Prevention of Rat Intestinal Injury with a Drug Combination of Melatonin and Misoprostol

A healthy intestinal barrier prevents uptake of allergens and toxins, whereas intestinal permeability increases following chemotherapy and in many gastrointestinal and systemic diseases and disorders. Currently, there are no approved drugs that target and repair the intestinal epithelial barrier while there is a medical need for such treatment in gastrointestinal and related conditions. The objective of this single-pass intestinal perfusion study in rats was to investigate the preventive cytoprotective effect of three mucosal protective drugs¿melatonin, misoprostol, and teduglutide¿with different mechanisms of action on an acute jejunal injury induced by exposing the intestine for 15 min to the anionic surfactant, sodium dodecyl sulfate (SDS). The effect was evaluated by monitoring intestinal clearance of 51Cr-labeled ethylenediaminetetraacetate and intestinal histology before, during, and after luminal exposure to SDS. Our results showed that separate pharmacological pretreatments with luminal misoprostol and melatonin reduced acute SDS-induced intestinal injury by 47% and 58%, respectively, while their use in combination abolished this injury. This data supports further development of drug combinations for oral treatments of conditions and disorders related to a dysregulated or compromised mucosal epithelial barrier

Permeability and clearance views of drug absorption: A commentary

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45051/1/10928_2006_Article_BF02354289.pd

Study protocol for locoregional precision treatment of hepatocellular carcinoma with transarterial chemoembolisation (TACTida), a clinical study:idarubicin dose selection, tissue response and survival

INTRODUCTION: Hepatocellular carcinoma (HCC) is a common cause of cancer-related death, often detected in the intermediate stage. The standard of care for intermediate-stage HCC is transarterial chemoembolisation (TACE), where idarubicin (IDA) is a promising drug. Despite the fact that TACE has been used for several decades, treatment success is unpredictable. This clinical trial has been designed believing that further improvement might be achieved by increasing the understanding of interactions between local pharmacology, tumour targeting, HCC pathophysiology, metabolomics and molecular mechanisms of drug resistance. METHODS AND ANALYSIS: The study population of this single-centre clinical trial consists of adults with intermediate-stage HCC. Each tumour site will receive TACE with two different IDA doses, 10 and 15 mg, on separate occasions. Before and after each patient's first TACE blood samples, tissue and liquid biopsies, and positron emission tomography (PET)/MRI will be performed. Blood samples will be used for pharmacokinetics (PK) and liver function evaluation. Tissue biopsies will be used for histopathology analyses, and culturing of primary organoids of tumour and non-tumour tissue to measure cell viability, drug response, multiomics and gene expression. Multiomics analyses will also be performed on liquid biopsies. PET/MRI will be used to evaluate tumour viability and liver metabolism. The two doses of IDA will be compared regarding PK, antitumour effects and safety. Imaging, molecular biology and multiomics data will be used to identify HCC phenotypes and their relation to drug uptake and metabolism, treatment response and survival. ETHICS AND DISSEMINATION: Participants give informed consent. Personal data are deidentified. A patient will be withdrawn from the study if considered medically necessary, or if it is the wish of the patient. The study has been approved by the Swedish Ethical Review Authority (Dnr. 2021-01928) and by the Medical Product Agency, Uppsala, Sweden. TRIAL REGISTRATION NUMBER: EudraCT number: 2021-001257-31

Human Jejunal Permeability of Two Polar Drugs: Cimetidine and Ranitidine

Purpose . To determine the human jejunal permeability of cimetidine and ranitidine using a regional jejunal perfusion approach, and to integrate such determinations with previous efforts to establish a baseline correlation between permeability and fraction dose absorbed in humans for soluble drugs.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41484/1/11095_2004_Article_302739.pd

Antibody-Drug Conjugates and Targeted Treatment Strategies for Hepatocellular Carcinoma : A Drug-Delivery Perspective

Increased understanding of cancer biology, pharmacology and drug delivery has provided a new framework for drug discovery and product development that relies on the unique expression of specific macromolecules (i.e., antigens) on the surface of tumour cells. This has enabled the development of anti-cancer treatments that combine the selectivity of antibodies with the efficacy of highly potent chemotherapeutic small molecules, called antibody-drug conjugates (ADCs). ADCs are composed of a cytotoxic drug covalently linked to an antibody which then selectively binds to a highly expressed antigen on a cancer cell; the conjugate is then internalized by the cell where it releases the potent cytotoxic drug and efficiently kills the tumour cell. There are, however, many challenges in the development of ADCs, mainly around optimizing the therapeutic/safety benefits. These challenges are discussed in this review; they include issues with the plasma stability and half-life of the ADC, its transport from blood into and distribution throughout the tumour compartment, cancer cell antigen expression and the ADC binding affinity to the target antigen, the cell internalization process, cleaving of the cytotoxic drug from the ADC, and the cytotoxic effect of the drug on the target cells. Finally, we present a summary of some of the experimental ADC strategies used in the treatment of hepatocellular carcinoma, from the recent literature

Review on the effect of chemotherapy on the intestinal barrier : Epithelial permeability, mucus and bacterial translocation

Chemotherapy kills fast-growing cells including gut stem cells. This affects all components of the physical and functional intestinal barrier, i.e., the mucus layer, epithelium, and immune system. This results in an altered intestinal permeability of toxic compounds (e.g., endotoxins) as well as luminal bacterial translocation into the mucosa and central circulation. However, there is uncertainty regarding the relative contributions of the different barrier components for the development of chemotherapy-induced gut toxicity. This review present an overview of the intestinal mucosal barrier determined with various types of molecular probes and methods, and how they are affected by chemotherapy based on reported rodent and human data. We conclude that there is overwhelming evidence that chemotherapy increases bacterial translocation, and that it affects the mucosal barrier by rendering the mucosa more permeable to large permeability probes. Chemotherapy also seems to impede the intestinal mucus barrier, even though this has been less clearly evaluated from a functional stand-point but certainly plays a role in bacteria translocation. Combined, it is however difficult to outline a clear temporal or succession between the different gastrointestinal events and barrier functions, especially as chemotherapy-induced neutropenia is also involved in intestinal immunological homeostasis and bacterial translocation. A thorough characterization of this would need to include a time dependent development of neutropenia, intestinal permeability, and bacterial translocation, ideally after a range of chemotherapeutics and dosing regimens

Intestinal Permeability and Drug Absorption : Predictive Experimental, Computational and In Vivo Approaches

The main objective of this review is to discuss recent advancements in the overall investigation and in vivo prediction of drug absorption. The intestinal permeability of an orally administered drug (given the value P-eff) has been widely used to determine the rate and extent of the drug's intestinal absorption (F-abs) in humans. Preclinical gastrointestinal (GI) absorption models are currently in demand for the pharmaceutical development of novel dosage forms and new drug products. However, there is a strong need to improve our understanding of the interplay between pharmaceutical, biopharmaceutical, biochemical, and physiological factors when predicting F-abs and bioavailability. Currently, our knowledge of GI secretion, GI motility, and regional intestinal permeability, in both healthy subjects and patients with GI diseases, is limited by the relative inaccessibility of some intestinal segments of the human GI tract. In particular, our understanding of the complex and highly dynamic physiology of the region from the mid-jejunum to the sigmoid colon could be significantly improved. One approach to the assessment of intestinal permeability is to use animal models that allow these intestinal regions to be investigated in detail and then to compare the results with those from simple human permeability models such as cell cultures. Investigation of intestinal drug permeation processes is a crucial biopharmaceutical step in the development of oral pharmaceutical products. The determination of the intestinal P-eff for a specific drug is dependent on the technique, model, and conditions applied, and is influenced by multiple interactions between the drug molecule and the biological membranes