Pain Relieving Effect of-NSAIDs-CAIs Hybrid Molecules: Systemic and Intra-Articular Treatments against Rheumatoid Arthritis

Abstract

: To study new target-oriented molecules that are active against rheumatoid arthritis-dependent pain, new dual inhibitors incorporating both a carbonic anhydrase (CA)-binding moiety and a cyclooxygenase inhibitor (NSAID) were tested in a rat model of rheumatoid arthritis induced by CFA intra-articular (i.a.) injection. A comparison between a repeated per os treatment and a single i.a. injection was performed. CFA (50 µL) was injected in the tibiotarsal joint, and the effect of per os repeated treatment (1 mg kg−1) or single i.a injection (1 mg ml−1, 50 µL) with NSAIDs-CAIs hybrid molecules, named 4 and 5, was evaluated. The molecules 4 and 5, which were administered daily for 14 days, significantly prevented CFA-induced hypersensitivity to mechanical noxious (Paw pressure test) and non-noxious stimuli (von Frey test), the postural unbalance related to spontaneous pain (Incapacitance test) and motor alterations (Beam balance test). Moreover, to study a possible localized activity, 4 and 5 were formulated in liposomes (lipo 4 and lipo 5, both 1 mg ml-1) and directly administered by a single i.a. injection seven days after CFA injection. Lipo 5 decreased the mechanical hypersensitivity to noxious and non-noxious stimuli and improved motor coordination. Oral and i.a. treatments did not rescue the joint, as shown by the histological analysis. This new class of potent molecules, which is able to inhibit at the same time CA and cyclooxygenase, shows high activity in a preclinical condition of rheumatoid arthritis, strongly suggesting a novel attractive pharmacodynamic profile.

Intra-Articular Route for the System of Molecules 14G1862 from Centella asiatica: Pain Relieving and Protective Effects in a Rat Model of Osteoarthritis

“…At the end of decalcification, these samples were routinely dehydrated in alcohol and embedded in paraffin. Sections (6 μM) thick were observed and an histological score (0: absent; 1: mild; 2: moderate; 3: severe) was attributed to the following morphological parameters: (a) inflammatory infiltrate; (b) synovial hyperplasia; (c) fibrin deposition; (d) synovial vascularity; (e) cartilage erosion; (f) bone erosion; (g) joint space [ 32 , 33 ].…”

Intra-articular Injection of Chitosan-Based Supramolecular Hydrogel for Osteoarthritis Treatment

“…In order to study the pain relief of IA injection, weight bearing capacity (WBC) test and paw withdrawal threshold (PWT) test were carried out to detect the gait and pain threshold [ 18 ]. A 3D gait analysis system (Kinama Tracer, Japan) was used for quantifying the WBC of the hind limb of rabbits while freely walking.…”

<p>Intraarticular Injection of Infliximab-Loaded Thermosensitive Hydrogel Alleviates Pain and Protects Cartilage in Rheumatoid Arthritis</p>

“…To study the pain relief elicited by the intraarticular injections, weight-bearing capacity (WBC) and paw withdrawal threshold (PWT) tests were carried out to detect the gait and pain threshold. 23 A 3D gait analysis system (Kinama Tracer, Japan) was used to quantify the WBC values of the hind limbs of rabbits while freely walking. Briefly, RA rabbits walked along a runway equipped with mechanical sensors.…”

“…In addition to study the mechanical allodynia (hypersensitivity), PWT was detected using a von Frey filament (Ugo Basile, Varese, Italy) as described in a previous study. 23 Briefly, the withdrawal threshold was gauged by the force exerted by the von Frey filament ranging from 0 to 40 g with a 0.2 g accuracy. An acicular stimulation was delivered to the mid planta pedis of the left hind limbs through the mesh at the bottom of the cage, with the withdrawal threshold being automatically recorded.…”