Synthesis and cytotoxic activity of new 7-acetoxy-12-amino-14-deoxy andrographolide analogues.

Two new series of 19-silylether- and 19-formyl-7-acetyl-12-amino-14-deoxyandrographolide analogues were designed and synthesized from natural andrographolide via key step reactions including allylic hydroxylation, tandem CAE reaction and one pot formylation. Evaluation of their cytotoxicity against eight cancer cells line found 6e exhibited the highest activity on MCF-7 cancer cell (IC50 2.93) and comparable to the drug elipticin. Replacement of silylether at C-19 with formyl group exhibited selective activity on P-388 cell line. Computational studies revealed the amino group at C-12 and O-acetoxy at C-7 position play significant roles in cytotoxicity against MCF-7 cancer cells. Cytotoxicity of these two series highlights the importance of 12-substituted-14-deoxyandrographolide scaffold and these types of compounds could be employed in future developments against breast cancer.

Synthesis of 14-deoxy-11,12-didehydroandrographolide analogues as potential cytotoxic agents for cholangiocarcinoma.

A series of 14-deoxy-11,12-didehydroandrographolide analogues were synthesized from naturally occurring andrographolide and their cytotoxicity evaluated against nine cancer cell lines including cholangiocarcinoma. Analogues 5a and 5b exhibited the most potent cytotoxicity with ED50s of 3.37 and 3.08 µM on KKU-M213 cell lines and 2.93 and 3.27 µM on KKU-100 cell lines, respectively. Selective cytotoxicity on cholangiocarcinoma cell lines identified in this study highlight the importance of structural modification in the development of drugs for this cancer.

Pharmacokinetic and Pharmacodynamic Interaction of Andrographolide and Standardized Extract of Andrographis paniculata (Nees) with Nabumetone in Wistar Rats.

The aim of the study was to investigate the herb-drug interaction of Andrographis paniculata Nees (Acanthaceae) and Andrographolide (AN) with nabumetone (NAB) in wistar rats. Pharmacokinetic and pharmacodynamic interactions were studied after co-administration of APE and AN with NAB in Wistar rats. In pharmacokinetic studies, significant decrease in Cmax, AUC0-t and AUC0-∞ of 6-MNA after co-administration with pure AN and APE has been observed. Tmax of 6-MNA has been increased to 2 h from 1.5 h in AN + NAB treated group. Changes in mean residential time, clearance and volume of distribution of 6-MNA in APE + NAB treated group and AN + NAB treated group indicated interference of other components of APE other than AN. In pharmacodynamic study, significant decrease in antiarthritic activity of NAB on concomitant administration with APE and AN has been observed. The study concludes that NAB exhibits pharmacokinetic and pharmacodynamic interactions with APE and AN in rats thus alarms the concomitant use of herbal preparations containing APE and AN with NAB. Further study is needed to understand the mechanism and predict the herb-drug interaction in humans. Copyright © 2016 John Wiley & Sons, Ltd.

Effect of Andrographis paniculata extract and Andrographolide on the pharmacokinetics of Aceclofenac and Celecoxib in rats.

Background: In India, for the treatment of cold, fever and inflammation, people consume herbal remedies containing Andrographis paniculata Nees (APE) as main ingredient, along with NSAIDs. So the purpose of this study is to investigate the effect of APE and pure andrographolide (AN) on the pharmacokinetic of with aceclofenac (ACF) and celecoxib (CXB) after oral co-administration in wistar rats. After co-administration of APE (equivalent to 20 mg/kg of AN) and AN (20 mg/kg) with ACF (5 mg/kg) and CXB (5 mg/kg) in rats, orally, drug concentrations in plasma were determined using HPLC method. Non-compartment model was used to calculate pharmacokinetic parameters like Cmax, Tmax, t1/2, MRT, Vd, CL, and AUC. Results: Co-administration of ACF and CXB with APE and pure AN altered the systemic exposure level of each compound in vivo. The Cmax, Tmax, MRT of CXB were increased whereas Vd and Cl of CXB were decreased significantly after co-administration of CXB with APE. Whereas co-administration of CXB with AN significantly decreased Vd, CL, and MRT of CXB. The concentration of ACF was increased significantly in co-administered groups with pure AN and APE. The AUC0-∞, AUMC0-∞, MRT, Vd and t1/2 of ACF were also significantly decreased in co-administered groups, hence CL of ACF was increased significantly. Conclusion: This study concludes that APE and pure AN have effect on pharmacokinetic of CXB and ACF in rat. Not only patients but medical practitioners using Andrographis paniculata should have awareness regarding probable herb-drug interactions with ACF and CXB.

Herb-drug interaction of Andrographis paniculata (Nees) extract and andrographolide on pharmacokinetic and pharmacodynamic of naproxen in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Andrographis paniculata Nees (Acanthacae) have broad range of pharmacological effects such as hepatoprotective, antifertility, antimalarial, antidiabetic, suppression of various cancer cells and anti-inflammatory properties and is widely used medicinal plant in the traditional Unani and Ayurvedic medicinal systems. Andrographolide (AN) is one of the active constituent of the A. paniculata Nees extract (APE). They have been found in many traditional herbal formulations in India and proven to be effective as anti-inflammatory drug. AIM OF THE STUDY: To evaluate the pharmacokinetic and pharmacodynamic (anti arthritic) herb-drug interactions of A. paniculata Nees extract (APE) and pure andrographolide (AN) with naproxen (NP) after oral co-administration in wistar rats. MATERIALS AND METHODS: After oral co-administration of APE (200mg/Kg) and AN (60mg/kg) with NP (7.5mg/kg) in rats, drug concentrations in plasma were determined using HPLC method. The main pharmacokinetic parameters of Cmax, tmax, t1/2, MRT, Vd, CL, and AUC were calculated by non-compartment model. Change in paw volume, mechanical nociceptive threshold, mechanical hyperalgesia, histopathology and hematological parameters were evaluated to study antiarthritic activity. RESULTS: Co-administration of NP with APE and pure AN decreased systemic exposure level of NP in vivo. The Cmax, tmax, AUC0-t of NP was decreased. In pharmacodynamic study, NP (10mg/kg) alone and NP+AN (10+60mg/kg) groups exhibited significant synergistic anti-arthritic activity as compared to groups NP+APE, APE and AN alone. CONCLUSION: The results obtained from this study suggested that NP, APE and pure AN existed pharmacokinetic herb-drug interactions in rat which is correlated with anti-arthritic study. The knowledge regarding possible herb-drug interaction of NP might be helpful for physicians as well as patients using AP. So further studies should be done to understand the effect of other herbal ingredients of APE on NP as well as to predict the herb-drug interaction in humans.

Hepatoprotective effect of poly herbal formulation against various hepatotoxic agents in rats.

BACKGROUND: Individually Andrographis paniculata Nees. (Acanthaceae), Phyllanthus niruri Linn.(Euphorbiaceae) and Phyllanthus emblica Linn. single plant extracts have been reported to have hepatoprotective activity. However, literature survey shows that no sufficient scientific data has been publish on pharmacological evaluation of these plants in combined form. METHOD: Hepatoprotective activity of the polyherbal hepatoprotaective formulation (PHF)-containing spray-dried aqueous extracts of Andrographis paniculata Nees. (Acanthaceae), Phyllanthus niruri Linn. (Euphorbiaceae) and Phyllanthus emblica Linn. (Euphorbiaceae), was screened against paracetamol, carbon tetrachloride (CCl(4)), and ethanol-induced hepatic damage in rats. PHF was evaluated by measuring levels of serum marker enzymes like SGOT, SGPT, ALP, direct bilirubin (DB), and lactate dehydrogenase (LDH). The histological studies were also studied support the biochemical parameters. Silymarin was used as standard drug. RESULTS: Administration of PHF (100 and 200 mg/kg p.o.) significantly inhibited paracetamol, CCl(4) and ethanol-induced elevation levels of SGPT, SGOT, ALP, DB and LDH. A comparative histopathological study of liver exhibited almost normal architecture as compared to toxicant group. CONCLUSION: Results suggests that the hepatoprotective effects of PHF might be useful for liver protection due to combined action of all plant extracts along with their phytoconstituents.