PLL-g-PEG Polymer Inhibits Antibody-Drug Conjugate Uptake into Human Corneal Epithelial Cells .

Antibody-drug conjugates (ADCs) are a relatively recent advance in the delivery of chemotherapeutics that improve targeting of cytotoxic agents. However, despite their antitumor activity, severe ocular adverse effects, including vision loss, have been reported for several ADCs. The nonspecific uptake of ADCs into human corneal epithelial cells (HCECs) and their precursors via macropinocytosis has been proposed to be the primary mechanism of ocular toxicity.

Improving corneal permeability of dexamethasone using penetration enhancing agents: First step towards achieving topical drug delivery to the retina.

With an ever-increasing burden of vision loss caused by diseases of the posterior ocular segment, there is an unmet clinical need for non-invasive treatment strategies. Topical drug application using eye drops suffers from low to negligible bioavailability to the posterior segment as a result of static and dynamic defensive ocular barriers to penetration, while invasive delivery systems are expensive to administer and suffer potentially severe complications. As the cornea is the main anatomical barrier to uptake of topically applied drugs from the ocular surface, we present an approach to increase corneal permeability of a corticosteroid, dexamethasone sodium-phosphate (DSP), using a novel penetration enhancing agent (PEA).

Setting the record straight-Correcting uterine cancer incidence and mortality in the Nordic countries by reallocation of unspecified cases.

Introduction: The incidence of and mortality from cancers of the cervix uteri and corpus uteri are underestimated if the presence of uterine cancers, where the exact topography (site of origin) is not specified, is omitted. In this paper we present the corrected figures on mortality from and incidence of cervix and corpus uteri cancers in the Nordic countries by reallocating unspecified uterine cancer deaths and cases to originate either from the corpus uteri or cervix uteri. To further validate the accuracy of reallocation, we also analyzed how well the reallocation captures the changes occurring as the result of a transition in cause of death coding in Norway that took place in 2005.

Poly(lactic-co-glycolic acid) Nanoparticles Encapsulating the Prenylated Flavonoid, Xanthohumol, Protect Corneal Epithelial Cells from Dry Eye Disease-Associated Oxidative Stress.

Oxidative stress is a known contributor to the progression of dry eye disease pathophysiology, and previous studies have shown that antioxidant intervention is a promising therapeutic approach to reduce the disease burden and slow disease progression. In this study, we evaluated the pharmacological efficacy of the naturally occurring prenylated chalconoid, xanthohumol, in preclinical models for dry eye disease. Xanthohumol acts by promoting the transcription of phase II antioxidant enzymes.

Decreasing trend and changing indications of hysterectomy in Finland.

Introduction: Hysterectomy has been one of the most common surgical procedures in women in Finland. We studied the population-based trends of hysterectomy and its indications from 1986 to 2017.

Material And Methods: A retrospective population-based cohort was created from the Care Register for Health Care by identifying women who had a hysterectomy from 1986 to 2017 and calculating the number of women from the Digital and Population Data Services Agency.

Penetration Enhancers for Topical Drug Delivery to the Ocular Posterior Segment-A Systematic Review.

There is an unmet clinical need for eye drop formulations to efficiently treat the diseases of the posterior ocular segment by non-invasive topical administration. Here, we systematically reviewed the literature on ocular penetration enhancers and their ability to transfer drugs to the posterior segment of the eye in experimental studies. Our aim was to assess which penetration enhancer is the most efficient at delivering drugs to the posterior segment of the eye, when topically applied.

Viability of Mouse Retinal Explant Cultures Assessed by Preservation of Functionality and Morphology.

Purpose: Retinal explant cultures provide simplified systems where the functions of the retina and the effects of ocular therapies can be studied in an isolated environment. The purpose of this study was to provide insight into long-term preservation of retinal tissue in culture conditions, enable a deeper understanding of the interdependence of retinal morphology and function, and ensure the reliability of the explant technique for prolonged experiments.

Methods: Retinal explants from adult mice were cultured as organotypic culture at the air-medium interface for 14 days in vitro (DIV).

Manganese(III) tetrakis(1-methyl-4-pyridyl) porphyrin, a superoxide dismutase mimetic, reduces disease severity in in vitro and in vivo models for dry-eye disease.

Purpose: To determine the efficacy of the superoxide dismutase mimetic, manganese(III) tetrakis(1-methyl-4-pyridyl) porphyrin (Mn-TM-2-PyP), in vitro in human corneal epithelial (HCE-T) cells and in vivo in a preclinical mouse model for dry-eye disease (DED).

Methods: In vitro, HCE-T cultures were exposed either to tert-butylhydroperoxide (tBHP) to generate oxidative stress or to hyperosmolar conditions modeling cellular stress during DED. Cells were pre-treated with Mn-TM-2-PyP or vehicle.

Efficacy of Trabodenoson in a Mouse Keratoconjunctivitis Sicca (KCS) Model for Dry-Eye Syndrome.

Purpose: To determine the efficacy of trabodenoson, an adenosine mimetic with highly selective adenosine A1 receptor binding properties, in a preclinical mouse model for dry-eye disease.

Methods: Dry-eye disease was induced in adult male C57BL/6 mice using a combination of desiccating environment and transdermal administration of scopolamine. Mice were treated concurrently and twice daily with either vehicle, 6% trabodenoson, or 0.

Acute cytotoxic effects of marketed ophthalmic formulations on human corneal epithelial cells.

The purpose of the study was to devise a fast, reliable and sensitive cell viability assay for assessment of acute cytotoxicity on human corneal epithelial cells by using a clinically relevant exposure time. Acute cytotoxic effects of the pharmaceutical excipients benzalkonium chloride (BAC), macrogolglycerol hydroxystearate (MGHS40), polysorbate 80 (PS80) and marketed ophthalmic formulations (Lumigan(®), Monoprost(®), Taflotan(®), Travatan(®), Xalatan(®)) containing these excipients were tested. Human corneal epithelial cell (HCE-T) viability was assessed by measuring the reduction of resazurin to highly fluorescent resorufin.

Genetically Modified Caco-2 Cells With Improved Cytochrome P450 Metabolic Capacity.

The human intestinal Caco-2 cell line has been extensively used as a model of small intestinal absorption but it lacks expression and function of cytochrome P450 enzymes, particularly CYP3A4 and CYP2C9, which are normally expressed in the intestinal epithelium. In order to increase the expression and activity of CYP isozymes in these cells, we created 2 novel Caco-2 sublines expressing chimeric constitutive androstane or pregnane X receptors and characterized these cells for their metabolic and absorption properties. In spite of elevated mRNA expression of transporters and differentiation markers, the permeation properties of the modified cell lines did not significantly differ from those of the wild-type cells.

Brain pharmacokinetics of ganciclovir in rats with orthotopic BT4C glioma.

Ganciclovir (GCV) is an essential part of the Herpes simplex virus thymidine kinase (HSV-tk) gene therapy of malignant gliomas. The purpose of this study was to investigate the brain pharmacokinetics and tumor uptake of GCV in the BT4C rat glioma model. GCV's brain and tumor uptakes were investigated by in vivo microdialysis in rats with orthotopic BT4C glioma.

Re-evaluation of the role of P-glycoprotein in in vitro drug permeability studies with the bovine brain microvessel endothelial cells.

1.  Currently available in vitro blood-brain barrier models all have recognized restrictions. In addition to leakiness, inconsistent data about P-glycoprotein mediated efflux limit the attractiveness of the primary bovine brain microvessel endothelial cells (BBMECs).

Similar molecular descriptors determine the in vitro drug permeability in endothelial and epithelial cells.

Endothelial and epithelial cells are commonly used for assessing blood-brain barrier (BBB) permeability of the drug candidates. However, the additional value provided by the endothelial cells as an in vitro BBB drug permeability model is not clear. The aim of the study was to identify the molecular descriptors that impact on drug permeability through the primary bovine brain microvessel endothelial cell model (BBMEC) and compare descriptors with those determined for epithelial cell models.

The effect of prolyl oligopeptidase inhibition on extracellular acetylcholine and dopamine levels in the rat striatum.

Prolyl oligopeptidase (PREP, EC 3.4.21.

Brain pharmacokinetics of two prolyl oligopeptidase inhibitors, JTP-4819 and KYP-2047, in the rat.

Prolyl oligopeptidase (PREP) inhibitors are potential drug candidates for the treatment of neurological disorders, but little is known about their ability to cross the blood-brain barrier and to reach the target site. This study characterizes brain pharmacokinetics of two potent PREP inhibitors, JTP-4819 and KYP-2047. Firstly, the in vitro permeability (P(app) ) of JTP-4819 and KYP-2047 through a bovine brain microvessel endothelial cell monolayer was assessed.

Comparison of in vitro cell models in predicting in vivo brain entry of drugs.

Although several in vitro models have been reported to predict the ability of drug candidates to cross the blood-brain barrier, their real in vivo relevance has rarely been evaluated. The present study demonstrates the in vivo relevance of simple unidirectional permeability coefficient (P(app)) determined in three in vitro cell models (BBMEC, Caco-2 and MDCKII-MDR1) for nine model drugs (alprenolol, atenolol, metoprolol, pindolol, entacapone, tolcapone, baclofen, midazolam and ondansetron) by using dual probe microdialysis in the rat brain and blood as an in vivo measure. There was a clear correlation between the P(app) and the unbound brain/blood ratios determined by in vivo microdialysis (BBMEC r=0.

Human and bovine milk oligosaccharides inhibit Neisseria meningitidis pili attachment in vitro.

Milk oligosaccharides have been shown to interfere with adhesion of many pathogens to host mucosal surfaces. Characterization of the adhesion mechanisms of the bacteria to host cell surface is needed to develop novel functional food, infant formulas, and anti-infective drugs. Adhesion of Neisseria meningitidis, a human specific pathogen causing meningitis and septicemia, is not completely understood but is mediated by type IV pili.