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| ORIGINAL ARTICLES |
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| Year : 2022 | Volume
: 10
| Issue : 3 | Page : 164-175 |
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In-vivo evaluation of chondroprotective activity of Ariflex tablet in comparison with aceclofenac tablet and chondroitin sulfate/glucosamine (CG) in monosodium iodoacetate-induced osteoarthritis in rats
Sanjay U Nipanikar1, Manohar J Patil2, Prasad V Kadam2
1 Ari Healthcare Pvt. Ltd, Office at No. 107, 1st Floor, S. No. 1, World Trade Center, Tower One, Opp. EON SEZ, Kharadi, Pune 411014, Maharashtra, India
2 Marathwada Mitra Mandal’s College of Pharmacy, S. No. 4/17, Sector-34, PCNTDA, Theragoan, Pune 411033, Maharashtra, India
| Date of Submission | 20-Jun-2022 |
| Date of Acceptance | 19-Sep-2022 |
| Date of Web Publication | 30-Sep-2022 |
Correspondence Address:
Sanjay U Nipanikar
Ari Healthcare Pvt. Ltd, Office at No. 107, 1st Floor, S. No. 1, World Trade Center, Tower One, Opp. EON SEZ, Kharadi, Pune 411014, Maharashtra
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/jism.jism_49_22
Background: Degenerative changes in a joint subsequent to alterations in cartilage formation equilibrium lead to development of osteoarthritis (OA). Aims: Chondroprotective activity of Ariflex tablet (a polyherbal formulation) was evaluated in comparison with chondroitin/glucosamine and aceclofenac in monosodium iodoacetate-induced OA in Wistar rat models. Materials and Methods: A total of 42 animals were divided into seven groups, viz., four control groups [negative, positive, standard and vehicle controls] and three test groups [low, medium, and high dosages]. Animals in seven groups were treated with various study drugs for the period of 28 days. In this study period, measurement of body weight and knee joint swelling was done periodically. Gait score was recorded on the last day, and histopathological examination of joints was done after sacrificing the animals. Results: Chondroprotective activity of medium and high dose of Ariflex tablet was comparable to that of aceclofenac and superior to chondroitin + glucosamine combination. In few rats of medium and high dose of Ariflex tablet groups, chondrocyte regeneration and formation of new blood vessels were seen, which indicated possibility of chondrocyte regeneration activity of Ariflex tablet. Conclusion: Ariflex tablet possesses significant chondroprotective activity comparable to aceclofenac and superior to chondroitin and glucosamine combination. There was a possibility of chondrocyte regeneration activity of Ariflex tablet, which can be confirmed by conducting another study with long-term treatment. Keywords: Ariflex tablet, chondroprotective, monosodium iodoacetate, osteoarthritis
How to cite this article:
Nipanikar SU, Patil MJ, Kadam PV. In-vivo evaluation of chondroprotective activity of Ariflex tablet in comparison with aceclofenac tablet and chondroitin sulfate/glucosamine (CG) in monosodium iodoacetate-induced osteoarthritis in rats. J Indian Sys Medicine 2022;10:164-75 |
How to cite this URL:
Nipanikar SU, Patil MJ, Kadam PV. In-vivo evaluation of chondroprotective activity of Ariflex tablet in comparison with aceclofenac tablet and chondroitin sulfate/glucosamine (CG) in monosodium iodoacetate-induced osteoarthritis in rats. J Indian Sys Medicine [serial online] 2022 [cited 2023 Jun 7];10:164-75. Available from: https://www.joinsysmed.com/text.asp?2022/10/3/164/357685 |
| Introduction | |  |
Osteoarthritis (OA) is the most common form of arthritis. It is associated with loss of cartilage, osteophyte formation, and modification of subchondral bones. Chondrocytes and matrix proteins such as collagen and proteoglycans are main components of articular cartilage. The alterations in chondrocyte transplantation and matrix proteins can lead to OA.[1] Apoptosis of cartilage tissues may occur due to excess production of oxidants. In addition, inflammatory cytokines such as IL-1α and IL-1β are responsible for cartilage degradation. Insulin-like growth factor (IGF) is believed to be regulating synthesis and accumulation of extracellular matrix (ECM). Nitric oxide (NO) produced by IL-1 leads to reduction in the synthesis of collagen and aggrecan of ECM, which leads to cartilage destruction.[2] This suggests therapeutic potential of antioxidants in OA treatment.[3]
Current management of OA includes acetaminophen and NSAIDs. These medications provide relief from pain and swelling; however, these are not effective in modifying structural deformity. Antioxidants have the potential to provide effective management of OA by preventing cartilage destruction.[3] However, studies have reported their direct negative effects on the cartilage metabolism when used for long term. This adverse effect in addition to their GI and cardiovascular effects limits their prolonged use in OA management.[1],[4] Few studies reported chondroprotective activities of glucosamine and chondroitin sulfate as a possible disease-modifying activity; however, their inability in preserving the histological architecture of cartilage tissue and inability to provide effective control of symptoms such as pain limit their use in the management of OA.[2],[5]
Therefore, there was an immense need of development of alternative pharmacotherapeutic drug for the effective management of OA that possesses anti-inflammatory as well as chondroprotective activities with overall disease-modifying activity. Anti-inflammatory and analgesic activities of Ariflex tablet were already established through experimental studies. Therefore, the present study was conducted to investigate possible chondroprotective activity of Ariflex tablet in experimental rats.
| Materials and Methods | | |
Study Site
The study was conducted at Marathwada Mitra Mandal’s College of Pharmacy, Theragoan, Pune, Maharashtra, India.
Ethical Consideration and Approval
All laboratory animal handling and experimental procedures were performed in accordance with the CPCSEA guidelines (198/99/CPCSEA) and study protocol approved by the Institutional Animal Ethics Committee of MMM’s College of Pharmacy, Theragoan, Pune, Maharashtra, India (approval number MMCOP/IAEC/001/2016, dated 20/02/2016).
Study Drugs
Drugs including chondroitin + glucosamine (CG) tablet and aceclofenac tablet were purchased from market, whereas Ariflex tablet was supplied by Ari Healthcare Pvt. Ltd. Compositions of Ariflex tablet are mentioned in [Table 1]. Other study material is mentioned in [Table 2]. | Table 1: Composition of Ariflex tablet (each film-coated tablet contains)
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Study Animals
Healthy young Wistar rats (male and female) of 2–3 months age and having weight between 150 and 200 g were procured from the National Institute of Biosciences (NIB) Pune. A total of 42 rats were randomly selected and divided into control and treatment groups. The females were non-pregnant. All the animals were acclimatized in cages for 5 days prior to start of the study and housed at 25 ± 2oC temperature and 45–55% of relative humidity with standard environmental conditions (12 h light and 12 h dark cycle). Food and water were provided ad libitum.
Study Procedure
Wistar rats of either sex were divided into seven study groups with six animals (3 males and 3 females) in each group. The groups were negative control (OA control), positive control [aceclofenac tablet (with a dose of 2.056 mg/kg)], standard control [CG tablet (123.33 + 154.17 mg/kg)], and vehicle control [normal saline (20 mL)], test group I [Ariflex tablet (with a low dose of 111 mg/kg)], test group II [Ariflex tablet (with a medium dose of 222 mg/kg)], and test group III [Ariflex tablet (with a high dose of 444 mg/kg)]. The dose for rats was calculated extrapolating the human therapeutic dose.
Rats were anesthetized with ketamine 50–60 mg/kg intraperitoneally (i.p.). The left knee of rats was shaved, and a 27G 0.5 inch needle was inserted through the patellar tendon into the intra-articular (IA) space. Vehicle control group animals received an IA injection of normal saline (20 mL). Rats from all other groups, viz., test groups I, II, III as well as positive control, standard control, and negative control groups, received a single injection of 3.0 mg monosodium-iodoacetate (MIA) in a total volume of 20 mL saline (six animals/group).
The normal/vehicle control (NC) and osteoarthritis control (OC) groups were given distilled water using oral gavage for 28 days starting from day 1 after MIA injection. Animals from treatment groups received test drugs (Ariflex, aceclofenac, and chondroitin + glucosamine tablets) suspended in distilled water using oral gavage.
On day 28, all animals were weighed; joint swelling and gait score were recorded. Animals were then sacrificed and histopathological examination was carried out.
Animals were weighed weekly and body weights of all animals were recorded. Body weights were also used to calculate the dose of test drugs.
Evaluation of Joint Diameter
Morphology of knee joints of rats was observed at an interval of 4 days up to 28 days. The joint swelling was measured using Vernier Calliper scale. The synovial fluid volume was estimated using the following formula:
where a is the length of the knee joint in mm and b is the width of the knee joint in mm.
Gait Score
At the end of the study, gait score was recorded to observe the changes in the movement of animals and correlated them with arthritis condition.
Gross Pathology and Histopathology of Joints
After above observations, animals were sacrificed by ether anesthesia. Soft tissues were removed from osteoarthritic legs. Patella was removed from each knee to facilitate thorough fixation of the joint. Tissue samples were prepared for light microscopy using standard procedures. The microscopic observations were done for chondrocytes damage area, chondrocytes necrosis, inflammatory cells in synovium, and synovial proliferation.
| Results | | |
Effect of Various Formulations on Body Weight in MIA-induced OA in Rats
In all study groups, the mean body weight of animals was increased suddenly on 3rd day when compared with baseline (day 0) value. This could be because of swelling/edema that occurred due to induction of arthritis with the help of intra-articular injection of MIA.
It was observed from the results that the mean body weight (g) in vehicle control animals was increased insignificantly (P > 0.05) from 176.67 ± 20.656 g at baseline to 193.33 ± 15.055 g at the end of the study.
The mean body weights of animals in test I, test II, and test III groups were decreased insignificantly (P > 0.05) from 179.17 ± 16.857, 186.67 ± 23.381, and 188.33 ± 24.833 g at baseline to 171.67 ± 23.166, 186.67 ± 18.619, and 175.00 ± 22.583 g at the end of the study, respectively.
In the aceclofenac group, the mean body weight of animals was increased insignificantly (P > 0.05) from 187.50 ± 21.389 g at baseline to 196.67 ± 12.111 g.
In the CG group, the mean body weight of animals decreased (insignificantly P > 0.05) from 187.50 ± 30.781 g at baseline to 181.67 ± 19.408 g at the end of the study.
In the negative control group, the mean body weight of animals was increased insignificantly (P > 0.05) from 188.33 ± 28.577 g at baseline visit to 191.67 ± 24.833 g at the end of the study.
Effect on Mean Joint Fluid Volume (mm3) in MIA-induced OA in Rats
Synovial fluid volume (mm3) was calculated on the basis of measurements of knee swelling with 4-day interval up to the end of the study (day 28).
In the vehicle control group, the mean synovial fluid volume (mm3) was increased significantly (P< 0.05) after the injection of normal saline in intra-articular space of the indexed joint than the mean synovial fluid volume of normal joint (without any injection) of same rats in the same group on day 0. After a day (next day), the mean fluid volume of the injected joint was 1205 mm3, which was greater than that of normal joint in same rats (708 mm3). On day 28, a significant (P < 0.05) reduction in mean synovial fluid volume was observed in the indexed joint, which was almost equivalent to the mean fluid volume of the normal joint. The percentage change in the reduction of mean synovial fluid volume in injected or indexed joint from baseline to day 28 was 46.97%.
In the negative control group (OC), the mean synovial fluid volume was found to be 1470 mm3 which was greater than the vehicle control group. After a 28-day period, the mean synovial fluid volume was 1023 mm3, which was significantly higher than that of knee joint of rats from the vehicle control group (639 mm3) on day 28 and normal joint of the same rats (758 mm3). The percentage change in the reduction of mean synovial fluid volume from baseline to 28 days was 30.40%.
At baseline, synovial fluid volume of the OA-induced joints in test groups I, II, and III was found to be significantly greater than that of the vehicle control group and almost equivalent to that of the negative control group. After the treatment with tablet Ariflex low dose, the mean synovial fluid volume reduced from 1656 to 848 mm3 (48.79%). In the test group II, treatment with tablet Ariflex medium dose led to a reduction of the mean synovial fluid volume from 1676 to 880 mm3 (47.49%), whereas in the test group III, treatment with high dose of Ariflex tablet led to a reduction in the mean synovial fluid volume from 1619 to 866 mm3 (46.51%). This reduction in volume was significantly greater when compared with all other treatment groups and negative control (OC) group.
The mean synovial fluid volume in the positive control group treated with aceclofenac was 1165 mm3 on day 1, which reduced to 966 mm3 (17.08%). This reduction in the volume was less than that of Ariflex tablet-treated groups and even negative control group.
In animals of standard control group treated with chondroitin and glucosamine, the mean synovial fluid volume reduced from 1544 to 967 mm3 (37.37%). This reduction was lesser than that of tablet Ariflex-treated groups and vehicle control groups. The details are given in [Table 3]. | Table 3: Changes in mean joint fluid volume (mm3) in MIA-induced OA in rats
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Effect on Gait Score in MIA-induced OA in Rats
The severity of arthritic pain was measured using a modified gait scoring system wherein grades range from 0 to 3, where 0: normal, rat runs and walks normally; 1: mild disability, rat runs and walks with difficulty; 2: rat walks with difficulty due to intermittent loading of the inflamed joint; and 3: rat stands on only three paws, i.e., total joint immobility.[6]
It was observed that in the vehicle control group gait score was lowest, i.e., 0, whereas it was highest in the negative control group, recorded as 1.83. Among the treatment groups, lowest gait score was observed in test III group and highest gait score was observed in the positive control and standard control groups. In all other groups, the gait score was found to be lesser than that of OC group but higher than that of vehicle control group. The details are given in [Table 4].
Effect on Gross Pathology and Histopathology of Joints in MIA-induced OA in Rats
Histopathological examination of knee joints of normal rats (males and females) showed normal articular surfaces with normal histology of chondrocytes. Superficial zone of chondrocytes was intact and subchondral bone was normal. Similar histology was observed in rats of vehicle control group. The details are given in [Figure 1] and [Figure 2], respectively.
Histopathological examination of joints of male rats of negative control group showed that there was a marked-to-severe fragmentation of calcified cartilage and subchondral bone. Roughened articular surfaces, fragmentation of calcified cartilage, and subchondral bone were observed in female rats of the negative control group. The details are given in [Figure 3]. | Figure 3: Staining with H & E (20×)—osteoarthritis control animals (negative control)
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In male rats treated with low dose of Ariflex tablet, articular surfaces of the joints were found to be minimally roughened, whereas hypertrophy and aggregation of chondrocytes were observed. In female rats treated with low dose of Ariflex tablet, articular surfaces were either lost or degraded leading to exposure of subchondral bone. Chondrocytes were not found. The details are given in [Figure 4]. | Figure 4: Staining with H & E (20×)—Ariflex tablet-treated animals-(Test-1 group)
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In the male rats of test II group, thinning or complete loss of articular surface was seen. It was interesting to note that in deeper layers newly formed articular surface was seen with clusters of chondrocytes. Few newly formed blood vessels and ossification were also found in deeper layers. In female rats of the test-II group, slightly rough articular surface, newly formed articular surfaces, newly formed blood vessels, and ossification were seen at deeper layers. It was surprising to see newly formed chondrocytes, which were little hypertrophied. The details are given in [Figure 5]. | Figure 5: Staining with H & E (20×)—Ariflex tablet-treated animals-(Test-2 group)
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One male rate died in the test-III group. In male rats of test-III group treated with high dose of Ariflex tablet, newly formed articular surface was seen which was slightly roughened. Subchondral bone cysts were found. Newly formed blood vessels along with few hypertrophied chondrocytes were observed in deeper layers. In female rats of the same group, articular surface was completely absent. Ossification was noted in the deeper layers. Newly formed articular surface was observed which was slightly roughened. Few hypertrophied chondrocytes were also seen. The details are given in [Figure 6]. | Figure 6: Staining with H & E (20×)—Ariflex tablet-treated animals-(Test-3 group)
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In male rats of the Chondroitin + Glucosamine-treated group, articular surfaces were found to be roughened. Calcified cartilage and subchondral bone were fragmented, and aggregation of chondrocytes was observed. In female rats, articular surface was rough, and articular cartilage was lost leading to exposure of subchondral bone. The details are given in [Figure 7]. | Figure 7: Staining with H & E (20×)—chondroitin and glucosamine-treated animals
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There was mortality of one male and one female animal in the positive control group. Rats in the aceclofenac-treated group showed completely preserved histological structure with almost normal articular surfaces and chondrocytes. Histology of cartilage cells was normal. However, female rats in the same group failed to show this effect. In the female rats, articular surface was degraded with loss of articular cartilage and subchondral bone cysts. The brief is given in [Figure 8]. | Figure 8: Staining with H & E (20×)—aceclofenac-treated animals-(positive control)
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Staining with Alcian blue (20×)
Histopathological examination of the tissues stained with Alcian blue revealed hypertrophy and aggregation of chondrocytes in the Ariflex tablet groups. Newly formed chondrocytes were observed in Ariflex-treated groups. Marked-to-severe fragmentation of calcified cartilage and subchondral bone along with loss of superficial zone of chondrocytes was observed in the negative control group. Rats in the vehicle control group demonstrated normal articular surfaces and chondrocytes histology. Superficial zone of chondrocytes was intact and subchondral bones were normal. The details are given in [Figure 9]. | Figure 9: Histopathological examination of the tissues stained with Alcian blue
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| Discussion | | |
The study is carried out to investigate chondroprotective activity of Ariflex tablet in MIA-induced OA in experimental rats. This chondroprotective activity of Ariflex tablet was evaluated in comparison with conventional drugs aceclofenac and a combination of chondroitin sulfate and glucosamine. Various studies have reported that there is stimulation of glycosaminoglycan (cartilage matrix) synthesis in human osteoarthritic cartilage by aceclofenac.[7] Glucosamine and chondroitin sulfate are also known to impart chondroprotective effect by increasing the accumulation of ECM of cartilage. Therefore, these two drugs were selected as comparators to evaluate chondroprotective activity of tablet Ariflex.[2],[5] OA was induced in left knee joint of rats with intra-articular injection of MIA. No statistically significant change in the weight of rats was observed in any of the seven groups on day 28.
Synovial fluid volume accumulated in joint space can be estimated with the help of measurements of swelling of the joint. On day 28, a significant reduction in synovial fluid volume was observed by 46.97%, 48.79%, 47.49%, and 46.51% in the vehicle control group, Ariflex low, medium, and high dosage groups, respectively. This reduction of synovial fluid volume was comparable to that of the vehicle control group. In the aceclofenac group, the reduction in synovial fluid volume on day 28 was only 17.08%, whereas in the chondroitin + glucosamine group, the reduction in synovial fluid volume on day 28 was 37.37%. These two groups were inferior when compared with Ariflex tablet groups in terms of reduction of synovial fluid volume.[8],[9]
The untreated arthritic rats showed prominent gait impairment as evident by the significant increase in gait score vs. normal control rats. Reduction in gait score was observed in all treated rats. The gait score was less in Ariflex tablet groups when compared with positive control and standard control groups, suggesting better pain management with Ariflex tablet over a period of 28 days.[10],[11]
During histopathological examination in normal rats’ articular surface, chondrocytes and subchondral bone were found to be normal; whereas in MIA-induced arthritic rats, articular cartilage was calcified, severely fragmented, or roughened. In chondroitin/glucosamine-treated rats, articular surface was not preserved. On the contrary, articular cartilage was calcified, fragmented, or completely lost similar to the negative control group. However, few aggregated chondrocytes were observed. aceclofenac-treated group of rats demonstrated excellent chondroprotective activity as evident from the normal cartilage and normal chondrocyte histology in male rats. In female rats, however, degradation and loss of articular cartilage were observed.[12],[13]
In rats treated with medium- and high-dose Ariflex tablet, newly formed articular surfaces, newly formed blood vessels, and hypertrophied chondrocytes were found indicative of probable regeneration of chondrocytes after treatment with Ariflex tablet. The cartilage and subchondral bone in Ariflex-treated groups was neither calcified nor fragmented as in the negative control group. This indicates that tablet Ariflex preserved the articular cartilage exhibiting chondroprotective activity.[14],[15]
Ariflex tablet is useful in the management of OA, RA, gout, low back pain, sciatica, and spondylitis. Few ingredients help to inhibit production of leukotrienes.[16] Most of the ingredients of Ariflex tablet inhibit COX, TNF-alpha enzymes and decrease the expression of inflammatory cascade and proinflammatory cytokines, thereby reducing inflammation.[17],[18],[19] These ingredients also possess antioxidant and immunomodulatory activities.[20],[21] Few ingredients show direct chondroprotective activity in vitro.[20],[21] These ingredients present in Ariflex tablet might have helped in the reduction of inflammation and preservation of articular cartilage probably by inhibiting MMP and gelatinase.
| Conclusion | | |
Ariflex tablet demonstrates chondroprotective activity in the MIA-induced osteoarthritic rats. This chondroprotective activity of Ariflex tablet was comparable to aceclofenac and perhaps superior to combination of chondroitin + glucosamine which was conventionally used as chondroprotective agent. Strong evidence of chondrocyte regeneration in osteoarthritic joints of few rats was observed with treatment of Ariflex tablet, which can be confirmed by conducting clinical study with sufficient sample size and long-term treatment.
Financial Support and Sponsorship
Nil.
Conflicts of interest
All the authors have substantially contributed in the concept, design, literature search, and analysis and interpretation of the study data. All the authors have substantially contributed in preparation, editing, and review of the manuscript. No author of the study has any conflict of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]
[Table 1], [Table 2], [Table 3], [Table 4]
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