Effect of Concomitant Hydroxyurea Therapy with Rutin and Gallic Acid: Integration of Pharmacokinetic and Pharmacodynamic Approaches

Abstract

Hydroxyurea (HU) is the first-ever approved drug by USFDA for sickle cell anemia (SCA). However, its treatment is associated with severe side effects like myelosuppression. Current studies are focused on the supplementation therapy for symptomatic management of SCA. In the present study, we aimed to explore rutin's and gallic acid's potential individually, for concomitant therapy with HU using pharmacokinetic and pharmacodynamic approaches since there is no such precedent till date. In vivo pharmacokinetic studies of HU in rats showed that rutin could be safely co-administered with HU, while gallic acid significantly raised the plasma concentration of HU. Both the phytochemicals did not have any marked inhibitory effect on urease but have considerable effects on horseradish peroxidase enzyme. The experimental phytoconstituents displayed a very low propensity to cause in vitro hemolysis. Gallic acid markedly enhanced the HU-induced decrease in lymphocyte proliferation. A substantial improvement by rutin or gallic acid was observed in HU-induced reduction of the main hematological parameters in rats. Combined treatment of HU with rutin and gallic acid reduced serum levels of both IL-6 and IL-17A. Overall, both rutin and gallic acid are found to have promising phytotherapy potential with HU. Further exploration needs to be done on both candidates for use as phytotherapeutics for SCA.

Pharmacokinetic Assessment of Rottlerin from Mallotus philippensis Using a Highly Sensitive Liquid Chromatography–Tandem Mass Spectrometry-Based Bioanalytical Method

“…Blood (∼120 μL) was withdrawn at each time point from the retro-orbital plexus. Then, the sample was centrifuged at 8000 rpm for 10 min to take out 50 μL of plasma and kept at −80 °C until analysis. , On the day of analysis, the plasma samples were thawed, processed, and analyzed as mentioned above for rottlerin.…”

Investigating the Potential Use of Andrographolide as a Coadjuvant in Sickle Cell Anemia Therapy

“… 4 The present study results of HU on key hematological parameters in the rat model are similar to the previously reported observations. 16 − 18 Concomitant treatment of andrographolide (100 mg/kg, oral) in the presence of HU showed significant boosting of the RBC level ( p < 0.01) when compared with the treatment of HU alone. Moreover, it exhibited a substantial improvement by 1.6 and 1.8 fold in HU-mediated reduction in Hb and platelet level, respectively, in comparison to HU alone, but it lacks statistical significance ( Table 1 ).…”

“…Vaso-occlusion causes the release of several inflammatory mediators leading to a pain crisis. 16 It is another major hurdle in SCA that needs to be managed symptomatically. 12 Literature reports describe that HU decreased lymphocyte proliferation and inhibited cytokine production.…”

“…Vaso-occlusion causes the release of several inflammatory mediators leading to a pain crisis . It is another major hurdle in SCA that needs to be managed symptomatically .…”

“…After a gap of 48 h, MTT dye (20 μL of 2.5 mg/mL) was added and incubated again for 4 h. The samples were analyzed at 570 nm by the plate reader. 16 At the end of the study, the cell culture supernatant was taken and analyzed for TNF-α and IFN-γ using ELISA kits (Invitrogen, Waltham, USA).…”