Current Drug Metabolism - Volume 19, Issue 10, 2018

Background: Drug-induced cholestasis is a risk factor in the progression of drug candidates, and poses a serious health hazard if not detected before going into a human. Intrahepatic accumulation of Bile Acids (BAs) represents a characteristic phenomenon associated with drug-induced cholestasis. Methods: This review will discuss the current knowledge and knowledge gaps regarding drug-induced cholestasis, such as complexity of BA-mediated toxicity mechanisms, disconnect in signatures of toxicity between clinical and preclinical models, and the impact of bile acids at different ‘targets’ such as transporters, enzymes and nuclear receptors. Results: It is important to assess drug-induced cholestasis mechanisms in a physiologically relevant holistic in vitro system. Lack of sensitive and early preclinical biomarkers relevant to the clinical situation, complicates proper detection of drug-induced cholestasis. Significant overlap in biomarker signatures between different mechanisms of Drug-induced Liver Injury (DILI) precludes identification of specific mechanisms. Unavailability of suitable animal models predictive of the toxicity observed in human add to the lack of prediction of clinical drug-induced cholestasis. Conclusion: Recent developments regarding BA-mediated inflammation as a trigger for toxicity significantly improved understanding of mechanisms of clinical drug-induced cholestasis. Increased insight into susceptibility factors in addition to Bile Salt Export Pump (BSEP) inhibition, biomarkers and involvement of immune system decreased knowledge gaps. Increased knowledge is assisting the development of the novel in vitro models providing a holistic understanding of processes underlying drug-induced cholestasis. This review summarizes the challenges and recent developments about drug-induced cholestasis with a potential path forward for informed decision-making during the drug development process.

Background: Most of the drugs are metabolized in the liver by the action of drug metabolizing enzymes. In hepatocellular carcinoma (HCC), primary drug metabolizing enzymes are severely dysregulated, leading to failure of chemotherapy. Sorafenib is the only standard systemic drug available, but it still presents certain limitations, and much effort is required to understand who is responsive and who is refractory to the drug. Preventive and therapeutic approaches other than systemic chemotherapy include vaccination, chemoprevention, liver transplantation, surgical resection, and locoregional therapies. Objectives: This review details the dysregulation of primary drug metabolizing enzymes and drug transport proteins of the liver in HCC and their influence on chemotherapeutic drugs. Furthermore, it emphasizes the adoption of safe alternative therapeutic strategies to chemotherapy. Conclusion: The future of HCC treatment should emphasize on understanding of resistance mechanisms and the finding of novel, safe, and efficacious therapeutic strategies, which will surely benefit patients affected by advanced HCC.

Background: Drug-induced Liver Injury (DILI) is an important cause of acute liver failure cases in the United States, and remains a common cause of withdrawal of drugs in both preclinical and clinical phases. Methods: A structured search of bibliographic databases – Web of Science Core Collection, Scopus and Medline for peer-reviewed articles on models of DILI was performed. The reference lists of relevant studies was prepared and a citation search for the included studies was carried out. In addition, the characteristics of screened studies were described. Results: One hundred and six articles about the existing knowledge of appropriate models to study DILI in vitro and in vivo with special focus on hepatic cell models, variations of 3D co-cultures, animal models, databases and predictive modeling and translational biomarkers developed to understand the mechanisms and pathophysiology of DILI are described. Conclusion: Besides descriptions of current applications of existing modeling systems, associated advantages and limitations of each modeling system and future directions for research development are discussed as well.

Background: Cancer is a foremost cause of mortality worldwide. Available treatments are non-specific and cannot cross biological barriers, which have restricted their usages. Furthermore, the side effects of existing treatments have promoted the exploration of nanotechnological approaches to achieve site-specific drug delivery. The diminutive sizes of nanoparticles, and hence, their large surface to volume ratios, means they are inherently more efficient at delivering drugs to specific tumor sites. This review highlights different approaches to cancer therapy, and the importance of nanoparticles in cancer therapy. Applications and limitations of different types of nanomedicines used for cancer imaging and treatment are discussed. Methods: We undertook extensive literature search of bibliographic databases (e.g. PubMed, Google Scholar, Medline, Web of Science etc.) using different keywords and combination of keywords to retrieve the relevant information. Results: This review provides overview of cancer and need for nanoparticle-based therapies for their treatment, and deliberates the different types of nanomaterials used as nanomedicines for cancer imaging and treatment in addition to their applications and limitations. Furthermore, applications of nanoparticles in modern cancer therapies and research strategies have been explored to overcome cancer. Conclusion: Nanotechnology has provided a lot of novel therapeutics for the diagnosis and treatment of different cancers over the last 2-3 decades. However, there are few limitations of nanotechnological based anti-cancer therapies. Nanotechnology is enabling novel, specialized treatments for cancer; this will be a high-impact area of nanomedicine yielding more medical advancements with the next 10 years.

Background: Higher animals, especially the human beings have the privilege of employing advanced central nervous system (CNS) as well as the evolved immune system to ward off various onslaughts throughout their life. Alterations in inflammatory and neural regulatory pathways lead to several disorders that are now becoming the cause of concern across the world. Deregulation in bidirectional network, particularly in aging population, leads to several neurodegenerative diseases such as dementia as a one of the major characteristics. Objective: Interestingly, research updates have signified the role of abrupt immune regulation in several brain diseases, establishing a link between altered immune system and CNS related diseases. In the later period of life, the altered immune response in the pathogenesis of major psychiatric disorders, has become more visible. In the present manuscript, we present a synopsis on the linkage of CNS and immune system with respect to psychology, with the aim to further understand the biological machinery of psychoneuroimmunological disorders. The immune system of human being plays an important role in keeping pathogen onslaughts on bay. Conclusion: Our manuscript concludes a close relationship between emotion and psychology to diseases and immunology, proclaiming the need of providing enhanced attention on mechanistic aspect of psychoneuroimmunological disorders.

Background: Blood platelets are crucial for maintaining hemostasis and several events in the woundhealing. However, platelet up-regulation leads to the development and the complications of several cardiovascular diseases. For the effective management of these complications, several synthetic drugs are in clinical practice such as aspirin, warfarin and other drugs. since a long time. But some adverse reactions like aspirin resistance and bleed disorders cause patient incompliance and reduce their therapeutic potential. Thus, the search for potent and safer antiplatelet agents is of great interest. Methods: Various search engines such as Google, GoogleScholar, PubMed and ScienceDirect were used for the search of antiplatelet glycosides. All peered review journals were considered in the review. Results: Glycoside is a class of naturally-occurring organic compounds that are frequently found in the plant kingdom. Similarly, platelet aggregation beyond the purpose of hemostasis is the underlying cause of blood clottingrelated diseases. The results showed strong potential of plant derived glycosides in various preclinical studies. Conclusions: This review presents a thorough understanding of plant-derived glycosides as antiplatelet agents with a possible mechanism of action based on the existing literature. In addition, this review discusses the possibility of formulating antiplatelet medications from plant glycosides with strong safety profile. On the basis of strong finding, clinical studies are recommended to ascertain their therapeutic utility.

Background: As society has developed and living standards have improved, diabetes has become a severe public health issue. Insulin plays a crucial role in managing hyperglycemia caused by type I diabetes and particular type II diabetes. Many researchers are seeking alternative, more acceptable methods of insulin delivery, such as oral insulin. An oral formulation has become a new goal for insulin delivery in recent years. Methods: The PubMed and CNKI databases were searched for “oral insulin, ” “drug delivery systems, ” and “pharmacokinetics, ” and 85 relevant articles were selected from the results as material for this review. These papers were authoritative and had a higher number of citations. Results: Oral insulin would be highly advantageous but is poorly absorbed. The main reason for low absorptivity is the hydrolysis of insulin by enzymes in the gastrointestinal tract. Lack of active transport vectors that pass through the intestinal epithelium is also a non-negligible problem. Additional issues need to be considered to facilitate appropriate research, such as long-term efficacy and safety, clinical data, and toxicological characteristics. Conclusion: This review summarized recent advances in oral insulin and the pharmacokinetic profile of the suitable delivery system, providing valuable reference material for future research.

Background: Progesterone is a sex steroid hormone. Since it has been discovered, it is widely used in the prevention of spontaneous preterm birth, hormone replacement therapy and other gynecological conditions. Methods: We will review the progesterone preparations based on a comprehensive study of papers and patents from the traditional preparations up through the very recent literatures. Results: This review mainly concentrates on oral, vaginal and micro delivery systems, involving different ways to prepare progesterone preparations. Conclusion: Although progesterone has first-pass effects, with these methods, the bioavailability and compliance can be greatly increased.

Background: Pasireotide (SOM230) is a multi-receptor ligand somatostatin analogue (SSA) developed as the successor of the first-generation SSAs. Currently, pasireotide is recommended for the treatment of patients with Cushing's disease in whom surgery was unsuccessful, and patients with acromegaly who either remain uncontrolled after surgical therapy or in whom tumor resection is not possible. Methods and Results: Phase II and III clinical trials have shown pasireotide efficacy in these diseases, with a similar rate of adverse events when compared with first-line SSA, although higher incidence of hyperglycemia has been observed. Conclusion: Pasireotide therapy provides biochemical control, tumor volume reduction, and improves the quality of life in patients with those disorders. Furthermore, pasireotide might be considered as second-line therapy in patients with metastatic neuroendocrine tumors, and it also might be effective in other neoplasms with a high expression of somatostatin receptors. In addition, therapy with this novel agent has been effective in prevention of postoperative complications after pancreatectomy. However, considering the diversified responsiveness to this drug in vivo, future studies should identify factors predicting better clinical response to pasireotide.

Background: Increasing evidence proves the pivotal role of gut microbiota in mammals' homeostasis. Gut bacterial metabolites may exert local effects on the intestines, and may enter the circulation, affecting the functions of virtually all organs. Here, we review the available evidence on metabolism and biological effects of gut microbiota- derived indoles. Methods: The PUBMED database and Google Scholar were searched to identify experimental and clinical studies investigating biological effects of gut bacteria-derived indoles. Key words included: gut microbiota, indoles, indole and tryptophan. Results: Indoles represent a wide group of gut bacteria-derived compounds produced from tryptophan, an essential amino acid and the precursor of endogenous synthesis of tryptamine, serotonin and melatonin. Ample evidence suggests that indoles derived from gut microbiota metabolism exert significant biological effects and may contribute to the etiology of cardiovascular, metabolic, and psychiatric diseases. However, a majority of the research is limited to experimental studies and only a small number of clinical trials. Conclusion: Bacterial indoles affect the function of many biological systems. Whether gut-derived indoles contribute to pathogenesis of cardiovascular, metabolic and other diseases, requires further clinical studies.