Population pharmacokinetic analysis to identify the possibility of interaction between anti-cancer agents.

BACKGROUND: A number of molecularly targeted agents in oncology are tested in clinical studies in combination with conventional chemotherapy and/or radiotherapy. There is the possibility that the pharmacokinetics and dynamics of these targeted agents may be different when administered alone as against when administered in combination with other agents. AIM: The aim of this study is to understand the effects of addition of combination agents on the pharmacokinetics of a new, investigational, cyclin dependent kinase inhibitor anti-cancer drug (Compound A) using population pharmacokinetic (pop-PK) analysis. MATERIALS AND METHODS: Integrated pop-PK analysis of data obtained from multiple phase I/II studies of Compound A, given alone or in combination with other agents. RESULTS: A two compartmental model was found suitable to explain the pharmacokinetics of Compound A. No statistically significant influence of patient covariates or combination agents on the pharmacokinetic parameters of the central compartment was detected up to a significance level of 0.01. Model evaluation showed that the parameter estimates are stable and that the variability in the data was well reproduced by the model. CONCLUSIONS: This study represents the first time that a pop-PK analysis was performed in India for a targeted anti-cancer agent being developed in India. Such an analysis is useful to not only understand the influence of patient covariates and combination agents on the pharmacokinetics of a new investigational agent, but would also be valuable in the simulation of later phase clinical trials for the agent under development.

Evaluation of sesquiterpene lactone fraction of Saussurea lappa on transudative, exudative and proliferative phases of inflammation.

The sesquiterpene lactone fraction of Saussurea lappa roots was evaluated for its effect on the transudative, exudative and proliferative phases of inflammation using the cotton pellet granuloma assay in rats. The fraction (25-100 mg/kg, p.o.) showed significant dose-dependent inhibition of the increase in wet weight of the cotton pellet at 3 h (transudative phase), leakage of dye from the bloodstream around granuloma at 24 h (exudative phase) and increase in dry weight of the cotton pellet on day 6 (proliferative phase). It significantly lowered the elevated biochemical parameters such as alkaline phosphatase, acid phosphatase, gamma-glutamyltranspeptidase and significantly elevated the lowered albumin concentration in serum. The studies suggest that the antiinflammatory activity of the sesquiterpene lactone fraction of S. lappa may, in part, be due to stabilization of lysosomal membranes and an antiproliferative effect.

Studies on the immunomodulatory activity of flavonoidal fraction of Tephrosia purpurea.

The flavonoid fraction of Tephrosia purpurea (FFTP) was studied for its effect on cellular and humoral functions and on macrophage phagocytosis in mice. Oral administration of FFTP (10-40 mg/kg) significantly inhibited sheep red blood cells (SRBC)-induced delayed-type hypersensitivity reactions. It also produced a significant, dose-related decrease in sheep erythrocyte-specific haemagglutination antibody titre. However, the fraction failed to show a significant change in the macrophage phagocytic activity. The results obtained indicate the ability of the flavonoidal fraction of T. purpurea to modulate both the cell-mediated and the humoral components of the immune system.

Investigations into the immunomodulatory activity of Argyreia speciosa.

The objective of the present study was to investigate the immunomodulatory activity of Argyreia speciosa on cellular and humoral immunity. Oral administration of the ethanolic extract of A. speciosa root (ASEE), at the doses of 50, 100 and 200 mg/kg in mice, dose-dependently potentiated the delayed-type hypersensitivity reaction induced both by sheep red blood cells (SRBC) and oxazolone. It significantly enhanced the production of circulating antibody titre in mice in response to SRBC. ASEE failed to show any effect on macrophage phagocytosis. Chronic administration of ASEE significantly ameliorated the total white blood cell count and also restored the myelosuppressive effects induced by cyclophosphamide. The present investigation reveals that ASEE possesses immunomodulatory activity.

Preliminary evaluation of anti-inflammatory and anti-arthritic activity of S. lappa, A. speciosa and A. aspera.

Saussurea lappa, Argyreia speciosa and Achyranthes aspera are well known Indian medicinal plants used in the indigenous systems of medicine for the treatment of inflammatory conditions. The ethanolic extracts of the plants at the doses of 50, 100 and 200 mg/kg, p.o. were screened for their effect on acute and chronic inflammation induced in mice and rats. S. lappa and A. speciosa were found to significantly inhibit paw edema induced by carrageenan and Freund's complete adjuvant and to prevent accumulation of inflammatory cells in carrageenan-induced peritonitis at doses of 50-200 mg/kg. A. aspera inhibited these inflammatory responses at doses of 100-200 mg/kg. The studies reveal that the ethanolic extracts of S. lappa, A. speciosa and A. aspera possess anti-inflammatory and anti-arthritic activity and support the rationale behind the traditional use of these plants in inflammatory conditions.

Influence of ethanolic extract of Tephrosia purpurea Linn. on mast cells and erythrocytes membrane integrity.

The ethanolic extract of T. purpurea Linn. was studied for its in vitro effect on rat mast cell degranulation and erythrocyte membrane integrity in vitro. The extract in concentration of 25-200 microg/ml showed a dose-dependant inhibition of rat mast cell degranulation induded by compound 48/80 and egg albumin. T. purpurea extract was found to inhibit haemolysis of erythrocytes induced by hypotonic solution but accelerated haemolysis induced by heat at a concentration of 100 microg/ml. The studies reveal that the ethanolic extract of T. purpurea may inhibit degranulation of mast cells by a mechanism other than membrane stabilization.