Current Drug Metabolism

A variety of factors can affect the patients' responses to therapeutic drugs, such as race, gender, age, etc., while genetic polymorphisms are the main causes of individual differences in drug responses. The genetic polymorphisms are not only closely related to the incidence of diseases such as tumors, Alzheimers, and Parkisnsons, but also affect the metabolism, activity, and toxicity of the drugs. The studies of genetic polymorphisms on drug metabolizing enzymes, transporters, and targets are helpful to clarify the relationships between gene mutation and efficacy or safety of drugs. Patients could be given different therapies according to different genotypes, which may significantly improve the therapeutic effect. Genetic polymorphisms provide a new way for individualized treatments besides therapeutic drug monitoring. At present, the relationships between genetic polymorphisms of many drugs and clinical outcomes have been very clear. For example, the guideline emphasizes that genetic testing has the vital significance when taking warfarin. However, although genetic polymorphisms of many drugs have been reported, some studies are controversial, it is also necessary to integrate various genetic factors for further research. Therefore, this special issue of Current Drug Metabolism is to publish some valuable reviews on how genetic polymorphisms affect the pharmacokinetics and pharmacodynamic parameters of several therapeutic drugs, including antitumor drugs, antiasthmatic drugs, immunosuppressive agents, anti-infective drug, EGFR Tyrosine Kinase Inhibitors (EGFR-TKIs), and Recombinant Human Growth Hormone (rhGH), new oral anticoagulant, humanized anti-α4 integrin monoclonal antibody, Platelet-Derived Growth Factor Receptor (PDGFR) kinase inhibitors. We aim to provide current genetic research progress on these therapeutic drugs which are widely used in clinic therapy.

Gamma-hydroxybutyrate (GHB) is a potent central nervous system depressant, used as a recreational drug of abuse. It is quite frequently found in forensic investigations of subjects alive or dead. GHB in the form of sodium salt is a registered therapeutic agent approved of by some countries in treating narcolepsy-associated cataplexy and is an adjuvant medication for detoxification and withdrawal in alcohol abusers. GHB is endogenously produced and traces can be found (0.5-1.0 mg/L) in various tissues, including the brain, where it functions as both a precursor and a metabolite of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA). Information available indicates that GHB serves as a neurotransmitter or neuromodulator in the GABAergic system, and in particular via binding to the GABA-B receptor subtype. Taking into account the dual nature of this compound, endogenous and exogenous, various points need to be clarified and this special issue aims to focus on them, trying to provide the most updated scientific evidence in this field. Moreover, the role of new GHB metabolites, such as GHB-glucuronide (GHB-Gluc) and the sulfonated metabolite of GHB (GHB-SUL) and their detection window in biological samples, with particular emphasis on alternative matrices, will be given for forensic purposes, especially in cases of drug facilitated sexual assault (DFSA), and clinical purposes both in the short and long-term monitoring of patients under sodium oxybate treatment.

Tumor is one of the most serious threats to human beings. Benefiting from the fast development of nanotechnology, many kinds of nanoparticles that constructed from various nanomaterials were developed for tumor diagnosis and therapy. Nanoparticles have gained great attention of both academy and industry. However, few nanoparticles were approved for clinical application although thousands were developed in lab. Therefore, in this theme issue, we invited several contributors to discuss the application of various kinds of nanoparticles in tumor targeting drug delivery, as well as their advantages and shortages. Based on their good biocompatibility and low toxicity, polymeric nanoparticles have gained much attention in gene and drug delivery to tumor. However, the drug delivery efficiency by polymeric nanoparticles is greatly hindered by the rapid opsonization, phagocytic uptake and subsequent clearance from bloodstream. Therefore, in the first review, Hu et al. firstly discussed the factors that influence the blood circulation of polymeric nanoparticles, including particle size, shape, zeta potential and hydrophilicity. Then some natural and synthetic polymers used in the constructing of nanoparticles were reviewed, such as gelatin, polysaccharides, cyclodextrin, and synthetic polymers. While several preparation methods were also discussed, including polymerization techniques, precipitation techniques, film extension techniques, and particle replication in non-wetting templates. Finally, methods to achieve long blood circulation time were reviewed. In the review provided by Zhang et al., authors further discussed the strategies in long circulating drug delivery by nanoparticles. To achieve the long blood circulation time, PEGylation is widely used in modification surface of nanoparticles to inhibit the adsorption of opsonins in blood. As an alternative of finding new nanomaterials especially new surface coating materials, biomimetic nanoparticles showed great potential because they can adopt the intrinsic long circulation behavior of biological components, such as red blood cells, cancer cells, macrophages, bacteria, viruses and lipoproteins. The application of these strategies and the constructed nanoparticles were detailed reviewed in the paper. Safety of nanomaterials is a great concern for clinical application, that is why only few formulations were approved by Food and Drug Administration (FDA) of US. To meet the safety concern, natural polymers are good candidates to constructing nanoparticles. Polysaccharide is one of the most widely explored and used natural polymers, and many kinds of derives were developed to provide excellent properties in drug delivery. In the review, Dr. Tong and Dr. Ma summarized the representative examples of polysaccharides used in drug delivery, such as chitosan, hyaluronic acid, dextran and pullulan. Because of their widely application in tumor targeting diagnosis and treatment, the reviewed discussed several aspects of the application of polysaccharide, including gene delivery, small molecular drug delivery, no matter polysaccharide- drug conjugates or drug encapsulation, combinational drug delivery, and finally theranostics. In the review, many examples were provided with in-deep discussion. As a supplement to the natural polymers, nature products could be directly used in treatment of cancers. Therefore, Dr. Cai and Dr. Yu reviewed the application of natural products in cancer therapy by targeting the apoptosis pathways. In the review, key proteins involved in the regulation of apoptosis were firstly summarized, including Cytochrome c, Bcl-2 family, p53, Fas, Survivin, Caspase family, Nuclear factor- B, and Protein Kinase B. Then various kinds of natural products that can target these proteins were reviewed. Gold nanoparticles are most widely used inorganic nanomaterials in cancer diagnosis and therapy, while many kinds of anisotropic gold nanoparticles are developed, including gold nanospheres, gold nanoclusters, one-dimensional gold nanorods, two-dimensional gold nanoplates, gold nanoshells, platonic gold nanoparticles, hollow gold nanoparticles and other types of gold nanoparticles. In the review provided by Dr. Shevtsov et al., the various synthesis methods for these kinds of gold nanoparticles were summarized. Then the application of gold nanoparticles in drug delivery was reviewed. Gold nanoparticles have been used in many aspects of tumor treatment and diagnosis, such as modification tumor microenvironment, radiosensitization, photothermal therapy, and photodynamic therapy. All these researches demonstrated the great potential of gold nanoparticles in tumor management. At last, as a kind of cancers with highest incidence, lung cancer was paid with particular attention. Zheng et al. reviewed the nanoparticles in management of lung cancer, including polymeric nanoparticles, lipid nanoparticles, human serum albumin nanoparticles, and inorganic nanoparticles. Then the various models used for different application routes were reviewed. Finally, the clinical application of these administration routes and formulations were discussed.

Mental disorders such schizophrenia, depression, bipolar and anxiety disorders are leading causes of disability and multimorbidity in the modern society. In recent years, major advances were made in order to understand the molecular basis of these disorders aiming to discover potential new drugs. Unfortunately, the majority of these efforts have been unsuccessful. Many other studies have been focused on understanding the mechanism of action of drugs used for the treatment of neuropsychiatric disorders, such as antidepressants, mood stabilizers and antipsychotics using isolated systems. Many incredible discoveries were made which allowed us to develop better treatment options to improve the quality of life of patients struggling with these disorders. Today, clinicians and scientists are combining forces to better understand different connections of the brain-body relationship that were refuted for many years because of the general idea of the brain as an independent and isolated tissue. The concept of a two-way relationship between depression and cardiovascular disease, or the gut-brain axis is only gaining more space and credibility. We are in the moment of understanding how our complex body is interconnected in the way that a single insult in a remote part of our body could lead to molecular changes in our brain. We are also better understanding the side effects of distinct drugs, such as antidepressants, and their impact on a population with cardiovascular disease or the relationship between long-term lithium intake and cancer proliferation. More studies are still needed to confirm these suggestions; however, they are thought-provoking. This thematic issue, devoted to the study of current pharmacological treatments involved in mental disorders introduce an interesting interface intended to explore (i) the safety limits of the use of antidepressants on cardiovascular function [1], (ii) the cross-talk between inflammation in depression and cardiovascular disease [2], (iii) the involvement of microbiota in the etiopathogenesis of mental illness [3], (iv) the relationship between lithium intake and cancer proliferation [4] and (v) the applicability of targeting GSK-3B for several incurable neuropsychiatric disorders [5]. It is evident that science reached a time where scientists and clinicians are combining strengths to better comprehend the molecular basis of pharmacological treatments to study the diseases as they occur; in combination, and not isolated. In this new era of technology and information, combining forces in a multidisciplinary environment to understand the pathological basis will only improve the treatment options and the quality of life of patients with psychiatric disorders.

Chronic kidney disease (CKD) leading to kidney failure is becoming a global public health problem. Acute kidney injury (AKI) is also a major kidney disease characterized by a rapid decline of renal function. Drug-induced nephrotoxicity is a contributing factor to AKI in 19-25% of critically ill patients. Drugs exert their toxic effects to cause nephrotoxicity by one or more common pathogenic mechanisms. The progressive loss of kidney function associated with CKD not only leads to impaired renal excretion of numerous drugs and their metabolites in the kidneys, but also alters the non-renal disposition of moieties that are extensively metabolized by the liver. Various alterations in activity of metabolic enzyme system have been reported in CKD models, for example, reductions in expression and activity of hepatic cytochrome P450 (CYP) enzymes including CYP3A1, CYP3A2, CYP2C11, and other enzymes such as N-acetyltransferases. What’s more, other mechanisms such as the dysregulation of drug transporter systems are involved in decreasing the clearance of drugs in renal failure. With the development of renal failure, the renal secretion of organic ions mediated by organic anion transporters (OATs) and organic cation transporters (OCTs) is decreased. Some organic anionic uremic toxins may directly inhibit the renal excretion of various drugs and endogenous organic acids by competitively inhibiting OATs. The objective of this mini-thematic issue is to report recent studies about most common mechanisms of drug-induced nephrotoxicity and prevention strategies, the alterations of drug enzymes and transporters in the kidney and liver in renal failure, the potential model systems to predict drug efficacy, interactions, and drug-induced kidney injury in drug development.

Neurological disorders cover a wide range of diseases; suffering patients all around the world. A study in UK shows about six percent of the population involved with neurological disorders [1]. Also, investigations stated that the imposed cost of these disorders is an important challenge for European societies [2]. Therefore, there are too many investigations to find new medical approaches and remedies to treat or manage neurological disorders. Natural products as well as complementary and alternative therapies are as the sources to find such therapeutics that are going to be more popular in the society. There are too many traditional and complementary systems of medicine, mostly with historical roots in ancient eras like Chinese medicine, Persian medicine, Ayurveda, Homeopathy, etc. [3] Alongside raising the popularity of using natural and traditional medications, interest of researchers to evaluate their efficacy and safety is going to be raise up. On the other hand, this popularity causes some concerns including the safety and probable interactions between these remedies with common drugs. Therefore, investigations to find the efficacy and safety of them with the help of accepted and academic methods are too important. World Health Organization (WHO) approves and encourages traditional therapies integrated with current and conventional medicine. It means using the opportunities in both medical systems, traditional and conventional medicines [4]. It is important to integrate Traditional and Complementary Medicine (T&CM) approaches to current medical systems. It is not only necessary for using T&CM opportunities to manage and treat neurological disorders and decrease the costs of treatment, but to find any probable side effects and interactions with such remedies. Therefore, in the first step, it needs scientific investigations to find T&CM drugs’ efficacy, safety and toxicology and then, in the next step training the neurologists and pharmacists is too important. Therefore, this thematic issue of Current Drug Metabolism aims to publish some valuable reviews on the principles, suggestions, efficacy of drugs and also herb-drug interactions of some types of T&CM systems in some neurological disorders; providing scientific data and discussions for medical practitioners, pharmacists and researchers in this field.

This thematic issue will provide a platform to share comprehensive information on advances and recent trends in various prophylactic and therapeutic regimens to effectively combat various diseases and other health problems, both infectious and non-infectious posing challenge to the humans and their companion animals (livestock & poultry). It will focus mainly on the novel, emerging and valuable alternate / complementary frontier therapeutic options especially in the era of emerging and rising drug resistance in microbial pathogens and increasing health disorders and conditions of high concerns due to changing life style and other various predisposing factors. Advances and interdisciplinary approaches of biotechnology, molecular biology, genetics, cellular immunology, immunomics, proteomics, pharmacology, bioinformatics, nanotechnology and others for designing and developing newer and effective therapeutic modules would be given priority. These will include phages, enzybiotics, apoptins, cytokines, monoclonal antibodies, egg yolk antibodies, TLR, stem cells, si-RNA, nanomedicines, nutritional immunomodulation, probiotics, antioxidants, phytonutrients, and herbal medicines, which could play promising role in curbing evolving pathogenic threats by their potent antimicrobial potential, treating non-infectious diseases, metabolic disorders, cancers as well as various general health problems. Other potential candidates being explored for targeting development of valuable medicines, drugs, pharmaceuticals, immunotherapeutics, antitoxins, tissue growth factors, gene therapy, regenerative medicines, therapeutic biologics, modern vaccines and vaccines based therapies will also be considered. Trends and advances in pharmacogenomics aided drug development and therapeutics, pharmacokinetics, pharmacodynamics and metabolism of effective/newer drugs and medicines, upcoming drug designing and novel drug delivery methods will also be given due attention. The compilation will be useful for medical and veterinary professionals, clinicians, researchers, students/scholars, public health experts, animal producers, and pharmaceutical industry in designing and adapting effective and safer therapeutics from clinics to the laboratory for countering important diseases. This thematic issue will accept submissions of comprehensive review papers on above mentioned topics / theme with their basics, modes of action, medicinal values, beneficial health applications, modern trends and advances, perspectives, which could lead to designing and development of effective therapeutics, drugs/medicines, nutraceuticals and pharmaceuticals in the area of biomedicine with an aim to safeguard health of both humans and animals in a better way.

Recent developments in nanomaterials for the therapy of deadliest diseases have gained significant interest because of their advantages, such as reduction in systemic toxicity, easy surface functionalization with passivation and targeting moieties, and enhanced drug accumulation in specific tissue. Nanomedicines and nanomaterials can be administrated by different strategies, including oral, local, intravenous, and transarterial administration, which are the underlying determinants for their therapeutic efficacy, pharmacokinetics and pharmacodynamics. In order to optimize the therapeutic outcomes, careful design and synthesis of nanomedicines are guided by the administration strategies. It requires a broad-system view for innovative nanomaterials and their clinical applications. The aim and scope of the issue is to introduce Current Drug Metabolism readers to this important topic of efficacy, toxicology, and PK/PD of nanomedicine administrated by different strategies. I would like to thank Editor-in-Chief, Michael Sinz, for his support and all authors for their contribution to this special issue. I am grateful for all peer reviewers’ time and expertise, which help to improve quality of articles. I also thank Maryam Shaikh for the excellent coordination in publication process.

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