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Effect of a topical copper indomethacin gel on inflammatory parameters in a rat model of osteoarthritis.

Yassin NZ, El-Shenawy SM, Abdel-Rahman RF, Yakoot M, Hassan M, Helmy S - Drug Des Devel Ther (2015)

Bottom Line: Cu-Indo gel at lower doses was superior to or at least as effective as its parent substance, indomethacin, in most of the studied parameters of inflammation.After 3 months of daily application, there were no notable changes in studied safety parameters with the lowest Cu-Indo dose, but the group treated with the higher dose showed a small but statistically significant increase in serum-unconjugated bilirubin and a slight decrease in hemoglobin levels, red blood cells, and platelet count, with normal indices denoting a slight hemolytic effect at the highest dose.The lowest studied dose was better on both safety and efficacy parameters.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, National Research Center, Cairo, Egypt.

ABSTRACT

Objective: We aimed to investigate the effect of topical application of a Copper indomethacin (Cu-Indo) gel preparation on monosodium iodoacetate (MIA) induced arthritis of the knee joint of rats and to test our hypothesis that copper complex of indomethacin could be a more potent anti-inflammatory agent than its parent compound.

Methods: After induction of osteoarthritis by the intracapsular injection of 50 μL with 40 mg/mL MIA, we compared the anti-inflammatory efficacy and safety of a topical application of 1% indomethacin gel in a dose of 1 g/kg of the gel (equivalent to 10 mg/kg of the active substance) daily for 3 weeks versus three decremental dose levels of Cu-Indo gel: an equivalent dose, half the dose, and 25% of the dose of indomethacin. Anti-inflammatory efficacy was assessed in all treated groups by measurement of serum inflammatory cytokines: interleukin 6, interleukin 8, and tumor necrosis factor alpha; and by the weekly assessment of knee joint swelling. Joint mobility and motor coordination were also assessed once weekly by the accelerating rotarod apparatus; histopathological examination of affected joints was also performed. Safety of topical application of Cu-Indo (0.25, 0.5, and 1 g/kg) for up to 3 months to rats' skin was determined by the estimation of a complete blood count, liver and kidney functions, and histopathologic examination for target tissues.

Results: Cu-Indo gel at lower doses was superior to or at least as effective as its parent substance, indomethacin, in most of the studied parameters of inflammation. The lowest tested dose of Cu-Indo, corresponding to 25% of the parent substance indomethacin, exhibited the highest efficacy in reducing the elevated serum-tested interleukins and in increasing the time of duration on the rotarod test, whereas its effect on reduction of edema and tumor necrosis factor alpha was comparable to that of the others. After 3 months of daily application, there were no notable changes in studied safety parameters with the lowest Cu-Indo dose, but the group treated with the higher dose showed a small but statistically significant increase in serum-unconjugated bilirubin and a slight decrease in hemoglobin levels, red blood cells, and platelet count, with normal indices denoting a slight hemolytic effect at the highest dose.

Conclusion: Cu-Indo gel has potent anti-inflammatory activity against joint inflammation in the MIA-treated rat model of osteoarthritis at doses of 0.25, 0.5, and 1 g/kg. The lowest studied dose was better on both safety and efficacy parameters.

No MeSH data available.


Related in: MedlinePlus

Photomicrograph of a knee joint from a control rat showing the normal structure of this joint. The upper surface of the cartilage is smooth, the chondroblasts (near the upper surface) are small and flattened, and the chondrocytes (below) are rounded, large, and enclosed in lacunae (H&E stain, ×100).Abbreviation: H&E, Haematoxylin & Eosin.
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f1-dddt-9-1491: Photomicrograph of a knee joint from a control rat showing the normal structure of this joint. The upper surface of the cartilage is smooth, the chondroblasts (near the upper surface) are small and flattened, and the chondrocytes (below) are rounded, large, and enclosed in lacunae (H&E stain, ×100).Abbreviation: H&E, Haematoxylin & Eosin.

Mentions: A histopathology study of knee joints (Figures 1–8) revealed widening in the space of the joint in the osteoarthritic group compared with normal, with the presence of fine collagenous fibers and the presence of fibrous tissue on the upper surface of the cartilage. Rats treated with Cu-Indo gel at a dose of 0.25 g/kg showed improvement of the joint structure, but there is a noticeable thinning of the cartilage of the joint, which is more marked on one side than the other. In contrast, the dose (0.5 g/kg) showed widening in the synovial space of the joint denoting edema. Moreover, the cartilage on one side of the joint shows thinning, with reduction of chondroblast layer thickness on both sides of the joint. Treatment with Cu-Indo gel in a dose of 1 g/kg resulted in discontinuity of the upper smooth surface of the cartilage at many places, although the synovial space is of normal width and the thickness of the cartilage is more or less normal.


Effect of a topical copper indomethacin gel on inflammatory parameters in a rat model of osteoarthritis.

Yassin NZ, El-Shenawy SM, Abdel-Rahman RF, Yakoot M, Hassan M, Helmy S - Drug Des Devel Ther (2015)

Photomicrograph of a knee joint from a control rat showing the normal structure of this joint. The upper surface of the cartilage is smooth, the chondroblasts (near the upper surface) are small and flattened, and the chondrocytes (below) are rounded, large, and enclosed in lacunae (H&E stain, ×100).Abbreviation: H&E, Haematoxylin & Eosin.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4362896&req=5

f1-dddt-9-1491: Photomicrograph of a knee joint from a control rat showing the normal structure of this joint. The upper surface of the cartilage is smooth, the chondroblasts (near the upper surface) are small and flattened, and the chondrocytes (below) are rounded, large, and enclosed in lacunae (H&E stain, ×100).Abbreviation: H&E, Haematoxylin & Eosin.
Mentions: A histopathology study of knee joints (Figures 1–8) revealed widening in the space of the joint in the osteoarthritic group compared with normal, with the presence of fine collagenous fibers and the presence of fibrous tissue on the upper surface of the cartilage. Rats treated with Cu-Indo gel at a dose of 0.25 g/kg showed improvement of the joint structure, but there is a noticeable thinning of the cartilage of the joint, which is more marked on one side than the other. In contrast, the dose (0.5 g/kg) showed widening in the synovial space of the joint denoting edema. Moreover, the cartilage on one side of the joint shows thinning, with reduction of chondroblast layer thickness on both sides of the joint. Treatment with Cu-Indo gel in a dose of 1 g/kg resulted in discontinuity of the upper smooth surface of the cartilage at many places, although the synovial space is of normal width and the thickness of the cartilage is more or less normal.

Bottom Line: Cu-Indo gel at lower doses was superior to or at least as effective as its parent substance, indomethacin, in most of the studied parameters of inflammation.After 3 months of daily application, there were no notable changes in studied safety parameters with the lowest Cu-Indo dose, but the group treated with the higher dose showed a small but statistically significant increase in serum-unconjugated bilirubin and a slight decrease in hemoglobin levels, red blood cells, and platelet count, with normal indices denoting a slight hemolytic effect at the highest dose.The lowest studied dose was better on both safety and efficacy parameters.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, National Research Center, Cairo, Egypt.

ABSTRACT

Objective: We aimed to investigate the effect of topical application of a Copper indomethacin (Cu-Indo) gel preparation on monosodium iodoacetate (MIA) induced arthritis of the knee joint of rats and to test our hypothesis that copper complex of indomethacin could be a more potent anti-inflammatory agent than its parent compound.

Methods: After induction of osteoarthritis by the intracapsular injection of 50 μL with 40 mg/mL MIA, we compared the anti-inflammatory efficacy and safety of a topical application of 1% indomethacin gel in a dose of 1 g/kg of the gel (equivalent to 10 mg/kg of the active substance) daily for 3 weeks versus three decremental dose levels of Cu-Indo gel: an equivalent dose, half the dose, and 25% of the dose of indomethacin. Anti-inflammatory efficacy was assessed in all treated groups by measurement of serum inflammatory cytokines: interleukin 6, interleukin 8, and tumor necrosis factor alpha; and by the weekly assessment of knee joint swelling. Joint mobility and motor coordination were also assessed once weekly by the accelerating rotarod apparatus; histopathological examination of affected joints was also performed. Safety of topical application of Cu-Indo (0.25, 0.5, and 1 g/kg) for up to 3 months to rats' skin was determined by the estimation of a complete blood count, liver and kidney functions, and histopathologic examination for target tissues.

Results: Cu-Indo gel at lower doses was superior to or at least as effective as its parent substance, indomethacin, in most of the studied parameters of inflammation. The lowest tested dose of Cu-Indo, corresponding to 25% of the parent substance indomethacin, exhibited the highest efficacy in reducing the elevated serum-tested interleukins and in increasing the time of duration on the rotarod test, whereas its effect on reduction of edema and tumor necrosis factor alpha was comparable to that of the others. After 3 months of daily application, there were no notable changes in studied safety parameters with the lowest Cu-Indo dose, but the group treated with the higher dose showed a small but statistically significant increase in serum-unconjugated bilirubin and a slight decrease in hemoglobin levels, red blood cells, and platelet count, with normal indices denoting a slight hemolytic effect at the highest dose.

Conclusion: Cu-Indo gel has potent anti-inflammatory activity against joint inflammation in the MIA-treated rat model of osteoarthritis at doses of 0.25, 0.5, and 1 g/kg. The lowest studied dose was better on both safety and efficacy parameters.

No MeSH data available.


Related in: MedlinePlus