Identification and preclinical characterization of a novel and potent poly (ADP-ribose) polymerase (PARP) inhibitor ZYTP1.

PURPOSE: Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme involved in the detection and repair of DNA damage. Studies have shown that inhibition of PARP and Tankyrase (TNKS) has significant antitumor effect in several types of cancers including BRCA-negative breast cancers. METHODS: Identification of ZYTP1, a novel PARP inhibitor, through a battery of in vitro assays and in vivo studies. PARP and TNKS inhibitory activity of ZYTP1 was assessed in cell-free kinase assay. In vitro cell killing potency of ZYTP1 was tested in a panel of cell lines including BRCA-negative cells. ZYTP1 was also tested in xenograft models in combination with temozolomide (TMZ). The pharmacokinetic profile of ZYTP1 was determined in rodent and non-rodent preclinical species. Safety of ZYTP1 was assessed in Wistar rats and Beagle dogs upon repeated dosing. RESULTS: ZYTP1 inhibited PARP1, PARP2, Tankyrase-1 and Tankyrase-2 with IC50 of 5.4, 0.7, 133.3 and 289.8 nM, respectively, and additionally trapped PARP1 onto damaged DNA. It also potentiated MMS-mediated killing of different cancer cell lines. Compound demonstrated good Caco-2 cell permeability. The oral bioavailability of ZYTP1 in mice, rats and dogs ranged between 40 and 79% and demonstrated efficacy in colon cancer xenograft model at a dose of 1-10 mg/kg in combination with TMZ. In a 28-day repeat dosing, oral toxicity study in rats, it was found to show > 10× safety margin. CONCLUSIONS: ZYTP1 is a novel PARP inhibitor that showed potential for development as a treatment for various solid tumors.

Preclinical evaluation of saroglitazar magnesium, a dual PPAR-α/γ agonist for treatment of dyslipidemia and metabolic disorders.

1. Saroglitazar, a novel peroxisome proliferator-activated receptor (PPAR) agonist, regulates lipid and glucose metabolism. The objective of this report is to provide a preclinical evaluation (in vitro/in vivo) of ADME properties of saroglitazar. In vitro studies included determination of permeability, metabolic stability, plasma protein binding, CYP reaction phenotyping and CYP inhibitory liability. In vivo studies included oral bioavailability and pharmacokinetic assessment in mouse, rat and dog. The excretion of saroglitazar was determined in rats. Exploratory metabolism of saroglitazar was evaluated using in vitro and in vivo samples. 2. Saroglitazar was metabolically more stable in human liver microsomes as compared to rat and dog liver microsomes, highly protein bound (98-99.6%) with high Caco2 permeability (104 nm/s) with <2 efflux ratio. In vitro metabolism in rat, dog and human liver microsomes revealed three putative metabolites corresponding to di-hydroxylation, mono-oxygenation and dehydrogenation moieties. 3. Oral bioavailability was 100%, 72% and 47% in mouse, rat and dog, respectively. The intravenous clearance and volume of distribution of saroglitazar were 3.6, 8.5 and 6.9 mL/min/kg and 1.3, 4.8 and 1.8 L/kg for mouse, rat and dog, respectively. The elimination half-life of saroglitazar ranged between 6 and 15 h. Saroglitazar appeared to be eliminated via hepatobiliary route with negligible renal excretion.

Consequences of daily corticosteroid dosing with or without pre-treatment with quinidine on the in vivo cytochrome P450 2D (CYP2D) enzyme in rats: effect on O-demethylation activity of dextromethorphan and expression levels of CYP2D1 mRNA.

1. Present investigation was carried out in rats to study influence of corticosteroids after repeated dosing with/without pre-treatment with CYP2D inhibitor quinidine on the CYP2D1 mRNA levels and CYP2D enzyme activity using dextromethorphan as probe substrate. 2. CYP2D1 mRNA was measured in liver homogenate using quantitative real-time polymerase chain reaction [qRT-PCR] and enzymatic reaction was studied ex vivo in liver S-9 fractions of rats treated with oral 10 mg/kg dexamethasone or prednisolone for five days or pre-treated with quinidine and followed by treatment with oral 10 mg/kg corticosteroids for five days. 3. Five days repeat dosing of dexamethasone or prednisolone decreased the activity of the rat liver CYP2D by 37% and 34%, at 30 min incubation and decreased CYP2D1 mRNA levels by 62% and 61%, respectively. 4. Pre-treatment of quinidine decreased the enzymatic activity of rat CYP2D by 58% and did not potentiate CYP2D inhibition by corticosteroids. This observation was further complemented by qRT-PCR data. 5. Corticosteroids caused CYP2D inhibition in rats vs. literature evidence of CYP2D induction in human hepatocytes/pregnant humans demonstrating lack of concordance. In vivo inhibition should be factored for interpretation of pharmacokinetic data of CYP2D substrates when treated with corticosteroids in rats.

'Trident sign' in pelvis: sinister sign with poor prognosis.

The perineural spread of the cancer through the lumbosacral plexus gives an appearance of 'trident sign' on contrast-enhanced CT scan and MRI. It is associated with adverse survival rates and carries a poor prognostic value.

Omental infarction: An unusual cause of right iliac fossa pain in children.

Omental infarction is an uncommon cause of acute abdomen in the pediatric population. We report a case of a 4-year-old male child with right iliac fossa pain. The final diagnosis was made on ultrasound and computed tomography findings. This entity needs to be differentiated from acute conditions like appendicitis, avoiding surgery.