Adelmidrol Protects Hyaluronic Acid against Oxidative Degradation and Improves the Outcome in Patients with Adhesive Capsulitis of the Shoulder Managed by Physical Therapy. In vitro Evidence and Two Case Reports

Adhesive capsulitis (AC) or frozen shoulder is an inflammatory condition characterized by joint stiffness and pain. Although its pathogenesis is not fully elucidated, inflammation (either acute or low-grade inflammation) is believed to play a crucial role. An increase in reactive oxygen and nitrogen species also occurs in AC. The management of AC is challenging for orthopedic surgeons and physical therapists. Intra-articular hyaluronate injection is a treatment option. Yet, failure is reported and may depend upon oxidative breakdown of hyaluronan. Adelmidrol is a palmitoylethanolamide analogue and azelaic acid derivative exerting antioxidant activity in a number of fibrotic disorders. Here we first report the in vitro ability of Adelmidrol to protect hyaluronan against oxidative degradation and to exert an antioxidant effect against hydrogen peroxide-induced increase in nitrite release and intracellular reactive oxygen species in the macrophage J774A.1 cell line. We then investigated a new intra-articular formulation of high molecular weight (1300-2000 kDa) hyaluronic acid (1%) and Adelmidrol (2%) in two AC patients partially responding to physical therapy. Within a tailored physical therapy approach, three fortnightly intra-articular injections of this formulation allowed for a progressive reduction in pain severity, as well as improved range of motion and daily living activities, with the good outcome being maintained at the six-month follow-up in both patients. Overall, the data show Adelmidrol's protective activity against hyaluronic acid oxidation and provide preliminary information for further studies to investigate the association of Adelmidrol and high molecular weight hyaluronic acid in the management of AC patients.