Analysis of the therapeutic benefits of symptomatic slow acting drugs in osteoarthritis: emphasis on structural-modifying action

The review presents an analysis of the therapeutic effect in osteoarthritis (OA) of the original complex injectable drug Alflutop (bioactive concentrate of small marine fish), which is one of the most widely used symptomatic slow acting drugs (SYSADOA) in Russia. It stimulates the proliferation of chondrocytes, activates the synthesis of the extracellular matrix by modulating transforming growth factor β (TGFβ), inhibits hyaluronidase, oxidative stress and the activity of extracellular expression of proinflammatory cytokine genes – interleukin (IL) 1β, IL6 and IL8 in vitro.

The results of prospective clinical studies are presented, which demonstrate the ability of Alflutop to slow down the X-ray progression of OA of the knee joints (inhibit the narrowing of the joint space, the growth of osteophytes and increase the intra-articular concentration of hyaluronic acid), as well as restore the mobility of the hip joints when it is locally introduced into the zone of pathological changes in the articular lip of the acetabulum. Combined therapy with Alflutop leads to activation of reparative processes and significant clinical improvement in patients with post-traumatic OA, and also slows down the progression of chondrodegeneration according to magnetic resonance imaging. The new Alflutop administration regimen for knee OA (2 ml every other day, №10) can increase patient adherence to therapy.

The results of clinical studies presented in the review prove the structural-modifying effect of Alflutop in OA of various localization and substantiate its widespread use in this disease in rheumatological, traumatological and orthopedic practice.

1. Lila AM, Trofimova AS, Trofimov EA. Osteoartrit [Osteoarthritis]. Saint-Petersburg: Izdatel’stvo SZGMU; 2017. 48 p.]

2. Mazurov VI, editor. Klinicheskaya revmatologiya. Rukovodstvo dlya vrachei. 3-e izdanie [Clinical rheumatology. A guide for doctors. 3rd edition]. Moscow: E-noto; 2021. 696 p.

3. Wallace IJ, Worthington S, Felson DT, et al. Knee osteoarthritis has doubled in prevalence since the mid-20th century. Proc Natl Acad Sci U S A. 2017 Aug 29;114(35): 9332-6. doi: 10.1073/pnas.1703856114.

4. Reyes C, Leyland KM, Peat G, et al. Association Between Overweight and Obesity and Risk of Clinically Diagnosed Knee, Hip, and Hand Osteoarthritis: A Population-Based Cohort Study. Arthritis Rheumatol. 2016 Aug;68(8):1869-75. doi: 10.1002/art.39707.

5. Misra D, Fielding RA, Felson DT, et al. Risk of Knee Osteoarthritis With Obesity, Sarcopenic Obesity, and Sarcopenia. Arthritis Rheumatol. 2019 Feb;71(2):232-7. doi: 10.1002/art.40692.

6. Poulsen E, Goncalves GH, Bricca A, et al. Knee osteoarthritis risk is increased 4-6 fold after knee injury – a systematic review and meta-analysis. Br J Sports Med. 2019 Dec; 53(23):1454-63. doi: 10.1136/bjsports-2018-100022.

7. Berenbaum F, Wallace IJ, Lieberman DE, Felson DT. Modern-day environmental factors in the pathogenesis of osteoarthritis. Nat Rev Rheumatol. 2018 Nov;14(11):674-81. doi: 10.1038/s41584-018-0073-x.

8. Sharma L. Osteoarthritis of the Knee. N Engl J Med. 2021 Jan 7;384(1):51-9. doi: 10.1056/NEJMcp1903768.

9. Molnar V, Matisic V, Kodvanj I, et al. Cytokines and Chemokines Involved in Osteoarthritis Pathogenesis. Int J Mol Sci. 2021 Aug 26;22(17):9208. doi: 10.3390/ijms22179208.

10. Jenei-Lanzl Z, Meurer A, Zaucke F. Interleukin-1β signaling in osteoarthritis – chondrocytes in focus. Cell Signal. 2019 Jan; 53:212-23. doi: 10.1016/j.cellsig.2018.10.005.

11. Olyunin YA, Nikishina NY. Osteoarthritis: key links of pathogenesis and modern means of pathogenetic therapy. Sovremennaya revmatologia = Modern Rheumatology Journal. 2017;11(3):121-8. (In Russ.) doi: 10/14412/1996-7012-2017-3-121-128

12. Grä ssel S, Muschter D. Peripheral Nerve Fibers and Their Neurotransmitters in Osteoarthritis Pathology. Int J Mol Sci. 2017 Apr 28;18(5):931. doi: 10.3390/ijms18050931.

13. Lila A.M., Denisov L.N., Zotkin E.G., et al. Pharmacological management of osteoarthritis with a focus on symptomatic slow-acting drugs recommendations from leading russian experts. J Clin Rheumatol. 2020 Jul 24. doi: 10.1097/RHU.0000000000001507. Online ahead of print.

14. Trofimov EA, Mazurov VI, Melnikov ES, et al. Medical and non-drug treatment of osteoarthritis of the hip joint during pregnancy. Vestnik Severo-Zapadnogo Gosudarstvennogo Meditsinskogo Universiteta im. I.I. Mechnikova. 2019;11(1):13-20. (In Russ.).

15. Mazurov VI, Trofimov EA, Trofimova AS. The effect of various combined drug treatments on clinical manifestations of gonarthrosis and indicators of T-2 mapping of cartilage. Doctor.ru. 2017;(10):53-6. (In Russ.).

16. McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage. 2014 Mar;22(3):363-88. doi: 10.1016/j.joca.2014.01.003. Epub 2014 Jan 24.

17. Mazurov VI, Lesnyak OM. Revmatologiya. Farmakoterapiya bez oshibok [Rheumatology. Pharmacotherapy without errors]. Moscow: E-noto; 2017. 528 p.

18. Denisov LN, Tsvetkova ES, Golubev GSh, et al. The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) algorithm for the management of knee osteoarthritis is applicable to Russian clinical practice: A consensus statement of leading Russian and ESCEO osteoarthritis experts. Nauchno-prakticheskaya revmatologiya. 2016;(6):641-53. (In Russ.).

19. Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/ Arthritis Foundation guidline for the management of osteoarthritis of the hand, hip, and knee. Arthritis Rheumatol. 2020;72(2):220-33. doi:10.1002/art.41142

20. Bruyere O, Honvo G, Veronese N, et al. An updated algorithm recommendation for the management of knee osteoar- thritis from the European Society for Clinical and Economic aspecrs of Osteoporosis, Osteoarthritis and Musculoskeletal diseases (ESCEO). Semin Arthritis Rheum. 2019 Dec; 49(3):337-50. doi: 10.1016/j.semarthrit.2019.04.008. Epub 2019 Apr 30.

21. Zhang W, Robertson WB, Zhao J, et al. Emerging Trend in the Pharmacotherapy of Osteoarthritis. Front Endocrinol (Lausanne). 2019 Jul 2;10:431. doi: 10.3389/fendo.2019.00431. eCollection 2019

22. Lila AM, Alekseeva LI, Taskina EA. Modern approaches to the treatment of osteoarthritis based on the updated international recommendations. Russkii meditsinskii zhurnal. 2019;(11):48-52. (In Russ.).

23. Bruyere O, Cooper C, Al-Daghri NM, et al. Inappropriate claims from non-equivalent medications in osteoarthritis: a position paper endorsed by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO). Aging Clin Exp Res. 2018 Feb;30(2):111-7. doi: 10.1007/s40520-017-0861-1. Epub 2017 Nov 24

24. Ibargoyen-Roteta N, Mateos Del Pino M, Gutierrez-Ibarluzea I, et al. Variability in the prescription of drugs with uncertain effectiveness. The case of SYSADOA in the Basque Country. GMS Health Technol Assess. 2018 Nov 5;14:Doc01. doi: 10.3205/hta000130. eCollection 2018

25. Belyaeva IB, Mazurov VI, Trofimov EA. Application of bioactive concentrate of small marine fish (Alflutop preparation): 25 years in Russia – research and practical conclusions. Effektivnaya farmakoterapia. 2021;17(7):6-12. (In Russ.).

26. Belyaeva IB, Mazurov VI. Modern possibilities of pathogenetic therapy of osteoarthritis at the molecular-cellular level. Russky meditsinsky zhurnal. Meditsinskoye obozrenie. 2017;1(1):26-30. (In Russ.).

27. Karateev AE. Bioactive concentrate from small sea fish: evaluation of the efficacy and safety of the drug on the basis of theanalysis of 37 clinical trials. Sovremennaya Revmatologiya = Modern Rheumatology Journal. 2020;14(4):111-24. (In Russ.). doi: 10.14412/1996-7012-2020-4-111-124.

28. Groppa L, Mynzatu I, Karasava M, et al. Effectiveness of Alflutop in patients with osteoarthritis. Klinicheskaya revmatologiya. 1995;(3):26-9. (In Russ.).

29. Olariu L, Dumitriu B, Ene DM, et al. Alflutop modulates «in vitro» relevant mechanism of osteoarthritic pathology. Ann Series Biol Scientist. 2017;6(1):82-99.

30. Alekseeva LI, Sharapova EP, Taskina EA, et al. A multicenter, blind, randomized, placebo-controlled study of the symptom-and structure-modifying effects of Alflutop in patients with knee osteoarthritis. Message 1. Symptom-modifying effect of the drug. Nauchno-prakticheskaya revmatologiya. 2013;51(5):532-8. (In Russ.).

31. Alekseeva LI, Sharapova EP, Taskina EA, et al. A multicenter, blind, randomized, placebo-controlled study of the symptom-and structure-modifying effects of Alflutop in patients with knee osteoarthritis. Message 2. Evaluation of the structural-modifying effect of the drug. Nauchno-prakticheskaya revmatologiya. 2014;52(2):174-7. (In Russ.).

32. Alekseeva LI, Taskina EA, Lila AM, et al. A multicenter, prospective, randomized trial of the efficacy and safety of Alflutop® in an alternating dosing regimen versus the standard one. Communication 1: Evaluation of the efficacy of the drug in different treatment regimens. Sovremennaya revmatologiya = Modern Rheumatology Journal. 2019;13(3): 51-9. (In Russ.). doi: 10.14412/1996-7012-2019-3-51-59

33. Svetlova MS. Radiological progression of osteoarthritis of the knee joints against the background of long-term treatment with Alflutop (5-year follow-up). Meditsinsky sovet. 2017:(1S):108-12. (In Russ.).

34. Sazonova NV, Maltseva LV, Luneva SN, et al. Experience of local targeted administration of chondroprotective drugs in the area of pathological changes of the articular lip of the acetabulum in coxarthrosis. Lechashiy vrach. 2021;(1):34-6. (In Russ.).

35. Trofimov EA, Mazurov VI, Melnikov ES. Combined drug therapy of posttraumatic gonarthrosis. Terapia. 2019;(6):44-9. (In Russ.).

36. Trofimov EA, Mazurov VI. Combined drug therapy of posttraumatic gonarthrosis: data from a three-year prospective study. Terapia. 2021;(4):155-61. (In Russ.).

37. Trofimova AS, Trofimov EA, Kakheli MA. Radiation diagnosis of osteoarthritis. Luchevaya diagnostika i terapia. 2016;(3):25-32. (In Russ.).

38. Mazurov VI, Trofimova AS. Using the color mapping of cartilage to assess the effectiveness of osteoarthritis treatment. Vestnik Novgorodskogo Gosudarstvennogo Universiteta. 2016;(6):44-8. (In Russ.).