Curcumin Decreases Cytokine Levels Involved in Mucositis in Autologous Transplant Setting: A Pharmacokinetic-Pharmacodynamic Study.
Authors: Khattry Navin , Gawande Jayant , Patil Pravin , Bagal Bhausaheb , Kannan Sadhna , Chiplunkar Shubha , Gota Vikram 
Published: October 2019

Abstract
Abstract 3039

Background:
Mucositis is an inevitable side effect of intensive chemotherapy used for hematopoietic stem cell transplantation. The incidence of WHO grade 1–4 oral mucositis (OM) has been reported in up to 90%. Proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-17, TNF-α, TGF-B, IFN-γ and PG E2 play a central role in its pathogenesis. Evidence suggests that curcumin inhibits inflammatory cytokines through inhibition of Nuclear Factor Kappa- β. There are no studies exploring the role of curcumin in mucositis in patients undergoing high dose chemotherapy. We studied the pharmacokinetics and pharmacodynamics of curcumin in the above setting and evaluated the effect of curcumin on mucositis after high dose chemotherapy and autologous transplant.

Methods:
This was a prospective, single centre, pilot pharmacokinetic and pharmacodynamic study evaluating the role of curcumin on the biomarkers of inflammation, oral mucositis and diarrhea. All patients in both groups had multiple myeloma and received melphalan 200 mg/m2. The study was done in 2 phases: a run - in phase (control group) to measure the level of cytokines in 10 patients without use of oral curcumin followed by treatment-phase where next 10 patients received curcumin lozenges.
Patients in the run-in phase had blood and salivary samples taken for the measurement of TNF- α, IL-1, IL-6, IL-8, IL-17, TGF-B, INF-γ and PGE2 1 hour before starting melphalan, on day0, then thrice weekly (Monday, Wednesday, Friday) till day+14 and then on day+28 post transplant.
Patients in the treatment-phase received chewable curcumin lozenges 4 gm (equivalent to 400 mg of curcumin; Pharmanza Herbals Pvt. Ltd., India) twice daily from 2 days prior to the start of melphalan till day+28. Blood samples for pharmacokinetic studies related to curcumin were done 1 hour prior to the first dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 (± 15 min) hours post first dose and then weekly (before the morning dose) till day+28. Blood and saliva sample for the above cytokines were done 1 hour prior to the first dose of curcumin and then at same time points as in run-in phase. Plasma levels of curcumin and its glucuronide conjugate were measured by High Performance Liquid Chromatography (HPLC). Cytokines were measured by enzyme-linked immunoassay (ELISA). Area Under the concentration-time Curve (AUC) for curcumin and its conjugate (AUC0–12) and cytokines (AUCDay4–13) was determined by linear trapezoid rule. The duration and grade of oral mucositis and diarrhea as per WHO and CTCAE v 3.0 grading criteria respectively were recorded and compared in the two group by Fisher-exact test. Median AUC and the median levels of serum and salivary cytokines at different time points were compared by Mann- Whitney test.

Results:
Nineteen patients were evaluable (control group-10, curcumin group-9).There was no difference in baseline demographic characteristics. Six (60%) patients in control group had grade 3 or 4 OM while 3 (33%) in curcumin group with median duration of 5.5 days vs 3 days respectively (P=NS). Seven (70%) patients in control group had grade 3 or 4 diarrhea compared to 3 (33%) in curcumin group with median duration of 2 vs 8 days respectively (P=NS). There was no difference in baseline serum and salivary levels of above cytokines between the groups. Significant difference was observed in IL-6, IL-8, IL-17, TGF-β, and PGE2 levels at various time points and/or their AUC Day 4–13between curcumin and control groups which are summarized below.
The median AUC0–12 of curcumin and its glucuronide conjugate was 1.92 ng/ml*hr (Range: 0 – 72.99) and 101.24ng/ml*hr (Range: 22.31 – 302.34) respectively. Curcumin AUC0–12 showed a strong negative correlation (ρ = -0.655, P=0.05) with duration of OM.

Conclusion:
Curcumin significantly altered the serum and salivary profiles of some cytokines involved in mucositis. Higher exposure to curcumin was found to reduce the duration of severe mucositis. A larger phase 2 study is warranted to confirm these findings.

Disclosures:
No relevant conflicts of interest to declare.