Asian Countries ◽

Pharmacological Activities ◽

Future Studies ◽

Traditional Uses ◽

The People ◽

Anti Inflammatory

Catunaregam spinosa (Thunb.) Tirveng. (Syn. Randia dumetorum (Retz.) Lam.), belonging to the Rubiaceae family, is distributed in south Asian countries. It is used as a traditional medicine to treat gastrointestinal and hepatic problems and as an anti-inflammatory and antimicrobial agent. The main aim of this review is to collect and analyze the available scientific information on traditional uses, phytochemistry, and pharmacological activities of C. spinosa. The scientific information related to C. spinosa was collected from various resources and databases such as SciFinder, Scopus, PubMed, and other databases. C. spinosa was found to be an important crude drug of the traditional medicinal systems such as Ayurveda. It was found to be used by the people of India as an alternative medicine, while the fruit of this plant was found to be used in dietary regimens as well. Active phytochemicals such as catunarosides, randianin, and several other saponins and triterpenoids possess various pharmacological activities such as anti-inflammatory, hepatoprotective, antibacterial, and immunomodulatory activities. Many studies have been performed to isolate the active compounds; however, there is a need for more activity-guided isolation studies. Various in vitro studies showed promising results but there are not many studies related to mechanism of actions using animal models. Hence, future studies on C. spinosa should focus on correlating the traditional uses with active phytoconstituents and modern pharmacological activities.

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