Liver-on-chips for drug discovery and development.

Recent FDA modernization act 2.0 has led to increasing industrial R&D investment in advanced 3D models such as organoids, spheroids, organ-on-chips, 3D bioprinting, and approaches. Liver-related advanced models remain the prime area of interest, as liver plays a central role in drug clearance of compounds.

and studies on the metabolism and pharmacokinetics of the selective gut microbial β-glucuronidase targeting compound Inh 1.

studies using rat, mouse, and human microsomes and hepatocytes on the bacterial β-glucuronidase inhibitor 1-((6,8-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl)-3-(4-ethoxyphenyl)-1-(2-hydroxyethyl)thiourea) (Inh 1) revealed extensive metabolism in all species.The intrinsic clearances of Inh 1 in human, mouse, and rat hepatic microsomes were 30.9, 67.

The metabolism and pharmacokinetics of the bacterial β-glucuronidase inhibitor UNC10201652.

incubation of the bacterial β-glucuronidase inhibitor UNC10201652 (4-(8-(piperazin-1-yl)-1,2,3,4-tetrahydro-[1,2,3]triazino[4',5':4,5]thieno[2,3-c]isoquinolin-5-yl)morpholine) with mouse, rat, and human liver microsomes and hepatocytes generated metabolites at multiple sites via deethylations, oxidations and glucuronidation.Two UNC10201652 metabolites were detected in human, and four in mouse and rat liver microsomal incubations. Intrinsic clearances of UNC10201652 in human, mouse, and rat liver microsomes were 48.

Three-dimensional aspects of formulation excipients in drug discovery: a critical assessment on orphan excipients, matrix effects and drug interactions.

Formulation/pharmaceutical excipients play a major role in formulating drug candidates, with the objectives of ease of administration, targeted delivery and complete availability. Many excipients used in pharmaceutical formulations are orphanized in preclinical drug discovery. These orphan excipients could enhance formulatability of highly lipophilic compounds.

Discovery and evaluation of novel FAAH inhibitors in neuropathic pain model.

Conceptual design and modification of urea moiety in chemotype PF-3845/04457845, the bench marking irreversible inhibitor of fatty acid amide hydrolase (FAAH), led to discovery of a novel nicotinamide-based lead 12a having reversible mechanism of action. Focused SAR around the pyridine heterocycle (Ar) in 12a (Tables 1 and 2) resulted into four shortlisted compounds, (-)-12a, (-)-12i, (-)-12l-m. The required (-)-enantiomers were obtained via diastereomeric resolution of a novel chiral dissymmetric intermediate 15.

Evaluation of separate role of intestine and liver in first pass metabolism of budesonide in rat.

1. Budesonide, a potent topical corticosteroid, reported to have low oral bioavailability in mice, rat, dog and human due to rapid first pass metabolism. However, there is insufficient information available in literature regarding the role of intestine and or liver responsible for the first pass metabolism of budesonide.

Discovery of Potent and Selective A Antagonists with Efficacy in Animal Models of Parkinson's Disease and Depression.

Adenosine A receptor (AAdoR) antagonism is a nondopaminergic approach to Parkinson's disease treatment that is under development. Earlier we had reported the therapeutic potential of 7-methoxy-4-morpholino-benzothiazole derivatives as AAdoR antagonists. We herein described a novel series of [1,2,4]triazolo[5,1-]purin-2-one derivatives that displays functional antagonism of the A receptor with a high degree of selectivity over A, A, and A receptors.

Discovery of liver-directed glucokinase activator having anti-hyperglycemic effect without hypoglycemia.

Glucokinase activators (GKAs) are among the emerging drug candidates for the treatment of type 2 diabetes (T2D). Despite effective blood glucose lowering in clinical trials, many pan-GKAs "acting both in pancreas and liver" have been discontinued from clinical development mainly because of their potential to cause hypoglycemia. Pan-GKAs over sensitize pancreatic GK, resulting in insulin secretion even at sub-normoglycemic level which might be a possible explanation for hypoglycemia.

Liquid chromatography-tandem mass spectrometry analysis of urine specimens for K2 (JWH-018) metabolites.

Marijuana is the most widely used drug of abuse all over the world. The major active constituent of the drug is Δ⁹- tetrahydrocannabinol (Δ⁹-THC). Δ⁹-THC exerts its psychological activities by interacting with the cannabinoid receptors (CB₁ and CB₂) in the brain.

Bioavailability, pharmacokinetics, and tissue distribution of the oxypregnane steroidal glycoside P57AS3 (P57) from Hoodia gordonii in mouse model.

P57AS3 (P57), an oxypregnane steroidal glycoside, is known to be responsible for the appetite suppressing activity of HOODIA GORDONII, a dietary supplement used for weight loss. In this study, bioavailability, pharmacokinetics, and tissue distribution of P57 were determined in CD1 female mice after administration of a single dose of enriched methanolic extract of HOODIA GORDONII (equivalent to a dose of 25 mg of P57/kg) by oral gavage or a single dose of purified P57 (25 mg/kg) intravenously. The level of P57 in plasma and tissues (brain, liver, kidney, and intestine) was determined by UPLC-MS.

Structure-activity relationship and mechanism of action studies of manzamine analogues for the control of neuroinflammation and cerebral infections.

Structure-activity relationship studies were carried out by chemical modification of manzamine A (1), 8-hydroxymanzamine A (2), manzamine F (14), and ircinal isolated from the sponge Acanthostrongylophora. The derived analogues were evaluated for antimalarial, antimicrobial, and antineuroinflammatory activities. Several modified products exhibited potent and improved in vitro antineuroinflammatory, antimicrobial, and antimalarial activity.

Intestinal and blood-brain barrier permeability of ginkgolides and bilobalide: in vitro and in vivo approaches.

In this study intestinal and blood-brain barrier (BBB) permeability of ginkgolides A, B, C, J and bilobalide, isolated from Ginkgo biloba (Ginkgoaceae), was evaluated in Caco-2 and MDR1-MDCK cell monolayer models. The transport was examined for 2 hours in both absorptive and secretory directions. Quantitation was performed by UPLC-MS.

Characterization of in vitro pharmacokinetic properties of hoodigogenin A from Hoodia gordonii.

This study was aimed to predict the pharmacokinetic properties of hoodigogenin A, which is the aglycone of the oxypregnane steroidal glycoside P57AS3 (P57) isolated from Hoodia gordonii. A series of in vitro assays was used to predict its gastric, intestinal and metabolic stability, intestinal and blood brain barrier (BBB) transport, protein binding and interaction with major drug metabolising enzymes. In the simulated gastric fluid, hoodigogenin A was stable (2 % degradation in 60 minutes) whereas P57 was unstable (45 % degradation in 30 minutes).

Alkaloids and saponins as cytochrome P450 inhibitors from blue cohosh (Caulophyllum thalictroides) in an in vitro assay.

Blue cohosh, Caulophyllum thalictroides (L.) Michx. is a popular herb, roots and rhizomes of which have been extensively used for women's health.

SSRD: simple sequence repeats database of the human genome.

Simple sequence repeats are predominantly found in most organisms. They play a major role in studies of genetic diversity, and are useful as diagnostic markers for many diseases. The simple sequence repeats database (SSRD) for the human genome was created for easy access to such repeats, for analysis, and to be used to understand their biological significance.

In vitro metabolic stability and intestinal transport of P57AS3 (P57) from Hoodia gordonii and its interaction with drug metabolizing enzymes.

Hoodia gordonii, a succulent cactus-like plant growing in South Africa, has been used in traditional medicine for its appetite suppressant properties. Its use as a dietary supplement to promote weight loss has recently gained popularity. An oxypregnane steroidal glycoside P57AS3 (P57) is reported to be the active constituent of the sap extract responsible for anorexigenic activity.

Transport of Schisandra chinensis extract and its biologically-active constituents across Caco-2 cell monolayers - an in-vitro model of intestinal transport.

We have determined the intestinal transport of Schisandra chinensis extract and its lignans (gomisin A, gomisin N and schisandrin C) in the Caco-2 cell monolayer model. The transport across monolayers was examined for 2 h in absorptive and secretory directions. Quantitation of lignans was performed by HPLC.

Transport of decursin and decursinol angelate across Caco-2 and MDR-MDCK cell monolayers: in vitro models for intestinal and blood-brain barrier permeability.

Decursin (DE) and decursinol angelate (DA) were isolated from the roots of Angelica gigas (Apiaceae) and purified by HPLC. DE and DA have been reported to exhibit significant neuropharmacological activities, but their intestinal transport and permeability in terms of CNS penetration across the blood-brain barrier (BBB) are unknown. This study was undertaken to evaluate the IN VITRO intestinal and BBB transport of DE and DA using Caco-2 and MDR-MDCK cell monolayer models, respectively.

Antitumor activity and antioxidant status of Caesalpinia bonducella against Ehrlich ascites carcinoma in Swiss albino mice.

The methanol extract of Caesalpinia bonducella FLEMING (Caesalpiniaceae) leaves (MECB) were evaluated for antitumor activity against Ehrlich ascites carcinoma (EAC)-bearing Swiss albino mice. The extract was administered at the doses of 50, 100, and 200 mg/kg body weight per day for 14 days after 24 h of tumor inoculation. After the last dose and 18 h fasting, the mice were sacrificed.

Triplet repeats in human genome: distribution and their association with genes and other genomic regions.

Motivation: Simple sequence repeats (SSRs) or microsatellite repeats are found abundantly in many prokaryotic and eukaryotic genomes. Among SSRs, triplet repeats are of special significance because some of them have been linked to various genetic disorders. The objective of the study is to analyze the triplet repeats of complete human genome and to identify the genes that contain the triplet repeats in their coding region.

MRD: a microsatellite repeats database for prokaryotic and eukaryotic genomes.

MRD is a database system to access the microsatellite repeats information of genomes such as archea, eubacteria, and other eukaryotic genomes whose sequence information is available in public domains. MRD stores information about simple tandemly repeated k-mer sequences where k= 1 to 6, i.e.