An approach to data collection in compassionate use/managed access.

Compassionate Use (CU)/Managed Access programs provide access to locally unapproved medicines. As these programs become more global and involve a broader range of products, determining whether patients derive benefit from treatment could provide insights into therapeutic use in a real-word setting with diverse pools of patients. CU primary purpose is to provide treatment and it is not targeting research.

International Country-Level Trends, Factors, and Disparities in Compassionate Use Access to Unlicensed Products for Patients With Serious Medical Conditions.

Importance: Compassionate use (CU) is a treatment option for patients with serious or life-threatening medical conditions that provides access to locally unlicensed medications (generally free of charge) when all available treatment options have been exhausted and enrollment in a clinical trial is not possible.

Objective: To examine the disparity in CU access observed across countries and explore the key driving factors.

Design Settings And Participants: This study analyzed all Novartis CU requests (for individual/named patients and cohort programs) received between January 1, 2018, and December 31, 2020, and investigated selected country-specific factors for association with request activity.

Vascular endothelial growth factor stimulates rat cholangiocyte proliferation via an autocrine mechanism.

Background & Aims: Vascular endothelial growth factor (VEGF) is secreted by several epithelia and modulates cellular functions by autocrine and paracrine mechanisms. The role of VEGF in cholangiocyte pathophysiology is unknown. We evaluated the role of VEGF in the regulation of cholangiocyte proliferation in rats that underwent bile duct ligation.

Administration of r-VEGF-A prevents hepatic artery ligation-induced bile duct damage in bile duct ligated rats.

The hepatic artery, through the peribiliary plexus, nourishes the intrahepatic biliary tree. During obstructive cholestasis, the nutritional demands of intrahepatic bile ducts are increased as a consequence of enhanced proliferation; in fact, the peribiliary plexus (PBP) displays adaptive expansion. The effects of hepatic artery ligation (HAL) on cholangiocyte functions during cholestasis are unknown, although ischemic lesions of the biliary tree complicate the course of transplanted livers and are encountered in cholangiopathies.

Ca2+-dependent cytoprotective effects of ursodeoxycholic and tauroursodeoxycholic acid on the biliary epithelium in a rat model of cholestasis and loss of bile ducts.

Chronic cholestatic liver diseases are characterized by impaired balance between proliferation and death of cholangiocytes, as well as vanishing of bile ducts and liver failure. Ursodeoxycholic acid (UDCA) is a bile acid widely used for the therapy of cholangiopathies. However, little is known of the cytoprotective effects of UDCA on cholangiocytes.

gamma-Aminobutyric acid inhibits cholangiocarcinoma growth by cyclic AMP-dependent regulation of the protein kinase A/extracellular signal-regulated kinase 1/2 pathway.

We studied the effect of the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), in the regulation of cholangiocarcinoma growth. We determined the in vitro effect of GABA on the proliferation of the cholangiocarcinoma cell lines (Mz-ChA-1, HuH-28, and TFK-1) and evaluated the intracellular pathways involved. The effect of GABA on migration of Mz-ChA-1 cells was also evaluated.

Adrenergic receptor agonists prevent bile duct injury induced by adrenergic denervation by increased cAMP levels and activation of Akt.

Loss of parasympathetic innervation after vagotomy impairs cholangiocyte proliferation, which is associated with depressed cAMP levels, impaired ductal secretion, and enhanced apoptosis. Agonists that elevate cAMP levels prevent cholangiocyte apoptosis and restore cholangiocyte proliferation and ductal secretion. No information exists regarding the role of adrenergic innervation in the regulation of cholangiocyte function.

cAMP stimulates the secretory and proliferative capacity of the rat intrahepatic biliary epithelium through changes in the PKA/Src/MEK/ERK1/2 pathway.

Background/aims: To evaluate if increased cholangiocyte cAMP levels alone are sufficient to enhance cholangiocyte proliferation and secretion.

Methods: Normal rats were treated in vivo with forskolin for two weeks. Cholangiocyte apoptosis, proliferation and secretion were evaluated.