Current Drug Metabolism (v.17, #2)

Zhi -Yao He, Kun Shi, Yu-Quan Wei, Zhi-Yong Qian
Keywords: Background: Poly(ether-ether) and poly(ether-ester) block copolymers have been widely applied in biomedical fields over two decades due to their good safety and biocompatibility. Poly(ethylene glycol), poly(ethylene glycol)-poly(propylene glycol) and poly(lactic-co-glycolic acid) have been approved as excipients by Food and Drug Administration. Because of the broad perspective in biomedical fields, many novel poly(etherether) and poly(ether-ester) block copolymers have been developed for drug delivery, gene therapy and tissue engineering in recent years. This review focuses on active targeting theranostic systems, gene delivery systems and tissue engineering based on poly(ether-ether) and poly(ether-ester) block copolymers.
Methods: We perform a structured search of bibliographic databases for peer-reviewed scientific reports using a focused review question and inclusion/exclusion criteria. The literatures related to the topics of this review are cataloged according to the developed copolymers or their applications such as active targeting theranostic systems, gene delivery systems and tissue engineering. Some important advances and new trends are summarized in this review.
Results: Some commercial poly(ether-ether) copolymers have been used as excipients for drug research and development. Amphiphilic and biodegradable poly(ether-ester) diblock copolymers are capable of formulating biomedical nanoparticulate theranostic systems, and targeting moiety-functionalized poly(ether-ester) diblock copolymers will be further developed and applied in biomedical nanotechnology fields in the near future. Meanwhile, triblock or multiblock poly(ether-ether) and poly(ether-ester) copolymers with environmentsensitive properties are suitable for gene delivery and tissue engineering. Poly(ether-ether) and poly(ether-ester) copolymers are being extensively applied in active targeting theranostic systems, gene delivery systems and tissue engineering.
Conclusions: Biodegradable, environment-sensitive and targeting moiety-functionalized block copolymers, which are being applied in active targeting theranostic systems, gene delivery systems and tissue engineering, are promising candidates for treatment of various diseases.

Meet Our Editorial Board Member by Albert P. Li (99-99).

UGT1A1 Mediated Drug Interactions and its Clinical Relevance by Chong Ping Goon, Ling Zhi Wang, Fang Cheng Wong, Win Lwin Thuya, Paul Chi-Lui Ho, Boon Cher Goh (100-106).
Background: The administration of multiple drugs for the treatment of diseases is an integral aspect of modern medicine. Though its purpose is to create the intended therapeutic effect, the unintended consequences of drug interactions can cause severe side effects and subsequent economic losses. Likewise, herbal extracts and supplements with pharmacologically active moieties also have the potential to interact with medications. There are many possible mechanisms on how these moieties could potentially interact, one of which is mediated by modulation of the activity of metabolizing enzymes. One such enzyme of high clinical significance is uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). Genetic polymorphism of UGT1A1 has been found to affect the plasma concentrations of many drugs, and may even be linked to treatment outcome.
Objective: This mini-review summarized the potential in vitro and in vivo interactions mediated by UGT1A1.
Method: Firstly, literature search was conducted using the Web of Knowledge database. No date limitation was applied to the search. Following which, the interactions were stratified into 3 main categories based on its clinical significance. Both herbal and pharmacological drug moieties are covered within the scope of this mini-review.
Results: Of 35 UGT1A1 induced drug interactions, likely and unlikely to be clinically significant interactions are 11 and 6 respectively. The rest of them are inconclusive.
Conclusion: We hope that this secondary literature can broaden and update the perspective of clinicians, pharmacists and academics on the interactions mediated by UGT1A1.

Cunninghamella Biotransformation - Similarities to Human Drug Metabolism and Its Relevance for the Drug Discovery Process by Kamil Piska, Dorota |elaszczyk, Marek Jamrozik, Paulina Kubowicz-Kwa|ny, El|bieta P|kala (107-117).
Background: Studies of drug metabolism are one of the most significant issues in the process of drug development, its introduction to the market and also in treatment. Even the most promising molecule may show undesirable metabolic properties that would disqualify it as a potential drug. Therefore, such studies are conducted in the early phases of drug discovery and development process. Cunninghamella is a filamentous fungus known for its catalytic properties, which mimics mammalian drug metabolism. It has been proven that C. elegans carries at least one gene coding for a CYP enzyme closely related to the CYP51 family. The transformation profile of xenobiotics in Cunninghamella spp. spans a number of reactions catalyzed by different mammalian CYP isoforms.
Objective: This paper presents detailed data on similar biotransformation drug products in humans and Cunninghamella spp. and covers the most important aspects of preparative biosynthesis of metabolites, since this model allows to obtain metabolites in sufficient quantities to conduct the further detailed investigations, as quantification, structure analysis and pharmacological activity and toxicity testing.
Conclusion: The metabolic activity of three mostly used Cunninghamella species in obtaining hydroxylated, dealkylated and oxidated metabolites of different drugs confirmed its convergence with human biotransformation. Though it cannot replace the standard methods, it can provide support in the field of biotransformation and identifying metabolic soft spots of new chemicals and in predicting possible metabolic pathways. Another aspect is the biosynthesis of metabolites. In this respect, techniques using Cunninghamella spp. seem to be competitive to the chemical methods currently used.

Preventive and Therapeutic Effects of the Retinoid X Receptor Agonist Bexarotene on Tumors by Lisi Qi, Yuanyuan Guo, Pei Zhang, Xiaorong Cao, Yuxia Luan (118-128).
We present a review of recent investigations of anticancer drug bexarotene in this article. As one of the novel synthetic analogs of retinoids, bexarotene selectively binds to and activates the retinoid X receptor (RXRs) subfamilies, exerting a prophylactic and therapeutic effect on a large series of tumors in vitro and in vivo covering cutaneous lesions, lung and breast cancers, nervous system diseases etc. Bexarotene has been proved to have a specifically favorable therapeutic profile in clinical dermatology or oncology with mild or absent retinoids side effects, especially in combination with other therapies. It is noteworthy that numerous previous outstanding researches have contributed to the chemical, biological, preclinical and clinical examinations of bexarotene during the past decades, with a relatively deficient progress of bexarotene in the field of pharmacy. In this review, the positive therapeutic results of bexarotene used as a monotherapy or combination therapy both in preclinical and clinical studies are reported based on relevant medical data; the distinct acting mechanisms of bexarotene are described; the potential studies and prospects of bexarotene in pharmaceutical domain are discussed. All the reports above collectively present bexarotene as a promising anti-cancer agent.

Prediction of Metabolism of Drugs using Artificial Intelligence: How far have we reached? by Rajnish Kumar, Anju Sharma, Mohammed Haris Siddiqui, Rajesh Kumar Tiwari (129-141).
Information about drug metabolism is an essential component of drug development. Modeling the drug metabolism requires identification of the involved enzymes, rate and extent of metabolism, the sites of metabolism etc. There has been continuous attempts in the prediction of metabolism of drugs using artificial intelligence in effort to reduce the attrition rate of drug candidates entering to preclinical and clinical trials. Currently, there are number of predictive models available for metabolism using Support vector machines, Artificial neural networks, Bayesian classifiers etc. There is an urgent need to review their progress so far and address the existing challenges in prediction of metabolism. In this attempt, we are presenting the currently available literature models and some of the critical issues regarding prediction of drug metabolism.

Neuroprotective Role of Nanoparticles Against Alzheimer';s Disease by Magisetty Obulesu, Magisetty Jhansilakshmi (142-149).
Background: Alzheimer's disease (AD) is a devastative neurodegenerative disorder with a complex etiology. Despite numerous novel nanotechnology methods targeted against cancer and neurodegenerative diseases such as AD in the past decade, several challenges impeded their success.

Objective: We ventured to circumvent these challenges by synthesizing redox nanoparticles (RNP) such as Nitroxide radical, 2,2,6,6 tetramethylpiperidinyl-N-oxyl (TEMPO). Piperine in association with RNP successfully scavenges reactive oxygen species (ROS). Our studies have also shown that the piperine associated with RNP confers enhanced protection against AD in vitro.

Conclusion: This review summarizes our recent findings on the protective roles of redox nanoparticles both in vitro and in vivo. In addition, vital role of nanoparticles employed to encapsulate natural compounds such as curcumin and metal chelators has been summarized. We warrant further studies in animal models using these protective nanoparticles.

Metabolic Alterations in Renal and Prostate Cancer by Chiara Ciccarese, Matteo Santoni, Francesco Massari, Alessandra Modena, Francesco Piva, Alessandro Conti, Roberta Mazzucchelli, Liang Cheng, Antonio Lopez-Beltran, Marina Scarpelli, Giampaolo Tortora, Rodolfo Montironi (150-155).
Background: Cancer metabolism is emerging as a promising research area in genitourinary tumors. Both renal cell carcinoma (RCC) and prostate cancer (PCa) cells exhibit marked alterations of their metabolism. These changes include increased aerobic glycolysis (the Warburg effect), increased protein and DNA synthesis and de novo fatty acid (FA) synthesis.
Objective: Understanding the molecular mechanisms underlying such alterations will represent a major step forward in cancer research. Indeed, reprogramming cancer cell energy metabolism represents a promising hallmark of cancer and may pave the way for novel personalized approaches.
Method: PubMed databases were searched for articles published about cancer metabolism in genitourinary tumors. Results and Conclusion: This review is focused on the metabolic alterations that occur in RCC and PCa and describes the mechanisms underlying such metabolic changes.

Background: Wound healing is a composite and vital process in which devitalized tissue layers and cellular structures repair themselves. Bronchiolitis is generally prompted by respiratory syncytial virus or human metapneumovirus; this condition is an acute inflammatory injury of bronchioles. Heart problems that develop before birth are known as congenital heart defects (CHDs), and pregestational diabetes is considered a major predisposing factor of CHDs. N-Acetylcysteine (NAC) is a transformed kind of amino acid cysteine which restores the intracellular levels of the natural antioxidant glutathione when taken internally, thereby assisting the cells' ability to diminish the damaging effects of reactive oxygen species (ROS).
Objective: In the present communication, NAC's therapeutic potential for wound healing, acute bronchiolitis, and congenital heart defects (CHDs) is critically analyzed by reviewing its effect on the various targets of these diseases. The multifunctional nature of NAC is outlined in a review of evidence from in vitro and in vivo studies.
Conclusion: In conclusion, NAC could be used as a therapeutic agent in the treatment of wound healing, acute bronchiolitis and congenital heart defects (CHDs). The focus of future research should be the following; (1) to examine NAC clinically to be considered in the treatment of wound healing; (2) to investigate whether NAC could be used alone or with insulin to prevent CHDs in infants with pregestational diabetes; (3) to evaluate the application of NAC as a potential agent for PAH treatment.

Digestive Enzyme Supplementation in Gastrointestinal Diseases by Gianluca Ianiro, Silvia Pecere, Valentina Giorgio, Antonio Gasbarrini, Giovanni Cammarota (187-193).
Background: Digestive enzymes are able to break down proteins and carbohydrates and lipids, and their supplementation may play a role in the management of digestive disorders, from lactose intolerance to cystic fibrosis. To date, several formulations of digestive enzymes are available on the market, being different each other in terms of enzyme type, source and origin, and dosage.
Methods: This review, performed through a non-systematic search of the available literature, will provide an overview of the current knowledge of digestive enzyme supplementation in gastrointestinal disorders, discussion of the use of pancreatic enzymes, lactase (-galactosidase) and conjugated bile acids, and also exploring the future perspective of digestive enzyme supplementation.
Results: Currently, the animal-derived enzymes represent an established standard of care, however the growing study of plant-based and microbe-derived enzymes offers great promise in the advancement of digestive enzyme therapy.
Conclusion: New frontiers of enzyme replacement are being evaluated also in the treatment of diseases not specifically related to enzyme deficiency, whereas the combination of different enzymes might constitute an intriguing therapeutic option in the future.

Effects Of Glycoprotein IIb/IIIa Antagonists: Anti Platelet Aggregation And Beyond by Arturo Giordano, Giuseppe Musumeci, Anna D';Angelillo, Roberta Rossini, Giuseppe Biondi Zoccai, Stefano Messina, Enrico Coscioni, Simona Romano, Maria Fiammetta Romano (194-203).
Background: The use of inhibitors of glycoprotein IIb/IIIa (GPIIb/IIIa) has provided dramatic results in terms of the prevention of acute stent thrombosis and a reduction in major adverse coronary events in patients subjected to percutaneous coronary intervention. GPIIb/IIIa or αIIbβ3 is a member of the β3 subfamily of integrins, which also includes αVβ3. GPIIb/IIIa functions as a receptor for fibrinogen and several adhesion proteins sharing an arginine-glycine-aspartic acid (RGD) sequence. GPIIb/IIIa antagonists, through blockade of the receptor, prevent platelet aggregation. Among the three GPIIb/IIIa antagonists used in therapy, abciximab is an anti-β3 monoclonal antibody, while tirofiban and eptifibatide mimic the binding sequence of the fibrinogen ligand. Although antiplatelet aggregation represents the central function of GPIIb/IIIa inhibitors, further actions have been documented for these compounds.
Objective: The aim of the present article is to review the structures and functions of GPIIb/IIIa antagonists and to highlight the clinical outcomes and results of randomized trials with these compounds. Hypotheses on the unexplored potential of GPIIb/IIIa antagonists will be put forward.
Conclusion: GPIIb/IIIa inhibitors were developed to prevent platelet aggregation, however, these compounds can exert further biological functions, both platelet- and non-platelet-related. Large-scale studies comparing the efficacy and safety of GPIIb/IIIa antagonists are lacking. More insights into the functions of these compounds may lead to generation of novel small molecules able to antagonize platelet aggregation while promoting vascular repair.