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Objective: This study aims to evaluate the adjunctive effect of locally delivered 4% Garcinia mangostana gel with scaling and root planing (SRP) on clinical periodontal parameters and gingival crevicular fluid (GCF) total antioxidant capacity in patients with periodontitis using a randomized split-mouth clinical trial design. Methods: Sixteen subjects diagnosed with generalized Stage III periodontitis were enrolled in a randomized split-mouth clinical trial, and periodontal sites with probing pocket depths (PPDs) of 4–5 mm were selected for analysis. Selected sites received SRP alone (control) or SRP followed by local delivery of 4% G. mangostana gel (test). Plaque index, gingival index, PPD, and clinical attachment level were recorded at baseline and 30 days. GCF total antioxidant capacity was assessed using an enzyme-linked immunosorbent assay. Conventional statistical analysis was performed using paired t tests, followed by structured systems-level interpretation of unaltered clinical and biochemical data using predefined biological domain mapping without data modification or statistical reanalysis. This study protocol was approved by the institutional ethics committee and registered with the Clinical Trials Registry of India (Ref/2022/08/057472). Results: Both groups demonstrated significant intragroup improvement in all clinical parameters. Intergroup comparison demonstrated a significantly greater increase in GCF total antioxidant capacity in the test group ( P < 0.05). Improvements in plaque index and gingival index were observed in both groups; however, intergroup comparison at 30 days demonstrated significantly higher plaque index values in the test group compared with the control group ( P = 0.0143), indicating no additional benefit of adjunctive G. mangostana gel on plaque control, whereas the gingival index did not differ significantly between groups. Differences in PPD and clinical attachment level were not statistically significant. Biochemical antioxidant modulation appeared to precede short-term structural clinical changes. Conclusion: Adjunctive use of 4% G. mangostana gel with SRP resulted in a significantly greater increase in GCF total antioxidant capacity. Although the gingival index, PPD, and clinical attachment level did not demonstrate statistically significant intergroup differences within the 30-day follow-up period, plaque index values were significantly higher in the test group, indicating no additional benefit of the adjunctive gel on plaque control. Trial reg No: CTRI: Ref/2022/08/057472
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