Showing papers in "Current Drug Metabolism in 2016"

Cannabinoids and Cytochrome P450 Interactions

Abstract: Objective: This review consists of three parts, representing three different possibilities of interactions between cannabinoid receptor ligands of both exogenous and endogenous origin and cytochrome P450 enzymes (CYPs). The first part deals with cannabinoids as CYP substrates, the second summarizes current knowledge on the influence of various cannabinoids on the metabolic activity of CYP, and the third outline a possible involvement of the endocannabinoid system and cannabinoid ligands in the regulation of CYP liver activity. Methods: We performed a structured search of bibliographic and drug databases for peer-reviewed literature using focused review questions. Results: Biotransformation via a hydrolytic pathway is the major route of endocannabinoid metabolism and the deactivation of substrates is characteristic, in contrast to the minor oxidative pathway via CYP involved in the bioactivation reactions. Phytocannabinoids are extensively metabolized by CYPs. The enzymes CYP2C9, CYP2C19, and CYP3A4 catalyze most of their hydroxylations. Similarly, CYP represents a major metabolic pathway for both synthetic cannabinoids used therapeutically and drugs that are abused. In vitro experiments document the mostly CYP inhibitory activity of the major phytocannabinoids, with cannabidiol as the most potent inhibitor of many CYPs. The drug-drug interactions between cannabinoids and various drugs at the CYP level are reported, but their clinical relevance remains unclear. The direct activation/inhibition of nuclear receptors in the liver cells by cannabinoids may result in a change of CYP expression and activity. Finally, we hypothesize the interplay of central cannabinoid receptors with numerous nervous systems, resulting in a hormone-mediated signal towards nuclear receptors in hepatocytes.

Delivery of Nanoparticles for Treatment of Brain Tumor.

Abstract: Background: Malignant brain tumor is a highly challenging disease for diagnosis, treatment, and management. Cytotoxicity, distribution and the ability to cross blood brain barrier are some of the most significant issues for the chemotherapy of brain tumors. Nanotechnology has been widely exploited in drug delivery with great potential in improving the drug efficiency and efficacy. The advent of nanotechnology would greatly facilitate the early detection and treatment of brain tumors. This review will be primarily focused on current nano drug delivery system for brain cancer therapy. Meanwhile, the existing impediments for therapeutic nanomedicines and critical analysis of the different delivery nanoparticles are also discussed. Methods: We systematically evaluated the major factors that impact the current nanomedicines for brain tumor therapy. Meanwhile, various nanoparticle-based formulations for brain cancer detection and therapy are evaluated. Results: 124 papers were included in this review. From the analysis of the nanomaterials, seven major nanomaterials have been discussed regarding the functionality and current therapeutic significance. The review also explains in detail about the different types of nanomaterials and their functionalities. This shows that each of these nanomaterials has specialized functions for the treatment of various kinds of brain cancer. Conclusion: Nanomaterials provide a viable potential diagnosis mechanis. In the future, more research needs to be focused on developing a better diagnosis tool for detection of cancer on an urgent basis. Blood-brain barrier and cytotoxicity are some of the primary root causes for the impediment of treatment of cancer using nanoparticles. Therefore, different delivery systems should be exploited for the nanoparticles to surmount these issues.

Digestive Enzyme Supplementation in Gastrointestinal Diseases

Abstract: 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.

Actively Targeted Nanoparticles for Drug Delivery to Tumor

Abstract: Background: Nanomedicine is an emerging therapeutic modality. Nanoparticles (NPs) are potential vehicles for delivery of anticancer therapeutics. NPs can be designed to facilitate tumor drug delivery both by passive and active targeting mechanisms. Passive targeting of NPs to tumors can be achieved through the enhanced permeability and retention (EPR) effect. Meanwhile, actively targeted NPs can be designed based on two different targeting mechanisms, ligand-directed targeting to the tumor cells and tumor microenvironment (TME)-directed targeting. Methods: We searched for and reviewed recently published literature on actively targeted NPs. Progress in this field was summarized in several focus areas, including methods for targeting of tumor cells and for targeting TME. Advantages and limitations of each approach were discussed. Results: This article covers data from 240 recent publications and provided numerous examples of ligand-directed NPs targeting tumor cell-selective surface receptors. Targeting ligands discussed include proteins such as transferrin and antibodies, as well as low molecular weight agents, such as peptides, aptamers, carbohydrates, and folate. In addition, extensive discussions of TME targeting NPs, designed to release drug in response to TME-specific stimuli, such as low pH, tumor-selective enzymes, and unique characteristics of tumor neovasculature, are also included in this review. In general, many novel actively targeting strategies have been developed and encouraging data have been reported in numerous settings, both in vitro and in animal studies. Conclusion: Active targeting of NPs has experienced rapid growth as a field of research and is continuously expanding. There are now some early examples of efforts on clinical translation and reported clinical trials on these NPs. Future development of actively targeted NPs depends on better understanding of the many factors affecting the behavior of NPs in vivo and likely involves combining the approaches of targeting the tumor cells and of targeting components of the TME.

Shaping Tumor Microenvironment for Improving Nanoparticle Delivery.

Abstract: Tumor microenvironment plays a great role in nanoparticles delivery to tumor. Although enhanced permeability and retention effect is the mainly driving force for tumor targeting of nanoparticles, the elevated interstitial fluid pressure, abnormal tumor vasculature, dense tumor extracellular matrix and elevated solid stress considerable hinder the extravasation and intratumor penetration of nanoparticles. Therefore, in this paper, the intrinsic tumor microenvironment was reviewed. Then we discussed the potential strategies to shape the tumor microenvironment for improving nanoparticles delivery, including vascular normalization, vasculature promotion therapy, lymph normalization, reducing tumor stroma components, elevating blood pressure, elevating receptor expression, cell cycle arrest and priming by cytotoxic therapy.

Methylglyoxal, A Metabolite Increased in Diabetes is Associated with Insulin Resistance, Vascular Dysfunction and Neuropathies

Abstract: Background: Diabetes mellitus (DM) is a pandemic metabolic disease characterized by a chronically elevated blood glucose concentration (hyperglycemia) due to insulin dysfunction. Approximately 50% of diabetics show diabetes complications by the time they are diagnosed. Vascular dysfunction, nephropathy and neuropathic pain are common diabetes complications. Chronic hyperglycemia contributes to reactive oxygen species (ROS) generation such as methylglyoxal (MGO). Methods: Peer reviewed research papers were studied through bibliographic databases searching focused on review questions and inclusion/exclusion criteria. The reviewed papers were appraised according to the searching focus. The characteristics of screened papers were described, and a deductive qualitative content analysis methodology was applied to the included studies using a conceptual framework to yield this comprehensive systematic review. Results: Sixty-six papers were included in this review. Eleven papers related methylglyoxal generation to carbohydrates metabolism, ten papers related lipid metabolism to methylglyoxal and 5 papers showed the proteolytic pathways that contribute to methylglyoxal generation. Methylglyoxal metabolism was derived from 7 papers. Descriptive figure 1 was drawn to explain methylglyoxal sources and how diabetes increases methylglyoxal generation. Furthermore, twenty-six papers related methylglyoxal to diabetes complications from which 9 papers showed methylglyoxal ability to induce insulin dysfunction, an effect which was described in schematic figure 2. Additionally, fifteen papers revealed methylglyoxal contribution to vascular dysfunction and 3 papers showed methylglyoxal to cause neuropathic pain. Methylglyoxal-induced vascular dysfunction was drawn in a comprehensive figure 3. This review correlated methylglyoxal with diabetes and diabetes complications which were summarised in table 1. Conclusion: The findings of this review suggesting methylglyoxal as an essential therapeutic target for managing diabetes in the future.

Oxidative and Non-Oxidative Metabolomics of Ethanol.

Abstract: Background It is well known that ethanol can cause significant morbidity and mortality, and much of the related toxic effects can be explained by its metabolic profile. Objective This work performs a complete review of the metabolism of ethanol focusing on both major and minor metabolites. Method An exhaustive literature search was carried out using textual and structural queries for ethanol and related known metabolizing enzymes and metabolites. Results The main pathway of metabolism is catalyzed by cytosolic alcohol dehydrogenase, which exhibits multiple isoenzymes and genetic polymorphisms with clinical and forensic implications. Another two oxidative routes, the highly inducible CYP2E1 system and peroxisomal catalase may acquire relevance under specific circumstances. In addition to oxidative metabolism, ethanol also originates minor metabolites such as ethyl glucuronide, ethyl sulfate, ethyl phosphate, ethyl nitrite, phosphatidylethanol and fatty acid ethyl esters. These metabolites represent alternative biomarkers since they can be detected several hours or days after ethanol exposure. Conclusion It is expected that knowing the metabolomics of ethanol may provide additional insights to better understand the toxicological effects and the variability of dose response.

Molecular Targets for Small-Molecule Modulators of Circadian Clocks.

Abstract: Background Circadian clocks are endogenous timing systems that regulate various aspects of mammalian metabolism, physiology and behavior. Traditional chronotherapy refers to the administration of drugs in a defined circadian time window to achieve optimal pharmacokinetic and therapeutic efficacies. In recent years, substantial efforts have been dedicated to developing novel small-molecule modulators of circadian clocks. Methods Here, we review the recent progress in the identification of molecular targets of small-molecule clock modulators and their efficacies in clock-related disorders. Specifically, we examine the clock components and regulatory factors as possible molecular targets of small molecules, and we review several key clock-related disorders as promising venues for testing the preventive/therapeutic efficacies of these small molecules. Finally, we also discuss circadian regulation of drug metabolism. Results Small molecules can modulate the period, phase and/or amplitude of the circadian cycle. Core clock proteins, nuclear hormone receptors, and clock-related kinases and other epigenetic regulators are promising molecular targets for small molecules. Through these targets small molecules exert protective effects against clock-related disorders including the metabolic syndrome, immune disorders, sleep disorders and cancer. Small molecules can also modulate circadian drug metabolism and response to existing therapeutics. Conclusion Small-molecule clock modulators target clock components or diverse cellular pathways that functionally impinge upon the clock. Target identification of new small-molecule modulators will deepen our understanding of key regulatory nodes in the circadian network. Studies of clock modulators will facilitate their therapeutic applications, alone or in combination, for clock-related diseases.

Progress on Actively Targeted Nanoparticles for Drug Delivery to Tumor.

Abstract: Nanomedicine is an emerging therapeutic modality. Nanoparticles (NPs) have been shown to be potential vehicles for the delivery of cancer therapeutics. NPs can facilitate tumor drug delivery both by passive and active targeting strategies. Passive targeting of tumors can be achieved through the enhanced permeability and retention (EPR) effect. Actively targeted NPs following different targeting mechanisms are divided into ligand-directed NPs and tumor microenvironment-directed NPs. Ligand-directed active NPs function by binding specific tumor receptors and have tumor-specific ligands coupled onto the surface of NPs. Targeting ligands include proteins, peptides, aptamers, saccharide and folate. Tumor microenvironment targeting NPs are triggered to release drugs by microenvironment-specific stimuli, such as pH, enzyme, and unique characteristics of tumor neovasculature. In this review, we pay special attention to the recent progress in the development of actively targeted NPs and tumor microenvironment-targeting NPs.

Emerging Role of microRNA in Neuropathic Pain.

Abstract: Background: Neuropathic pain is an incurable disease which is defined as a chronic pain caused by a disease or lesion of the nervous systems. Current treatments can provide a long-lasting pain relief only in a very limited number of patients with neuropathic pain. MicroRNA can regulate multiple genes and pathways involved in human diseases. This review focuses on: a) Molecular mechanisms of microRNA biogenesis. b) Targeting, modifications, and delivery of microRNAs. c) Aberrant expression of microRNAs and their potential therapeutic targets in neuropathic pain. d) Potential challenges of microRNA therapy in clinical practice, such as off-target effects, toxicity, delivery hurdles, and target prediction. Results: This review introduces: 1. Canonical/non-canonical pathway of microRNA biogenesis. 2. Viral/non-viral vectors transporting microRNAs into target cells. 3. MicroRNA mimics/inhibitors targeting strategies. 4. Aberrantly expressed microRNAs in different animal neuropathic pain models and their links to underlying mechanisms such as inflammation and ion channel expression. 5. Potential challenges of microRNAs therapy such as off-target effect, pseudogenes, liver toxicity, delivery hurdles and target prediction. Conclusion: Although using microRNAs to target neuropathic pain seem promising, their off-target/toxic effects and delivery hurdles still need to be surmounted.

Current Therapeutics, Their Problems and Thiol Metabolism as Potential Drug Targets in Leishmaniasis.

Abstract: Leishmaniasis is one of the six diseases regarded most neglected by World Health Organization which is predominant in developing countries. Clinically, among the different forms of leishmaniasis, visceral leishmaniasis is the most fatal, serious disease, in which several organs of the body such as liver and spleen are affected. A limited number of drugs against leishmaniasis are available for the treatment and also, no suitable vaccine is available for the control of leishmaniasis. However, the drugs currently used for the treatment of leishmaniasis have serious side effects as well as drug resistance issues. Therefore, search for alternative drugs to treat leishmaniasis is widely pursued; often targeting the metabolic pathways of Leishmania which are either absent or different from the mammalian host and involved in survival, pathogenesis and drug resistance of parasite. Herein, we review the aspects of chemotherapy of leishmaniasis by synthetic and natural drugs, their mechanism of action, pharmacokinetics and involvement in the development of drug resistance. Furthermore, regulatory role of trypanothione as key molecule for redox homeostasis via antioxidant enzymes and proteins like tryparedoxin, tryparedoxin peroxidase, superoxide dismutase, and ascorbate peroxidase are presented. We have comprehensively discussed thiol metabolism as drug target and its role in parasite survival.

Coenzyme Q10 Supplementation and Exercise in Healthy Humans: A Systematic Review.

Abstract: Objective: Coenzyme Q10 (CoQ10) is an endogenous lipid-soluble benzoquinone compound that functions as a diffusible electron carrier in the electron transport chain. It is prevalent in all human tissues and organs, although it is mainly biosynthesised and concentrated in tissues with high energy turnover. The aim of this review was to perform an exhaustive analysis of the influence and effects of CoQ10 supplementation on parameters related to exercise in healthy humans, and to clarify the current state of knowledge of this field of study, presenting the relevant data in a systematic manner. Method: This paper describes a transversal descriptive systematic review of published research in this field; the study was conducted using a method adapted from the PRISMA guidelines. The inclusion criteria applied were based on the PICO (population, intervention, comparison, and outcome) model. Results: The database search performed yielded 372 citations. Finally, 13 studies met all the inclusion criteria and were incorporated in the present review. Conclusion: CoQ10 has properties related to bioenergetic and antioxidant activity; thus, it is intimately involved in energy production and in the prevention of peroxidative damage to membrane phospholipids and of free radical-induced oxidation. These properties make it suitable as a dietary supplement to improve cellular bioenergetics and to inhibit certain age-related pathologies.

Drug-metabolizing Enzymes and Efflux Transporters in Nasal Epithelium: Influence on the Bioavailability of Intranasally Administered Drugs.

Abstract: Background: The interest in administering drugs by intranasal route is currently increasing, particularly because it has shown to ensure drug therapeutic action by a rapid systemic absorption through the respiratory mucosa and/or a direct delivery of some molecules into the brain through the olfactory mucosa. Nevertheless, although intranasal administration avoids the first-pass hepatic biotransformation, several enzymes as well as efflux transporters can be found in the mammalian nasal epithelium. Methods: This work reviewed the expression and localization of the drug-metabolizing enzymes and efflux transporters in the mammalian nasal mucosa epithelium, as well as their influence on the pharmacokinetic and pharmacodynamic profiles of specific drugs, using one hundred and thirty five peer-reviewed papers undertaken from MEDLINE database, including review and research papers. Results: Most of the studies analyzed corroborate that oxidative and conjugative enzymes as well as multidrug resistance proteins and multidrug resistance-associated proteins efflux transporters are expressed in the nasal cavity, particularly in olfactory and respiratory mucosae, determining the access of drugs to central nervous system and bloodstream. Nonetheless, besides their well-documented anatomic location, either in laboratory animals or humans, there is still a lack of experimental information regarding the substrates of these enzymes and efflux transporters at the nasal cavity.  Conclusion: The knowledge herein discussed important not only to select the drugs with better potential to be administered by intranasal route but also to optimize drug formulations, in which inhibitors of enzymes or efflux transporters may be included to increase drug systemic and central delivery.

Valproic Acid Metabolism and its Consequences on Sexual Functions

Abstract: Background: Valproic acid (VPA) is a broad spectrum antiepileptic drug (AED) that is generally regarded as a first-choice agent for most forms of idiopathic and symptomatic generalised epilepsies. Available data suggest that menstrual disorders and certain endocrine manifestations of reproductive system disorders may be more common in women treated with VPA than in those treated with other AEDs. Methods: A PubMed search for MEDLINE was undertaken to look for studies using the terms “VPA metabolism”, “VPA and sexual functions in men”, “VPA and sexual functions in women” and “VPA metabolism and endocrine disorders” as key words. The period covered was approximately 20 years. Results: In women, VPA medication is associated with hyperandrogenism, polycystic ovary/polycystic ovarian syndrome, menstrual disorders and ovulatory failure. Men on VPA therapy show abnormalities in androgens blood levels, sperm motility and erectile dysfunctions. VPA negatively affects the release of luteinizing hormone, follicle stimulating hormone and prolactin but also the drug interferes in peripheral endocrine hormones. Its broad inhibitory action on cytochrome and glucuronidation systems can lead to high serum concentration of testosterone, androstenedione and dehydroepiandrosterone sulfate. VPA-dependent obesity and hyperinsulinemia can further contribute to an increase in sexual dysfunctions. Conclusions: VPA interferes with the endocrine system at multiples levels causing several reproductive and sexual dysfunctions in women and men with epilepsy, especially when administered in pubertal age. Since VPA is a first line AED both in children and adult with epilepsy and long-term medication with this drug is sometimes necessary, it is very important for physicians to implement strict monitoring of patients taking VPA in order to identify these kinds of side effects at an early stage.

Intracellular Metabolism of Nucleoside/Nucleotide Analogues: a Bottleneck to Reach Active Drugs on HIV Reverse Transcriptase

Abstract: Background: To date, the most effective way to treat HIV is to use a highly active antiretroviral therapy (HAART) that combines three or more different drugs. The usual regimen consists of two nucleoside reverse transcriptase inhibitors and either a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor, or an integrase strand transfer inhibitor. Due to the emerging resistance against the nucleoside analogues in use, there is a continuous need for the development of such therapeutic molecules with different structural features. Objectives: In this review, we would like to summarize the state of knowledge of the antiretroviral nucleoside analogues intracellular metabolism. Indeed, these molecules have to be phosphorylated in the cell, a process that is often a bottleneck, to produce their pharmacologically active triphosphorylated forms. These forms can be used by the HIV reverse transcriptase. Because they lack a 3'-hydroxyl group, they block further extension of the viral DNA, and finally lead to early chain termination. Several kinases can act on the phosphorylation of these drugs; most of them have low nucleoside/nucleotide specificity. On the other hand, there are also nucleotidases in the cell, which can reverse the phosphorylation process, thus shifting the equilibrium from the active triphosphorylated state to the non-active (not-, mono- or di-phosphorylated) states of these analogues. Conclusion: Here, we would like to bring to the attention of the medicinal chemists that they have to take into account the limitation of the intracellular phosphorylation machinery when designing new nucleoside analogue drugs.

Drug Transporters and Multiple Drug Resistance in the Most Common Pediatric Solid Tumors

Abstract: Solid tumors account for approximately 30% of all pediatric cancers. Although chemotherapy has largely contributed to strongly improve patient outcome, multidrug resistance (MDR) remains one of the major mechanisms limiting the overall survival. The enhanced efflux rate of chemotherapeutic drugs from tumor cells through drug transporters is one of the most important mechanisms of MDR. Drug transporters play a pivotal role in preserving the balance between sensitivity and resistance of tumor cells to anti-neoplastic drugs. Their functional activities have been barely investigated in pediatric solid malignancies. Here, we provide evidence from the current literatures on drug transporters and MDR in the most common types of pediatric solid tumors, including neuroblastoma, Wilms’ tumor, rhabdomyosarcoma, retinoblastoma, medulloblastoma and hepatoblastoma.

Indole-3-Carbinol (I3C) and its Major Derivatives: Their Pharmacokinetics and Important Roles in Hepatic Protection.

Abstract: Background: Indoles, including indole-3-carbinol (I3C) and its derivatives, are the products of glucosinolate hydrolysis catalyzed by the enzyme myrosinase. Under acidic conditions, I3C polymerizes into 3, 3- diindolylmethane (DIM), [2-(indol-3-ylmethyl)-indol-3-yl]indol-3-ylmethane (LTr1), 1-(3-hydroxymethyl)- indolyl-3-indolylmethane (HI-IM) and indolo[3,2b]carbazole (ICZ). Recently, I3C and its dimer DIM have shown pleiotropic protective effects on chronic liver injuries, including viral hepatitis, hepatic steatosis, hepatic cirrhosis, hepatocellular carcinoma, and so on. Methods: We reviewed the published papers about the pharmacokinetics of I3C and its derivatives in vitro and in vivo, and summarized their multiple protective roles in the processes of chronic liver diseases. Results: Indoles not only regulate transcriptional factors and their respective signaling pathways, but also relieve oxidative stress and inhibit the synthesis of DNA to influence the activation, proliferation and apoptosis of target cells. Moreover, indoles modulate the enzymes that are relevant to hepatitis viral replication, lipogenesis, and the metabolism of ethanol and some hepatotoxic substances to protect the liver. Currently, the immunomodulatory biofunction of indoles contributes to improving non-alcoholic steatohepatitis. In addition, indoles also function as the inhibitors of pro-inflammatory cytokines and chemokines to reduce microbial-induced liver injures. Conclusion: Indoles, especially I3C and DIM as phytochemicals, exert anti-fibrosis, anti-tumor, anti-oxidant, immunomodulatory, detoxification and anti-inflammation effects on hepatic protection through pleiotropic mechanism.

Metabolism of Acrylamide: Interindividual and Interspecies Differences as Well as the Application as Biomarkers

Abstract: Background: Acrylamide (AA), a known neurotoxin, has been considered to be a probable human carcinogen. The discovery of AA in many common foods in 2002 has caused worldwide attention and led to numerous research efforts on the metabolism of AA. Methods: By collecting research literatures related to metabolism of AA, the present review not only summarized the major metabolic pathways and enzymes of AA, but also compared the interindividual and the interspecies differences of AA metabolism among humans, rats and mice. Moreover, the application of the metabolites as biomarkers for the AA exposure assessment in human population was also discussed. Results: The interindividual differences of AA metabolism may be attributed to the activity and/or genetic polymorphisms of metabolic enzymes in individuals with different gender, age, smoking and alcohol status. Moreover, the metabolism of AA in humans may be more prone to the phase II conjugation with glutathione (GSH) than the phase I conversion of AA to glycidamide (GA) when compared with rats and mice. Both the hemoglobin (Hb) adducts and urinary mercapturic acid (MA) metabolites have been successfully used as biomarkers for the risk assessment of AA and new metabolic biomarkers are being developed. Conclusion: The genotoxic risk from AA may be determined by the balance between the phase I P450 2E1 (CYP2E1)-dependent toxification pathway to form genotoxic GA and the phase II GSH-conjugated detoxification pathway to form MA metabolite. Understanding the metabolism of AA in the body is helpful for developing effective intervention strategies to mitigate its toxicity.

P-gp Inhibition-Based Strategies for Modulating Pharmacokinetics of Anticancer Drugs: An Update.

Abstract: Background P-glycoprotein (P-gp), a well known ATP dependent efflux membrane transporter, has been attracting considerable interests of medical researchers due to its efflux pump effect being a primary cause of multidrug resistance (MDR) and poor bioavailability (BA) of anticancer agents. How to resolve the aforesaid problems has become the research hot-points in the medical and pharmaceutical fields. The past three decades have witnessed rapid development of the P-gp inhibition-based strategies used for modulating pharmacokinetics (PK) and thus overcoming MDR and improving BA of anticancer drugs. Methods An electronic search of PubMed database from inception to April, 2016 was conducted. Additionally, we searched the reference lists of included studies and carried out a citation search for the included studies via Web of Science to find other potentially relevant studies. Results and conclusion Lots of the studies of the P-gp inhibition-based strategies are under preclinical phase and the obtained results are exciting and may represent great promise in the clinical application potential. In order to provide useful information for the development of novel strategies for improving BA of anticancer drugs, this article aims to review the research progress in the P-gp inhibition-based strategies that has been acquired over the last three decades, with focus on the P-gp inhibitors, herbal constituents and pharmaceutical excipients as well as novel P-gp-linked drug delivery systems (DDSs). Additionally, the fundamental knowledge on P-gp also is briefly discussed.

Cunninghamella Biotransformation - Similarities to Human Drug Metabolism and Its Relevance for the Drug Discovery Process

Abstract: 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.

Effects Of Glycoprotein IIb/IIIa Antagonists: Anti Platelet Aggregation And Beyond

Abstract: 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.

Factors Affecting the Pharmacokinetics, Biodistribution and Toxicity of Gold Nanoparticles in Drug Delivery.

Abstract: Owing to the straightforward synthesis, good biological compatibility, and ease of surface functionalization, gold nanoparticles (AuNPs) have shown great potential in various biomedical applications, including diagnostic imaging, photothermal therapy (PTT), and drug delivery. Physicochemical properties (e.g. shape, size and surface chemistry) may potentially affect the interaction of AuNPs with biological systems, thus ultimately influencing their cell uptake, pharmacokinetics, biodistribution, drug delivery efficiency, and biological effects. This review focuses on recent advances in understanding the relation between physicochemical characteristics of AuNPs and their navigation through different biological processes, including biodistribution, penetration of biological barriers (e.g. blood-brain barrier), clearance, and metabolism. Furthermore, the in vitro and in vivo toxicological effects of AuNPs and their possible mechanisms were discussed. A thorough understanding of these influencing factors will be crucial for the rational design, customized functionalization, and clinical translation of AuNPs in drug delivery.

Diabetic Nephropathy: Focus on Current and Future Therapeutic Strategies.

Abstract: Background Diabetic nephropathy (DN) is currently the most common cause of end-stage renal disease (ESRD). Although nowadays much is known about its classification, pathogenesis, clinical manifestations and evolution, to date we are not yet able to stop the natural progression of nephropathy in diabetic patients. Methods Treatment options are: lifestyle change with close blood pressure monitoring and tight glycemic control. The most common therapies adopted for this condition are Angiotensing Converting Enzyme-inhibitors (ACEi). However these drugs are able to block the progression of renal damage only in a small proportion of patients. In the remaining, DN progresses and may evolve into ESRD. Conclusion The purpose of this review is to summarize the "state of art" of current novel therapeutic strategies to stem this debilitating kidney disease.

Recent Developments of Magnetic Nanoparticles for Theranostics of Brain Tumor.

Abstract: Background Glioblastoma multiforme, one of the most aggressive brain tumors, has a very poor clinical outcome. Despite the introduction of the alkylating reagent temozolomide (TMZ) to surgery and radiotherapy, the survival of patients could only be modestly increased up to less than 15 months. Therefore, innovative treatment strategies are urgently needed to improve survival of glioma patients. Objective Superparamagnetic iron oxide nanoparticles (SPIONs) have attracted a lot of attention due to their widespread diagnostic and therapeutic applications in neuro-oncology. In this review article we discuss the possible application of the SPIONs for the diagnostic and theraputic approaches in brain cancer. Additionally we report on recent pre-clinical and clinical developments on the generation of heat in the tumors through the application of SPIONs subjected to an alternating magnetic field (AMF). Methods A comprehensive review of the literature on the current status of using targeted SPIONs in brain tumor detection and therapy and also the potential hurdles to overcome was performed. Results Functionalized nanoparticles carrying tumor-specific agents, such as antibodies or proteins might further improve their tumor targeting capacity. Furthermore, multifunctional, theranostic SPIONs can be used for simultaneous in vivo tumor imaging and targeted drug deliery. Application of the ultrasound and external magnetic field technologies significantly improves accumulation of nanoparticles in brain tumors. Hyperthermic treatment using AMF has a therapeutic potential in management of brain tumors. Conclusion Superparamagnetic nanoparticle-based imaging, drug delivery and hyperthermic treatment can potentially be a powerful tool for precise diagnosis and treatment of brain tumors.

Brain Aging and Disorders of the Central Nervous System: Kynurenines and Drug Metabolism.

Abstract: Introduction: The kynurenine pathway includes several neuroactive compounds, including kynurenic acid, picolinic acid, 3-hydroxykynurenine and quinolinic acid. The enzymatic cascade of the kynurenine pathway is tightly connected with the immune system, and may provide a link between the immune system and neurotransmission. Main Areas Covered: Alterations in this cascade are associated with neurodegenerative, neurocognitive, autoimmune and psychiatric disorders, such as Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, migraine or schizophrenia. Highlights: This review highlights the alterations in this metabolic pathway in the physiological aging process and in different disorders. A survey is also presented of therapeutic possibilities of influencing this metabolic route, which can be achieved through the use of synthetic kynurenic acid analogues, enzyme inhibitors or even nanotechnology.

Recent Updates on the Systemic and Local Safety of Intranasal Steroids.

Abstract: Background Allergic rhinitis is a global health problem, and its prevalence rate and socioeconomic burden continue to increase. Intranasal steroid (INS) is the first treatment choice in the majority of patients, because of its ability to effectively control allergic symptoms. However, patients and clinicians are concerned about the potential adverse effects of prolonged INS use. Methods We performed to review for evaluating systemic and local safety of INS use, by searching MEDLINE, EMBASE, and Cochrane Library database for identification of relevant articles. Results In the present study, the systemic bioavailabilities of several commercially available INSs were researched, and then systemic safeties were reviewed with focus on suppression of the hypothalamus-pituitary-adrenal axis and their effects on pediatric growth. In addition, local adverse effects, such as, epistaxis and nasal septal perforation, were investigated. Finally, the authors proposed some techniques in order to avoid these complications. Conclusion INSs offer a safe, effective means of treating allergic rhinitis in the short- and long-term with no or minimal adverse systemic and local effects.

Medication-Induced Nephrotoxicity in Older Patients.

Abstract: Objective: To summarize current evidence about mechanisms, clinical features, diagnostic issues, and strategies for prevention of medication-induced nephrotoxicity among older people. Methods: A Pubmed search was performed, and studies concerning age-related changes in kidney structure and function predisposing to nephrotoxicity, pathophysiological mechanisms, kidney drug metabolism enzymes, clinical epidemiology of medication-induced kidney damage, biomarkers for early identification of nephrotoxicity and strategies for prevention of medication-induced nephrotoxicity among older people were selected. Finally, 245 papers were included in the review. Results: Medications may induce nephrotoxicity through several pathophysiological mechanisms. People aged 75 or more are especially exposed to potential nephrotoxic medications or combinations of medications in the context of complex polypharmacy regimens. Estimated glomerular filtration rate (eGFR) may be useful to identify medication-induced alterations in kidney function, but creatinine-based methods have important limitation in older patients. Several innovative biomarkers have been proposed to identify AKI but these methodologies are not standardized and older people have not been evaluated systematically. Factors related to patient, medication, and interactions should be taken into account for effective prevention. Conclusions: Medication-induced nephrotoxicity is a relevant problem in older populations. Nevertheless, several areas of uncertainty remain to be explored, including the impact of nephrotoxicity on functional outcomes relevant to older patients, the reliability of currently recommended methods for diagnosing and staging AKI, the use of innovative biomarkers in such a heterogeneous population, the effectiveness of preventing strategies and treatments and their impact on functional outcomes.

Therapeutic microRNA Delivery Strategies with Special Emphasis on Cancer Therapy and Tumorigenesis: Current Trends and Future Challenges.

Abstract: Background: Over the decade, miRNAs are the most important molecules for the biopharmaceutical industry due to their relation with several human diseases. Presently, the phase-II clinical trial has been initiated for the first miRNA-based therapeutics (“Miravirsen”) to treat HCV infection. It has been expected that many more miRNA-based therapeutics will enter the clinical trials. Therefore, it is important to develop different kinds of novel delivery systems with better efficacy and more efficiency, but fewer side effects. Methods: We have undertaken a structured search of bibliographic databases for peer-reviewed research literature to solve our review question. Literature survey was performed widely to write this review article. Results: In this review, we have discussed the various types of miRNA delivery systems such as viral vectors, lipid-based systems, nanocarriers, and LNA-customized DNA delivery without any delivery-mediated agent. Current status, technical support, and the future challenges for miRNA-based delivery are also discussed. Conclusion: Recent development and understanding of miRNA had shown the therapeutic potentiality of miRNA.

Drug Interactions with Angiotensin Receptor Blockers: Role of Human Cytochromes P450

Abstract: Background: Angiotensin receptor blockers (ARBs) are the most recent class of agents for the treatment of hypertension. However, ARBs may cause a low incidence of headache, upper respiratory infection, back pain, muscle cramps, fatigue, dizziness, and many other side effects. In some cases, such toxicity is associated with pharmacokinetic alterations. Methods: The cytochrome P450 (CYP) enzyme system plays an important role in a lot of clinically important pharmacokinetic drug interactions. To identify relevant studies on drug-drug and food-drug pharmacokinetic interactions with the ARBs, a literature search of Google Scholar was performed from January 1994 to June 2015, with the following keywords: ‘losartan’, ‘valsartan,’ ‘candesartan,’ ‘irbesartan,’ ‘telmisartan,’ ‘eprosartan,’ ‘olmesartan,’ and ‘azilsartan’, combined with the keyword ‘pharmacokinetic interactions’ and ‘CYP’. Results: Based on the literatures published, it has been demonstrated that pharmacokinetic interactions of losartan with other agents are mainly via CYP2C9- and CYP3A4-mediated, the role played by CYP enzyme system in the metabolism of valsartan, candesartan, irbesartan, and azilsartan appears modest, and cytochrome P450 system has no influence on the metabolism of telmisartan, eprosartan, olmesartan. Therefore, according to these pharmacokinetic findings, no dosage adjustment is recommended when eprosartan, telmisartan and olmesartan are combined with other pharmacological agents in patients with hypertension. Conclusion: This review summarize the available data on cytochrome P450 – related drug–drug interactions reported in the literature for the eight ARBs. Knowledge of the pharmacokinetic properties of the ARBs should allow the avoidance of the majority of drug interactions without compromising therapeutic benefits.

Metabolic Alterations in Renal and Prostate Cancer.

Abstract: 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.