Friisfloyd2511

The 5T4 oncofetal antigen (trophoblast glycoprotein) is expressed in a wide range of malignant tumors but shows very limited expression in normal adult tissues. ASN004 is a 5T4-targeted antibody drug conjugate (ADC) that incorporates a novel single-chain scFv-Fc antibody and Dolaflexin drug-linker technology, with an Auristatin F Hydroxypropylamide payload drug-to-antibody ratio of ca. 10-12. The pharmacology, toxicology and pharmacokinetic properties of ASN004 and its components were investigated in vitro and in vivo. ASN004 showed high affinity for the 5T4 antigen and was selectively bound to and internalized into 5T4-expressing tumor cells, and potent cytotoxicity was demonstrated for a diverse panel of solid tumor cell lines. ASN004 induced complete and durable tumor regression in multiple tumor xenograft models, derived from human lung, breast, cervical, and gastric tumor cell lines having a wide range of 5T4 expression levels. A single dose of ASN004, as low as 1 mg/kg iv, achieved complete tumor regression leading to tumor-free survivors in the A431 cervical cancer model. In head-to-head studies, superior activity of ASN004 was demonstrated against trastuzumab-DM1, in a low-5T4/high-HER2 expressing gastric tumor model, and 10-fold greater potency was found for ASN004 against the 5T4-targeted ADC PF-06263507 in a lung tumor model. see more In marmoset monkeys, ASN004 was well tolerated at doses up to 1.5 mg/kg Q3W iv, and showed dose-dependent exposure, linear pharmacokinetics, and markedly low exposure of free payload drug. Taken together, these findings identify ASN004 as a promising new ADC therapeutic for clinical evaluation in a broad range of solid tumor types.DNA methyltransferase inhibitors have improved the prognosis of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, because these agents are easily degraded by cytidine deaminase (CDA), they must be administered intravenously or subcutaneously. Recently, two orally bioavailable DNA methyltransferase inhibitors, CC-486 and ASTX727, were approved. In previous work, we developed 5-O-trialkylsilylated decitabines that resist degradation by CDA. However, the effects of silylation of a deoxynucleotide analog and enzymatic cleavage of silylation have not been fully elucidated. Enteric administration of OR21 in a cynomolgus monkey model led to high plasma concentrations and hypomethylation, and in a mouse model, oral administration of enteric-coated OR21 led to high plasma concentrations. The drug became biologically active after release of decitabine (DAC) from OR21 following removal of the 5'-O-trisilylate substituent. Toxicities were tolerable and lower than those of DAC. Transcriptome and methylome analysis of MDS and AML cell lines revealed that OR21 increased expression of genes associated with tumor suppression, cell differentiation, and immune system processes by altering regional promoter methylation, indicating that these pathways play pivotal roles in the action of hypomethylating agents. OR21 induced cell differentiation via upregulation of the late cell differentiation drivers CEBPE and GATA-1. Thus, silylation of a deoxynucleotide analog can confer oral bioavailability without new toxicities. Both in vivo and in vitro, OR21 exerted anti-leukemia effects, and had a better safety profile than DAC. Together, our findings indicate that OR21 is a promising candidate drug for phase 1 study as an alternative to azacitidine or decitabine.

To investigate the efficacy and safety of pegfilgrastim administered on the day of chemotherapy completion (same day) versus at least 1 day after chemotherapy (next day).

We searched relevant literature published before April 2020 from the following databases Embase, PubMed, Cochrane databases and Web of science.

One randomised controlled trial and 12 observational studies met all of the prespecified criteria for eligibility. The meta-analysis showed a significantly higher febrile neutropenia (FN) rate for the same-day group than that for the next-day arm in the first chemotherapy cycle (OR=2.56, 95% CI 1.19 to 5.48, p=0.02), and in all chemotherapy cycles (OR=1.54, 95% CI 1.29 to 1.84, p<0.00001). Results of subgroup analysis showed a higher FN rate in the same-day arm than in the next-day group for patients with breast cancer (OR=5.50, 95% CI 2.29 to 13.23, p=0.0001) and lymphoma (OR=1.53, 95% CI 1.00 to 2.34, p=0.05). The pooled analysis of studies on gynaecological malignancies showed that patients in the same-day group had a higher incidence of bone pain (OR=1.30, 95% CI 1.01 to 1.68, p=0.04) and a lower incidence of chemotherapy delay (OR=0.71, 95% CI 0.53 to 0.96, p=0.03) compared with the next-day group.

Same-day administration of pegfilgrastim resulted in increased incidence of FN compared with the next-day schedule. This is especially true for patients with breast cancer or lymphoma. These results do not support same-day administration of pegfilgrastim .

Same-day administration of pegfilgrastim resulted in increased incidence of FN compared with the next-day schedule. This is especially true for patients with breast cancer or lymphoma. These results do not support same-day administration of pegfilgrastim .

The association between the development of cystoid macular oedema (CMO) following uneventful cataract surgery and prostaglandin analogue (PGA) therapy has not been fully determined. The study aim was to investigate whether discontinuation of PGA therapy following uneventful cataract surgery affected the incidence of postoperative CMO.

A prospective randomised controlled trial of 62 eyes of 62 participants with ocular hypertension (OH) or primary open angle glaucoma (POAG) treated with PGAs prior to cataract surgery. Participants were randomised to continue with PGA therapy after cataract surgery (CPGA) (n=31) or to discontinue PGA therapy (n=31). The primary outcome measure was the development of CMO at 1-month postoperatively, determined by a masked observer assessment of optical coherence tomography scans. The secondary outcome measure was change from baseline intraocular pressure (IOP).

The incidence of CMO was identical in both groups at 12.9% (4 of 31 eyes) at the 1-month postoperative visit (OR 1.000; 95% CI 0.227 to 4.415). At 1-month postoperatively, the IOP was significantly lower in the CPGA group compared with baseline IOP.

Continuation of PGA therapy following uneventful cataract surgery in eyes with normal macular morphology did not increase the incidence of CMO. Continuation of PGA therapy significantly reduced IOP at 1-month postoperatively suggesting that, when indicated, it might be beneficial to continue PGA therapy in patients with POAG or OH after uneventful cataract surgery in the absence of other risk factors for developing CMO.

Continuation of PGA therapy following uneventful cataract surgery in eyes with normal macular morphology did not increase the incidence of CMO. Continuation of PGA therapy significantly reduced IOP at 1-month postoperatively suggesting that, when indicated, it might be beneficial to continue PGA therapy in patients with POAG or OH after uneventful cataract surgery in the absence of other risk factors for developing CMO.This study aimed to comprehensively investigate the in vitro metabolism of statins. The metabolism of clinically relevant concentrations of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin and their metabolites were investigated using human liver microsomes (HLMs), intestine microsomes (HIMs), liver cytosol, and recombinant cytochrome P450 (CYP) enzymes. We also determined the inhibitory effects of statin acids on their pharmacological target, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. In HLMs, statin lactones were metabolized to a much higher extent than their acid forms. Atorvastatin lactone and simvastatin (lactone) showed extensive metabolism (intrinsic clearance (CLint) values of 3,700 and 7,400 µl/min/mg), while the metabolism of the lactones of 2-hydroxyatorvastatin, 4-hydroxyatorvastatin, and pitavastatin was slower (CLint 20-840 µl/min/mg). The acids had CLint values in the range less then 0.1-80 µl/min/mg. In HIMs, only atorvastatin lactone and simvastatin (lactone) exhibited notable metabolism, with CLint values corresponding to 20% of those observed in HLMs. CYP3A4/5 and CYP2C9 were the main statin-metabolizing enzymes. The majority of the acids inhibited HMG-CoA reductase with 50% inhibitory concentrations of 4-20 nM. The present comparison of the metabolism and pharmacodynamics of the various statins using identical methods provides a strong basis for further application, e.g., comparative systems pharmacology modelling. Significance Statement The present comparison of the in vitro metabolic and pharmacodynamic properties of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin and their metabolites using unified methodology provides a strong basis for further application. Together with in vitro drug transporter and clinical data, our findings are applicable for use in comparative systems pharmacology modelling to predict the pharmacokinetics and pharmacological effects of statins at different dosages.Model-based assessment of the effects of liver disease on drug pharmacokinetics requires quantification of changes in enzymes and transporters responsible for drug metabolism and disposition. Different proteomic methods are currently used for protein quantification in tissues and in vitro systems, each with specific procedures and requirements. The outcome of quantitative proteomic assays from four different methods (one targeted and three label-free), applied to the same sample set, were compared in this study. Three pooled cirrhotic liver microsomal samples, corresponding to cirrhosis with non-alcoholic fatty liver disease, biliary disease or cancer, and a control microsomal pool, were analyzed using QconCAT-based targeted proteomics, the total protein approach (TPA), high three (Hi3) ion intensity approach, and intensity-based absolute quantification (iBAQ), to determine the absolute and relative abundance in disease compared with control. The relative abundance data provided a 'disease perturbation factorss proteomic methods observed with absolute levels. Using this approach, differences were revealed in the expression of enzymes/transporters in cirrhosis associated with different etiologies.

To study the implementation of a cluster randomised controlled effectiveness-implementation hybrid trial testing the effectiveness of a medication review at hospital discharge combined with a communication stimulus between hospital physicians (HPs) and general practitioners (GPs) on rehospitalisation of multimorbid older patients.

Extension of Grant's mixed method process evaluation framework to trials with multilevel clustering.

General internal medicine wards in Swiss hospitals.

Convenience samples of 15 chief physicians (of 21 hospitals participating in the effectiveness trial), 60 (74) senior HPs, 65 (164) junior HPs and 187 (411) GPs.

Two-hour teaching sessions for senior HPs on a patient-centred, checklist-guided discharge routine.

Data collection on recruitment, delivery and response from chief physicians (semistructured interviews), senior HPs, junior HPs, GPs (surveys) and patients (via HPs). Quantitative data were summarised using descriptive statistics, and interviews analysed using thematic analysis.