Pharmacokinetics, pharmacodynamics and safety profiling of IS01957, a preclinical candidate possessing dual activity against inflammation and nociception.

In spite of unprecedented advances in modern systems of medicine, there is necessity for exploration of traditional plant based secondary metabolites or their semisynthetic derivatives which may results in better therapeutic activity, low toxicity and favourable pharmacokinetics. In this context, computational model based predictions aid medicinal chemists in rational development of new chemical entity having unfavourable pharmacokinetic properties which is a major hurdle for its further development as a drug molecule. Para-coumaric acid (p-CA) and its derivatives found to be have promising antiinflammatory and analgesic activity. IS01957, a p-CA derivative has been identified as dual acting molecule against inflammation and nociception. Therefore, objective of the present study was to investigate pharmacokinetics, efficacy and safety profile based on in-silico, in-vitro and in-vivo model to assess drug likeliness. In the present study, it has excellent pharmacological action in different animal models for inflammation and nociception. Virtual pharmacokinetics related properties of IS01957 have resemblance between envision and experimentation with a few deviations. It has also acceptable safety pharmacological profile in various animal models for central nervous system (CNS), gastro intestinal tract (GIT)/digestive system and cardiovascular system (CVS). Finally, further development of IS01957 is required based on its attractive preclinical profiles.

Discovery of a marine-derived bis-indole alkaloid fascaplysin, as a new class of potent P-glycoprotein inducer and establishment of its structure-activity relationship.

The screening of IIIM natural products repository for P-gp modulatory activity in P-gp over-expressing human adenocarcinoma LS-180 cells led to the identification of 7 natural products viz. withaferin, podophyllotoxin, 3-demethylcolchicine, agnuside, reserpine, seseberecine and fascaplysin as P-gp inducers. Fascaplysin (6a), a marine-derived bis-indole alkaloid, was the most potent among all of them, showing induction of P-gp with EC50 value of 25 nM. P-gp induction is one of the recently targeted strategy to increase amyloid-ß clearance from Alzheimer brains. Thus, we pursued a medicinal chemistry of fascaplysin to establish its structure-activity relationship for P-gp induction activity. Four series of analogs viz. substituted quaternary fascaplysin analogs, D-ring opened quaternary analogs, D-ring opened non-quaternary analogs, and ß-carbolinium analogs were synthesized and screened for P-gp induction activity. Among the total of 48 analogs screened, only quaternary nitrogen containing analogs 6a-g and 10a, 10h-l displayed promising P-gp induction activity; whereas non-planar non-quaternary analogs 9a-m, 13a-n, 15a-h were devoid of this activity. The P-gp induction activity of best compounds was then confirmed by western-blot analysis, which indicated that fascaplysin (6a) along with 4,5-difluoro analog of fascaplysin 6f and D-ring opened analog 10j displayed 4-8 fold increase in P-gp expression in LS-180 cells at 1 µM. Additionally, compounds 6a and 6f also showed inhibition of acetylcholinestease (AChE), an enzyme responsible for neuronal loss in Alzheimer's disease. Thus, fascaplysin and its analogs showing promising P-gp induction along with AChE inhibition at 1 µM, with good safety window (LS-180: IC50 > 10 µM, hGF: 4 µM), clearly indicates their promise for development as an anti-Alzheimer agent.

Anticancer activity of Aristolochia ringens Vahl. (Aristolochiaceae).

Cancer is a leading cause of death worldwide and sustained focus is on the discovery and development of newer and better tolerated anticancer drugs especially from plants. The sulforhodamine B (SRB) in vitro cytotoxicity assay, sarcoma-180 (S-180) ascites and solid tumor, and L1210 lymphoid leukemia in vivo models were used to investigate the anticancer activity of root extracts of Aristolochia ringens Vahl. (Aristolochiaceae; mǎ dou líng). AR-A001 (IC50 values of 20 µg/mL, 22 µg/mL, 3 µg/mL, and 24 µg/mL for A549, HCT-116, PC3, and THP-1 cell lines, respectively), and AR-A004 (IC50 values of 26 µg/mL, 19.5 µg/mL, 12 µg/mL, 28 µg/mL, 30 µg/mL, and 22 µg/mL for A549, HCT-116, PC3, A431, HeLa, and THP-1, respectively), were observed to be significantly active in vitro. Potency was highest with AR-A001 and AR-A004 for PC3 with IC50 values of 3 µg/mL and 12 µg/mL, respectively. AR-A001 and AR-A004 produced significant (p < 0.05-0.001) dose-dependent inhibition of tumor growth in the S-180 ascites model with peak effects produced at the highest dose of 120 mg/kg. Inhibition values were 79.51% and 89.98% for AR-A001 and AR-A004, respectively. In the S-180 solid tumor model, the inhibition of tumor growth was 29.45% and 50.50% for AR-A001 (120 mg/kg) and AR-A004 (110 mg/kg), respectively, compared to 50.18% for 5-fluorouracil (5-FU; 20 mg/kg). AR-A001 and AR-A004 were also significantly active in the leukemia model with 211.11% and 155.56% increase in mean survival time (MST) compared to a value of 211.11% for 5-FU. In conclusion, the ethanolic (AR-A001) and dichloromethane:methanol (AR-A004) root extracts of AR possess significant anticancer activities in vitro and in vivo.

In Vitro and In Vivo Anticancer Activity of Root Extracts of Sansevieria liberica Gerome and Labroy (Agavaceae).

Introduction. Sansevieria liberica Gerome and Labroy (Agavaceae) is a perennial plant widely distributed in tropical Africa. Preparations of the plant are commonly used across Nigeria for the treatment of inflammatory conditions. Based on the fact that herbal medicine is a strong component of integrative medicine, this study was conducted to evaluate the anticancer activity of root extracts of Sansevieria liberica. Methods. Sulforhodamine B (SRB) in vitro cytotoxicity assay, Sarcoma-180 (S-180) ascites and solid tumor, and L1210 lymphoid leukemia in vivo models were used in this study. Results. SL-A002 (IC50 23 µg/mL with HeLa), SL-A003 (IC50 22 µg/mL with HCT-116), and SL-A004 (IC50 23 and 18 µg/mL with A549 and THP-1, resp.) demonstrated significant activity in the SRB cytotoxicity assay. Potency was highest with the following pairs of extract : cancer cell line: SL-A002 : HeLa (IC50 23 µg/mL), SL-A003 : HCT-116 (IC50 22 µg/mL), and SL-A004 : THP-1 (IC50 18 µg/mL). SL-A002 demonstrated significant dose-dependent antitumor activity in the Sarcoma-180 (S-180) ascites model with peak effect produced at the dose of 120 mg/kg (i.p.) with inhibition of 89.36% compared to 97.96% for 5-FU (20 mg/kg i.p.). The inhibition of tumor growth by SL-A002 in the S-180 solid tumor model was 47.40% compared to a value of 50.18% for 5-FU. SL-A002 was also significantly active in the L1210 lymphoid leukemia model with 158.33% increase in mean survival time, the same value for 5-FU. Conclusions. The hydroethanolic extract of Sansevieria liberica, SL-A002, possesses significant anticancer activity to warrant further extensive study to identify, isolate, and characterize the specific bioactive molecules responsible for the observed antitumor activity and the precise mechanism(s) of action.

Anticancer activity of the phytomedicine DAS-77.

This study was designed to investigate the anticancer activity of extracts of the phytomedicine DAS-77. The sulforhodamine B (SRB) in vitro cytotoxicity assay, Sarcoma-180 (S-180) ascites and solid tumor, and L1210 lymphoid leukemia in vivo models were employed. DAS-A001 (ethanol extract, IC50 12 and 13 µg/mL with HCT-116 and PC3, respectively); DAS-A002 (hydroethanol extract, IC50 <5 and 13 µg/mL with HCT-116 and PC3, respectively); DAS-A003 (aqueous extract, IC50 <5 µg/mL with THP-1); and DAS-A004 (dichloromethane:methanol extract; IC50 <5 and 17 µg/mL with HCT-116 and PC3, respectively) demonstrated significant activity in vitro. DAS-A002 and DAS-A003 (80-120 mg/kg) elicited significant (P < .05-.001) dose-dependent inhibition of tumor growth in the S-180 ascites model. Peak effects were produced at the highest dose of 120 mg/kg with inhibition values of 87.50% and 89.23% for DAS-A002 and DAS-A003, respectively, compared with a value of 97.27% for 5-FU (20 mg/kg). As regards the S-180 solid tumor model, inhibition of tumor growth was found to be 52.56% and 37.95%, respectively, for DAS-A002 and DAS-A003. The effect of DAS-A002 was comparable and not significantly different (P > .05) from that of 5-FU (20 mg/kg; 50.18% inhibition). DAS-A003 but not DAS-A002 showed significant activity in the leukemia model with 177.78% increase in mean survival time relative to 211.11% for 5-FU. Findings in this study suggest that the hydroethanol and aqueous extracts of DAS-77 possess significant anticancer activity.

Protective effect of Withania somnifera roots extract on hematoserological profiles against lead nitrate-induced toxicity in mice.

The in vivo protective role of hydro-methanolic root extract of Withania somnifera (WS) was evaluated in alleviating lead nitrate (LN)-induced toxicity in male Swiss albino mice by measuring hematoserological profiles. The lead-treated (20 mg/kg body wt, p.o.) albino mice (25-30 g) concurrently received the root extract (200 and 500 mg/kg body wt, p.o.) once daily for the duration of six weeks. Animals exposed to LN showed significant (P < 0.001) decline in haemoglobin content, red blood cell count, white blood cell count, packed cell volume and insignificant decrease in mean corpuscular haemoglobin and mean corpuscular haemoglobin content, while mean corpuscular volume and platelet count were increased. A significant elevation (P < 0.001) in serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, alkaline phosphatase, acid phosphatase and total cholesterol were also observed, when compared with control mice. Thus, the study demonstrated that the concurrent daily administration of root extract of WS protected the adverse effects of LN intoxication in mice.

Chemopreventive effect of hydroethanolic extract of Euphorbia neriifolia leaves against DENA-induced renal carcinogenesis in mice.

The present study was conducted to investigate the chemopreventive effects of hydro-ethanolic extract of Euphorbia neriifolia (EN) on N-nitrosodiethylamine (DENA) induced renal cancer in male Swiss albino mice. Animals were pretreated with EN extract (150 and 400 mg/kg body weight; p.o) and butylated hydroxyanisole (BHA) as a standard (0.5% and 1% BHA p.o) both for two week prior to the administration of single dose of DENA (50 mg/kg body weight; p.o). Various in vivo antioxidant biochemical parameters like lipid peroxidation (LPO), superoxide dismutase (SOD), and catalase (CAT) were evaluated to determine the reno-protective and antioxidant activity of EN. DENA increased oxidative stress through increase in LPO and decrease in antioxidant enzymes (SOD, and CAT). The EN extract significantly restored the antioxidant enzyme level in the kidney and exhibited significant dose dependant protective effect against DENA induced nephrotoxicity, which can be mainly attributed to the antioxidant property of the extract. This study rationalized the ethno-medicinal use of EN for protection against renal cancer.

Multivitamin-mineral and vitamins (E + C) supplementation modulate chronic unpredictable stress-induced oxidative damage in brain and heart of mice.

Brain is a target of stress along with the immune, metabolic, and cardiovascular systems of the body. In the present work, the preventive roles of a multivitamin-mineral supplement and vitamins (E + C) in chronic unpredictable stress (CUS)-induced oxidative damage were studied in the brain and heart of Swiss albino mice. Thirty-two mice were randomized to one of the following groups: control + vehicle, CUS + vehicle, CUS + multivitamin-mineral, and CUS + vitamins (E + C). CUS was applied for 4 weeks, and multivitamin-mineral and vitamins (E + C) were administered orally for the same period. CUS led to a negative impact on all the biochemical parameters analyzed. Elevation in malondialdehyde and reduction in glutathione levels were found. The activities of superoxide dismutase, catalase, glutathione S-transferase, and glutathione reductase were decreased. Treatment with multivitamin-mineral and vitamins (E + C) brought these parameters to near normal levels. Multivitamin-mineral was found more restitutive than combined vitamins (E + C) doses. The present study hypothesizes that supplementation with a multivitamin-mineral may prove more effective than vitamin treatment alone in the alleviation of oxidative damage in brain and heart during periods of chronic stress.