Nitrooxyethylation Reverses the Healing‐Suppressant Effect of Ibuprofen

Abstract

Nonsteroidal antiinflammatory drugs like ibuprofen impede tissue repair by virtue of retarding inflammation. The present study was undertaken to explore if linking of nitrooxyethyl ester to ibuprofen reverses its healing-depressant propensity. Nitrooxyethyl ester of ibuprofen (NOE-Ibu) was synthesized in our laboratory through a well-established synthetic pathway. NOE-Ibu was screened for its influence on collagenation, wound contraction and epithelialization phases of healing, and scar size of healed wound in three wound models, namely, incision, dead space, and excision wounds. Besides, its influence on the oxidative stress (levels of GSH and TBARS) was also determined in 10-day-old granulation tissue. NOE-Ibu was further screened for its antiinflammatory activity in rat paw edema model. NOE-Ibu promoted collagenation (increase in breaking strength, granulation weight, and collagen content), wound contraction and epithelialization phases of healing. NOE-Ibu also showed a significant antioxidant effect in 10-day-old granulation tissue as compared to ibuprofen. Results vindicate that the esterification of ibuprofen with nitrooxyethyl group reverses the healing-suppressant effect of ibuprofen. The compound also showed equipotent antiinflammatory activity as ibuprofen.

Factors That Impair Wound Healing

“…Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to have a depressant effect on wound healing while simultaneously decreasing the granulocytic inflammatory reaction. 27,28 NSAIDs inhibit the production of PGE2, an inflammatory mediating prostaglandin, and can thereby reduce pain. 24 The suppression of PGE2 also occurs with excessive wound scarring and therefore NSAIDs may increase scar formation, especially if they are used during the proliferative phase of healing.…”

“…The negative impact on wound healing results from the tendency of steroids to impede wound contraction and decrease tensile strength. 27 Glucocorticoids are known to have dermal effects that can impact wound healing, including inhibition of fibroblast proliferation and decreased collagen production. To further assess the effects of glucocorticoids on the epidermis, Stojadinovic et al utilized human keratinocytes to determine the effects of dexamethasone on genes that are expressed in skin.…”

“…A study by Feeser et al assessed the effects of androstenediol (AED), an immune-regulating hormone and metabolite of the adrenal steroid DHEA, on steroidinduced immunosuppression. 27 Mice were injected with methyl prednisolone to elicit immunosuppression and given full thickness wounds. Wound contraction rates were measured and the mice that received steroids and AED had accelerated wound closure rates versus the mice that did not receive AED but had steroids.…”

The effect of Ringer's solution within a dressing to elicit pain relief

“…4 However, due to the anti-inflammatory action, they have the potential to inhibit the inflammation required to progress wound healing. 18 Previous theoretical work has suggested ten potential mechanisms for the analgesic effect of a dressing. 19 These mechanisms include aspects common to most wound dressings, such as covering the wound to remove it from sight, which decreases anxiety and acting as a barrier to mechanical stimuli.…”

Design, Synthesis and Study of Nitrogen Monoxide Donors as Potent Hypolipidaemic and Anti-Inflammatory Agents

“…Two more compounds, one representing the NSAIDs group (2) and one from the antioxidant acids set (8), with a p-nitrophenyl moiety, were synthesised for comparison, due to their comparable lipophilic and electron withdrawing character. Compound 1 is reported in the literature [10] as an agent promoting wound healing, without synthetic details or structure characterisation. Compound 5 has been synthesised previously [11] via a different method (nitration of 2-bromoethanol with a 70% HNO3-95% H2SO4 mixture gave nitrooxyethyl bromide, which yielded the final product after condensation with ketoprofen in the presence of Cs2CO3) and was tested for anti-proliferative activity using prostate cancer cells.…”