The article is published in Ukrainian in the journal.
The English text is given in the author's version.

UDC 615.262.1: 616.721-001.7: 615,454: 547.459.5

RATIONAL THERAPY OF OSTEOARTHRITIS: PROSPECTS OF COMBINED CHONDROPROTECTORS IN TOPICAL DOSAGE FORMS.

N.V.Davishnia, I.A.Zupanets, S.K.Shebeko

NationalUniversity of Pharmacy

Key words: osteoarthritis; rational therapy; chondroprotectors; topical dosage form

One of the most common diseases in the structure of the pathology of the musculoskeletal system is osteoarthritis. The disease takes the fourth place among all diseases in women and the eighth - in men.Due to the significant aging of the population, including the Ukrainian population, issues of diagnosis, prevention and treatment of osteoarthritis has particular relevance. Progression of the disease leads to significant costs in the economic, social and psychological areas that are associated with the prevalence of this disease, the loss of health of patients and the high economic costs, not only in the treatment of the underlying disease, but also prevention and treatment of complications of pharmacotherapy.According to the recommendations of the «European Antirheumatic League» EULAR for osteoarthritis treatment using drugs that affect the pathogenesis of the disease and pain. Therefore, for rational treatment of the disease, international experts advised to use chondroprotectors, nonsteroidal anti-inflammatory drugs, or combinations thereof. The latter can successfully combine the effect on the metabolism of articular cartilage proteoglycan failure to impact on the articular syndrome. That pain is one of the main reasons for the decline in quality of life of patients with osteoarthritis. An important role is played by the proper choice of the dosage form, because patients with this disease require a long, almost continuous use of the drug. The use of combined drugs in topical dosage forms, can have a positive influence on the treatment of the disease, improve the quality of life of patients and partially exclude the possibility of side effects.

INTRODUCTION

Osteoarthritis (OA) - a chronic degenerative joint disease, characterized by progressive destruction of articular cartilage, proliferative reaction of cartilage and bone tissue and is accompanied by reactive synovitis [8, 13]. The disease is one of the most common pathology in the structure of musculoskeletal system: OA prevalence in the population is 14% of the adult population WHO recently published statistical data on healthy aging European population. The most common cause of disability in old age is dementia, followed by factors such as the weakening of hearing and osteoarthritis [16]. In Ukraine, in 2011 the incidence of OA was 227 661 persons (605.6 per 100 thousand of population) and prevalence - 1,290,509 (3432.7) [9]. The development of the disease leads to significant costs in the economic, social and psychological areas that are connected with the widespread of the disease, a common disability of patients and high economic costs, including the underlying disease treatment as well as prevention and treatment of possible complications of pharmacotherapy [19] . Losses associated with diseases of this group have increased in recent years and up to 3% of the gross national income of developed countries such as USA, Canada, UK, France and Australia. [18]

According to modern concepts, osteoarthritis is a multifactorial disease. In the degeneration of articular cartilage involved several factors: chronic cartilage damage, age, obesity, stress on the joints, congenital or acquired defects of the musculoskeletal system, genetic predisposition [8, 12, 13].

But there are two basic - excessive physical activity and reduced resistance of the cartilage to the normal load [12]. Primary OA develops under conditions of healthy cartilage excessive load. When a known cause of the disease - is always secondary OA. [8].

The main pathogenetic mechanism of OA is the basic substance metabolism of articular cartilage that leads to degenerative changes and proteoglycan failure [4, 12]. Proteoglycans - large macromolecule composed of a protein core to which are attached multiple chains of glycosaminoglycans (GAG) and oligosaccharides [21]. Proteoglycans play an important role in maintaining fluid and electrolyte balance, adsorption and reparative functions cartilage [4].

The content of proteoglycans in cartilage reduced due to the loss of GAG [4]. All the above changes occur as a result of deep metabolic cells of cartilage - chondrocytes. With the development of dystrophic and destructive disturbances in the articular cartilage decreases their metabolic activity, increased intensity of catabolic processes, which reduces their density by death [13].

Whatever the reason, distinguish three stages of osteoarthritis [8, 13]. At the first or initial stage osteoarthritis expressed no morphological tissue disorders joint. The changes apply only to the function of the synovial membrane, namely biochemical composition of synovial fluid [8].

The joint loses its ability to withstand normal for a load, overload accompanied by joint inflammation and pain. In the second stage begins destruction of articular cartilage and meniscus. The second stage inevitably becomes the third - stage severe osteoarthritis. Its symptoms - severe bone deformity support area of the joint that changes the axis of the limb. Failure - shortening connection joint mobility leads to abnormal joint or combined with joint stiffness bags - to a drastic reduction in natural movements - contractures [8, 13].

Chronic inflammation and chronic pain usually accompanied by 2 or 3 stage. With the progression of osteoarthritis pain becomes more intense, prolonged, arising in any movements do not disappear at rest and can be confusing even at night. That is the light of the foregoing, for the treatment of osteoarthritis of the necessary preparations that would impact on the pathogenesis of the disease and pain [13].

Therefore, for the treatment of osteoarthritis efficient use chondroprotectors, nonsteroidal anti-inflammatory drugs (NSAIDs) or combinations thereof. As you know NSAIDs not only reduce inflammation in osteoarthritis, but pain to [3].The combined use of NSAIDs and chondroprotectors can cause analgesics potentiation of NSAIDs and minimize their side effects [7].Preparations of chondroprotectors can reduce major clinical manifestations and provide pathogenetic influence on its course, preventing destruction of articular cartilage tissues and promoting their regeneration [13, 18]

According to the recommendations of the «European Antirheumatic League» (EULAR) symptomatic drugs of slow motion (glucosamine (GA), chondroitin sulfate (CS), diatsereyin, compounds of avocado / soybean, hyaluronic acid) are on the list of recommendations for the treatment of patients with knee OA, data based on evidence-based medicine and expert opinion [17, 20, 24].

Analysing the arsenal of chondroprotectors in historical perspective, it should be noted that the preparations of the first generation were presented by cartilage extracts of animal or marine origin7.The second generation drugs are more peeled and presented to low-aminosugars(glucosamine) and macromolecular polysaccharides (chondroitin sulfate, hyaluronic acid)7.

The third generation include combination therapies based on GA and cholesterol, sometimes with extra additives (metilsulfonilmetan, ascorbic acid, etc.)7.These combinations can be used separately or in the complex treatment of osteoarthritis.

Compared with first generation drugs, medications latter two are more accurate composition, proven clinical efficacy, confirmed a beneficial effect on cartilage, which defines high level of validity of their application in OA [11, 13]. Comparative characteristics pharmacodynamic properties of these substances is presented in Table 1 [14, 15, 20].

Table 1

Pharmacodynamic properties of glucosamine hydrochloride and chondroitin sulfate

Pharmacodynamic properties / Glucosamine hydrochloride / Chondroitin sulfate
The anabolic property / the substrate for synthesis of glycosaminoglycans, stimulates the synthesis of proteoglycans / increases RNA content in chondrocytes, inhibits IL-2-dependent inhibition of synthesis of hyaluronic acid stimulates the synthesis of proteoglycans
The anticatabolic properties / inhibits the action of catabolic enzymes (stromelizin, ahhrekanozin, collagenase, A2), activates the adhesion to fibronectin / inhibits leukocytic elastase activity, synthesis and activity of collagenase and ahhrekanase
Anti-inflammatory properties / prevents formation of superoxide radicals, inhibits the activity of lysosomal enzymes, reduces IL-1 in synovial fluid / inhibits IL-1 stimulated prostaglandin synthesis

Today, along with the regular use of drugs in the treatment of articular syndrome in osteoarthritis focuses on local therapy, including the use of ointments, gels and creams [1, 3, 6]. Since all topical dosage forms have certain advantages in the application, namely:

- The relative ease and safety of use;

- The use of both local and resorptive action;

- Slightly pronounced systemic effects;

- High concentration of active substances in the site of application;

- The possibility of prolonged action;

- In the one form may contain different active ingredients.

According to the scientific literature the smaller molecular weight substances so it is better passes through the transdermal barrier [23].So low chondroprotectors will better penetrate the tissues of the joint than substances with high molecular weight. Most of the topical dosage forms part chondroprotective effect of chondroitin sulfate [3, 6, 21]. This chondroprotectors characterized by high molar mass (20 - 30 kDa) [9], which makes it a low ability to penetrate tissues under conditions transdermal administration. Obviously, compared to chondroitin sulfate low chondroprotectors such as glucosamine (molar mass 179.17 Da) [10]and its derivatives have certain advantages. First of all it is a greater ability to penetrate into the cartilage matrix and contribute to GAG synthesis in chondrocytes a highly sulfated GAG that underlies chondroprotective action.

In the pharmaceutical market of Ukraine are dozens of items of local drugs, which can be usedfor the treatment of osteoarthritis, but most of them are mono-drugs and affect only the specific symptom of the disease. A large number of topical medicines containing NSAIDs and locally irritant components. As for the preparations with chondroprotective action, their number is not so large, most of them part mono preparations containing chondroitin sulfate (Table 2) [5].

Table 2

The chondroprotective drugs in the local pharmaceutical form which are registered in Ukraine

Назва / Форма / Склад / Виробник
CHONDROYITYN OINTMENT / Ointment 5% to 25 grams in tubes number 1 in packs / 1 g ointment contains sodium chondroyityn sulfat (in recalculation on dry basis) 50 mg; / LLC "DCT" Pharmaceutical Factory ", Ukraine
CHONDROITIN-FITOFARM / 5% gel 25 g or 40 g tubes number 1 / 1 g of gel containing sodium chondroitin sulfate (in recalculation on 100% dry basis) 50 mg / PJSC "Fitofarm", m. Artemivsk, Donetsk region., Ukraine
CHONDROXID®
/ Ointment 5% to 30 grams in tubes number №1
Gel 5% to 30 grams in tubes №1 / 1 g ointment contains 50 mg of chondroitin sulfate / JSC "Nizhpharm" m. Nizhny Novgorod, Russian Federation
HONDRA-SYLA® / Ointment 5% to 30 grams in tubes number №1 / 100 g of ointment containing chondroitin sulfate 5 g Sodium in recalculation on 100% substance / JSC "Farmak", m.Kyiv, Ukraine
HONDROFLEX / Ointment, 50 mg /g and 30 g tubes number one in the pack / 1 g ointment contains 50 mg of chondroitin sulfate / LLC "Ternopharm"
m. Ternopil, Ukraine

Consequently the presented above table shows that the development and application of new combined chondroprotective drugs is reasonable, because the treatment of osteoarthritis requires new forms suitable for topical use the pharmaceutical market of Ukrainehas almost no similar drugs for use.

CONCLUSIONS

1. For the rational therapy of osteoarthritis is recommended to use drugs that can affect the metabolism of articular cartilage and pain.

2. The combination of chondroprotectors and NSAIDs may positively influence the course of the disease and improve quality of life for patients.

3. Treatment of osteoarthritis, especially in the 2nd and 3rd stages is almost constant and ongoing process that requires convenient dosage forms, both for monotherapy and for complex applications, these are topical dosage forms. In view of the foregoing information use of combined drugs in topical dosage form is appropriate and reasonable.

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About the Authors:

Natalia Davishnіa - PhD student of the Department of Clinical Pharmacology and Clinical Pharmacy

Igor Albertovich Zupanets - MD, Professor, Head of the Department of Clinical Pharmacology and Clinical Pharmacy.

Sergey Kostyantynovich Shebeko - Candidate of Pharmaceutical Sciences (PhD), Associate Professorof the Department of Clinical Pharmacology and Clinical Pharmacy