Showing papers in "Current Drug Metabolism in 2017"

A Review on Nano-Antimicrobials: Metal Nanoparticles, Methods and Mechanisms

Abstract: Nanotechnology is a scientific and engineering technology conducted at the nano-scale, such as in the fields of compound fabric manufacturing, food processing, agricultural processing, and engineering, as well as in medical and medicinal applications. In recent decade, nanomaterial applications for antimicrobial works have of prime interest of by many researchers. Available reports show that some of the metal oxide nanoparticles (NPs) including Al2O3, TiO2, ZnO, CuO, Co3O4, In2O3, MgO, SiO2, ZrO2, Cr2O3, Ni2O3, Mn2O3, CoO, and Nickel oxide have toxicity toward several microorganisms and they could successfully kill numerous bacteria. Based on our literature review there are some effective factors that can influence the ability of nanomaterials in reducing or killing the cells, and there are mechanisms for nanomaterial against bacteria, which are briefly listed as follows: surface charge of the metal nanomaterial, shape, type and material, concentration of nanomaterial, dispersion and contact of nanomaterial to the bacterial cell, presence of active oxygen, liberation of antimicrobial ions, medium components and pH, physicochemical properties, specific surface-area-to-volume ratios, size, role of growth rate, role of biofilm formation, cell wall of bacteria, and effect of UV illumination. It can be considered that in the use of nanomaterials as antimicrobial agents, consideration of many factors remain principal. Antibacterial resistance to common chemical antibacterial agents can be due to long production-consumption cycle, thereby reducing their efficiency, and use of poor quality or fake medicines in undeveloped and developing countries. NPs as antimicrobial agents have become an emerging approach against this challenge, which can establish an effective nanostructure to deliver the antimicrobial agents for targeting the bacterial community efficiently. In addition, they are so potent that microbial pathogens cannot develop resistance to wards them. On the other hand, most of the metal oxide NPs have no toxicity toward humans at effective concentrations used to kill bacterial cells, which thus becomes an advantage for using them in a full scale. However, over the present decade, several studies have suggested that NPs are excellent antibacterial agents, at least at the research level.

Protein-Protein Interaction (PPI) Network: Recent Advances in Drug Discovery.

Abstract: Background The investigation of the cellular components, their interactions and related functions constitute the major conditions in order to understand the cell as an integrated system. More specifically, the Protein-Protein Interactions and the obtained networks are very important in the majority of biological functions and processes, while most of the proteins appear to activate their functionalities through their interaction. Methods Our in depth review analysis, include Sixty-five peer-reviewed research and review studies from several bibliographic databases. The most significant components were fully described, filtered, combined and analyzed in order to provide documented proofs on the Protein-Protein Interaction Network' applications in biomedicine. Results The Protein-Protein Interaction Network' alignment and mapping give the opportunity of further knowledge extraction concerning the evolutionary relationships between the species through conserved pathways and protein complexes. Additionally, Protein-Protein Interaction Network information has been demonstrated to be able to predict functionally orthologous proteins within sequence homology clusters. Our review analysis concluded that, while Protein- Protein Interaction was used to be characterized just by their large and plain interacting surfaces, they were considered inapplicable for drug discovery studies for a long time. Conclusion The present review explores multiple technologies implicated in Protein-Protein Interaction Networks, implicating their potential role in drug discovery mechanisms.

Long Circulating Polymeric Nanoparticles for Gene/Drug Delivery.

Abstract: Background The prolonged circulation time of nanoparticles in the blood is a prerequisite to realize a controlled and targeted (passive or active targeting) release of the encapsulated gene/drug at the desired site of action. The most popular method to mask or camouflage nanoparticles is the adsorbed, grafted or conjugated of poly (ethylene glycol) (PEG) or other hydrophilic polymers (e.g. polysaccharides) to the particle surface. However, the circulation half-life of nanoparticles still cannot satisfy the need of clinical use. Method This review focuses on several recent advances in the design and fabrication of polymeric nanoparticles with long circulating characters in blood. The factors influencing the physicochemical characteristics of nanoparticle surface and its surface modification have been discussed. Results Gene/drug carriers can also be combined with functionalized physical, chemical or biological stimuli to improve passive and active targeting strategies. The choice of suitable manufacturing technique of polymeric nanoparticles depends on the gene/drug to be encapsulated in the particle, the physicochemical properties of the polymer, their therapeutic goal to be reached and the scalability of the fabrication which allows for a clinical realization of the most promising nanomedicines. The factors influencing long circulating properties of nanoparticles are mainly particle size, surface charge and hydrophilicity. Surface modification of polymeric nanoparticles has been focused on PEG, polysaccharides, and so on. Conclusion Identification of novel potential coating materials with satisfied characters is an emerging field of interest in the design of long circulating polymer-based nanoparticulate gene/drug delivery.

Drug Metabolism in Preclinical Drug Development: A Survey of the Discovery Process, Toxicology, and Computational Tools.

Abstract: Background While establishing efficacy in translational models and humans through clinically-relevant endpoints for disease is of great interest, assessing the potential toxicity of a putative therapeutic drug is critical. Toxicological assessments in the pre-clinical discovery phase help to avoid future failure in the clinical phases of drug development. Many in vitro assays exist to aid in modular toxicological assessment, such as hepatotoxicity and genotoxicity. While these methods have provided tremendous insight into human toxicity by investigational new drugs, they are expensive, require substantial resources, and do not account for pharmacogenomics as well as critical ADME properties. Computational tools can fill this niche in toxicology if in silico models are accurate in relating drug molecular properties to toxicological endpoints as well as reliable in predicting important drug-target interactions that mediate known adverse events or adverse outcome pathways (AOPs). Methods We undertook an unstructured search of multiple bibliographic databases for peer-reviewed literature regarding computational methods in predictive toxicology for in silico drug discovery. As this review paper is meant to serve as a survey of available methods for the interested reader, no focused criteria were applied. Literature chosen was based on the writers' expertise and intent in communicating important aspects of in silico toxicology to the interested reader. Conclusion This review provides a purview of computational methods of pre-clinical toxicologic assessments for novel small molecule drugs that may be of use for novice and experienced investigators as well as academic and commercial drug discovery entities.

Transdermal Drug Delivery: Opportunities and Challenges for Controlled Delivery of Therapeutic Agents Using Nanocarriers

Abstract: Background Transdermal drug delivery represents an extremely attractive and innovative route across the skin owing to the possibility for achieving systemic effect of drugs. The present scenario demands a special focus on developing safe medicine with minimized toxic adverse effects related to most of the pharmacologically active agents. Transdermal drug delivery would be a focal paradigm which provides patient convenience, first-pass hepatic metabolism avoidance, local targeting and reduction in toxic effect related to various categories of drugs like, analgesics, antiinflammatory, antibiotics, antiviral, anaesthetic, anticancer etc. Even this route has challenges due to highly organized structure of skin which acts as a main barrier to penetration of drug via the skin. Method Several alternative possible strategies are available which overcome these barriers, including use of penetration enhancer, eletroporation, iontophoresis and various nanotechnologically developed nanocarrier systems. The latest one includes employing liposome, dendrimers, nanoparticles, ethosome, carbon nanotube and many more to avoid associated limitations of conventional formulations. Numerous transdermal products such as Estrasorb, Diractin, VivaGel®, Daytrana®, Aczone, Sileryst® are available in the market having a novel strategy to achieve higher penetration of drugs. This encourages formulation fraternity to develop structurally deformable and stable nanocarriers as an alternative approach for controlled and reliable drug delivery across the skin barrier. Discussion In this review, we will discuss nanocarriers mediated approaches that come-up with the solutions to the different challenges towards transdermal drug delivery, its clinical importance and latest insight to research in it. Conclusion The reports presented in this review confirm the wide application of nanocarriers for transdermal delivery of drug/gene.

Natural or Plant Products for the Treatment of Neurological Disorders: Current Knowledge.

Abstract: Background In recent decades, complementary and alternative medicine (CAM) has become very popular in the treatment of several chronic diseases. Natural products as one of the CAM modalities offer potential opportunities to discover lead compounds for novel drug development. The use of CAM or natural products in the prevention of neurodegenerative diseases is comparatively a newer area. Method A structured online literature search for peer-reviewed research articles was conducted on the PubMed, Europe PMC, Medline and Google Scholar portals, using phrases: natural products for neurologic disorders, phytomedicine for neurodegenerative diseases, natural therapeutics for neurological symptopms etc. Results: The retrieved data showed the natural therapeutics with anti-oxidative and anti-inflammatory salutations evidently plays a crucial role in protecting neurons. Of these, the most promising are caffeine, trigonelline, shogaol, curcumin, resveratrol, baicalein, wogonin, ginsenosides, tanshinones, withanolides, picrosides, parthenolide, cannabinoids, Devil's claw and white willow bark, including Chinese formulations Renshen Shouwu and Shengmai San. Though several herbs and their active ingredients have been studied in laboratory and clinical settings, only a few have been investigated for their molecular mechanisms of action. Notably, despite the promising and safe therapeutic benefits of CAM/herbal medicines, there exists a possible risk when combining them with prescription drugs. As a result, many drugs have shown changes in blood pressure, hepatotoxicity, seizures etc. when combined with certain herbs. Conclusion Certainly, extensive work is needed to make sure that patients should take a regimen of protective and restorative therapy under an experienced healthcare professional. This article updates on the current knowledge of promising natural products used in neurological disorders.

Differential Regulation of CYP3A4 and CYP3A5 and its Implication in Drug Discovery.

Abstract: Background Cancer cells use several mechanisms to resist the cytotoxic effects of drugs, resulting in tumor progression and invasion One such mechanism capitalizes on the body's natural defense against xenobiotics by increasing the rate of xenobiotic efflux and metabolic inactivation Xenobiotic metabolism typically involves conversion of parent molecules to more soluble and easily excreted derivatives in reactions catalyzed by Phase I and Phase II drug metabolizing enzymes Methods We performed a structured search of peer-reviewed literature on P450 (CYP) 3A, with a focus on CYP3A4 and CYP3A5 Results Recent reports indicate that components of the xenobiotic response system are upregulated in some diseases, including many cancers Such components include the pregnane X receptor (PXR), CYP3A4 and CYP3A5 enzymes The CYP3A enzymes are a subset of the numerous enzymes that are transcriptionally activated following the interaction of PXR and many ligands Conclusion Intense research is ongoing to understand the functional ramifications of aberrant expression of these components in diseased states with the goal of designing novel drugs that can selectively target them

Rivaroxaban - Metabolism, Pharmacologic Properties and Drug Interactions

Abstract: Background: Rivaroxaban represents a selective direct inhibitor of activated coagulation factor X (FXa) having peroral bioavailability and prompt onset of action Objective: The absorbtion of rivaroxaban is quick, reaching maximum plasma concentration 2-4 hours following its administration Peroral bioavailability is high (80-100 %) and pharmacokinetic variability is considered to be moderate (coefficient of variation 30-40 %) This review discusses the properties, drug interactions, pharmacokinetics and clinical indications of rivaroxaban Method: Dosing regimen of rivaroxaban was derived from pharmacologic data of the development program aimed to gain strong antithrombotic drug and balance between efficacy and risk of bleeding in patients Results of dose-ranging trials, pharmacokinetic models and randomised studies of phase III advocate the use of such scheme in everyday practice Results: The drug has been manufactured to fulfill clinical requirements in a variety of indications in adults: prophylaxis of venous thromboembolism (VTE) following elective knee or hip replacement surgical intervention, therapy and secondary prophylaxis of VTE, prophylaxis of ischemic stroke and embolism in individuals diagnosed with nonvalvular atrial fibrillation (NVAF) with risky characteristics, and in Europe the prophylaxis of atherothrombotic episodes following an acute coronary syndrome in subjects with increased levels of cardiac biomarkers Conclusions: Rivaroxaban may offer benefit in many clinical situations In the comparison with low molecular weight heparin and fondaparinux requiring subcutaneous way of administration, and with vitamin K antagonists (VKAs), which require regular monitoring of international normalized ratio, rivaroxaban is relatively easy to use However, adjustments of dose are needed in individuals with impaired renal functions

Bacteria From Marine Sponges: A Source of New Drugs.

Abstract: Background: Sponges are rich source of bioactive natural products synthesized by the symbiotic bacteria belonging to different phyla Due to a competition for space and nutrients the marine bacteria associated with sponges could produce more antibiotic substances To explore the proactive potential of marine microbes extensive research has been done These bioactive metabolites have some unique properties that are pharmaceutically important Methods: For this review, we have performed a non-systematic search of the available literature though various online search engines This review provides an insight that how majority of active metabolites have been identified from marine invertebrates of which sponges predominate Results: Sponges harbor abundant and diverse microorganisms, which are the sources of a range of marine bioactive metabolites From sponges and their associated microorganisms, approximately 5,300 different natural compounds are known Current research on sponge-microbe interaction and their active metabolites has become a focal point for many researchers Various active metabolites derived from sponges are now known to be produced by their symbiotic microflora Conclusion: In this review, we attempt to report the latest studies regarding capability of bacteria from sponges as producers of bioactive metabolite Moreover, these sponge associated bacteria are an important source of different enzymes of industrial significance In present review, we will address some novel approaches for discovering marine metabolites from bacteria that have the greatest potential to be used in clinical treatments

Adverse Events of Proton Pump Inhibitors: Potential Mechanisms.

Abstract: OBJECTIVE We aimed at summarizing current evidence about mechanisms for potentially harmful effects of Proton Pump Inhibitors (PPIs). METHODS A Pubmed search was performed, and 207 studies concerning the relationship between use of PPIs and cardiovascular diseases, kidney impairment, nutritional disorders, fractures, infections, functional decline, and mortality were selected and reviewed. RESULTS PPIs may cause potentially harmful effects by several mechanisms, including endothelial dysfunction, hypomagnesemia, drug interactions, reduced absorption of selected nutrients, increased gastric microbiota and small intestine bacterial overgrowth, reduced immune response, tubular-interstitial inflammation, increased bone turnover, accumulation of amyloid in the brain. Clinical and epidemiologic evidence is not consistent in regard to some negative outcomes during PPI treatment. Data from randomized clinical trials seem to deny most of them, but they are usually designed to investigate efficacy of drugs in ideal conditions and are not powered enough to detect adverse events. Besides being at special risk of experiencing negative outcomes during long-term treatment with PPIs, older and complex patients treated with polypharmacy regimens are persistently excluded from randomized clinical trials. Thus, large observational studies involving real-world patients should be considered as an important informative source about potential risks related to PPIs. CONCLUSIONS Current evidence suggests that use of PPIs may be associated with negative outcomes by eliciting several different pathophysiologic mechanisms. While short-term PPIs could be considered effective and safe in adult patients with acid-related disorders, their long-term and often inappropriate use in patients carrying vulnerability to adverse events and/or high risk of drug-interactions should be avoided.

Laboratory Monitoring or Measurement of Direct Oral Anticoagulants (DOACs): Advantages, Limitations and Future Challenges

Abstract: Background The Direct Oral Anticoagulants (DOACs) represent a new generation of antithrombotic agents, providing direct inhibition of either thrombin (factor IIa; FIIa) or activated factor X (FXa). Around the globe, their use is progressively rising, as these new agents replace the historical anticoagulants (heparin and vitamin K antagonists including warfarin) for various clinical conditions in medical practice. Other acronyms used to designate DOACs include TSOAC (target specific oral anticoagulants) and NOAC (novel; or non-vitamin K antagonist oral anticoagulants). Currently available DOACS include dabigatran (FIIa inhibitor), along with rivaroxaban, apixaban, edoxaban and betrixaban (FXa inhibitors). Objective This narrative review aims to briefly summarise the evidence concerning utility of different laboratory assays for qualitative or quantitative assessment of DOACs, emphasizing the difference between 'drug monitoring' and 'drug measurement' and ultimately discussing advantages and limitations of these processes. Results and conclusion Recently, the dogma that these innovative anticoagulant agents will not necessitate laboratory testing has been challenged with the recognition that assessment of drug concentration or activity may be required in some circumstances, although this does not immediately translate to the concept of 'drug monitoring'.

Urinary Biomarkers for Prostate Cancer.

Abstract: Background Urine may represent a convenient source of biomarkers for the early detection of Prostate Cancer (PCa) since it contains secreted prostatic products and exfoliated tumor cells. Furthermore, urine is easy to collect with non-invasive procedures which are repeatable. Method Several urinary biomarkers for PCa have been proposed in the past but only one (PCA3) has been approved for clinical use and even this is not widely utilized in the routine practice. Most of these, particularly the proteins, were abandoned due to lack of confirmation. DNA markers have been proposed but they are less suitable compared to other malignancies, such as bladder cancer due to the limited amount of DNA somatic alterations in PCa compared to gene fusions and pathway activations. Conclusion RNA biomarkers are still the most promising and particularly miRNA and AMACR mRNA but the main weaknesses that prevented the full clinical implementation are the absence of a validated of the cut-off levels and the identification of consistent reference standards.

Lipid-Based Nanoparticles as Carriers for Dermal Delivery of Antioxidants.

Abstract: Background The skin, being the outermost layer of our body, is constantly exposed to oxidative stress induced by UV-radiation, pollutants, smoke and xenobiotics. To counteract the deleterious effects of such exposure, the skin is equipped with a complex anti-oxidation system, involving both exogenous and endogenous antioxidants. As low molecular weight antioxidants undergo depletion in counteracting oxidative stress occurring in the skin, topical supplementation with these agents is regarded as a suitable strategy to restore skin oxidative balance. Unfortunately, most antioxidants show unfavorable physico-chemical properties (e.g. excessive lipophilicity or hydrophilicity, chemical instability) that strongly limit their skin penetration and hence their effectiveness after topical application. To overcome these drawbacks, nanocarriers such as liposomes, niosomes, nanoemulsions and nanoparticles have been widely investigated as dermal delivery systems for antioxidants. Objective The present paper will review two different types of lipid-based nanocarriers, solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), which represent the latest innovation in the field of nanoparticles designed as topical drug delivery systems. The effects of loading different topical antioxidants into SLN or NLC will be examined along with the usefulness of these antioxidant delivery systems in improving skin defenses against oxidative stress. Conclusion In this review, recent studies regarding ability of solid lipid nanoparticles and nanostructured lipid carriers to improve dermal delivery of low molecular weight antioxidants have evidenced that these carriers show technological properties that make them particularly useful for topical delivery of antioxidants, both in pharmaceutical and cosmetic field.

Role of Mitochondrial Mechanism in Chemotherapy-Induced Peripheral Neuropathy.

Abstract: Background Even though chemotherapeutic regimens show considerable importance, it may cause progressive, continuing and sometimes irreversible peripheral neuropathy. Chemotherapy induced peripheral neuropathy (CIPN) is comprised of sensory abnormalities that are most distressing issues. The mechanism associated with CIPN pathogenesis is not completely revealed and its treatment is still questionable. The purpose of this review was to investigate the role of mitochondria in CIPN. Methods This review is literature based that describes the mitochondrial mechanism underlying CIPN and the neuropathic complications associated with different antineoplastic agents. Results For severe pain, a modification towards less efficient chemotherapeutic drugs could possibly be needed and/or patients perhaps prefer to withdrawal therapeutic regimen. The epidemiology of CIPN is still debatable. The major recurrent molecules causing CIPN are platinum based drugs including cisplatin and oxaliplatin, thalidomide, bortezomib, vinka alkaloids and taxanes. Neuropathic pain is one of the symptoms of CIPN. Various neuropathic disorders as well as CIPN are due to mitochondrial impairment, relevant impairment of Ca2+ signalling pathways and reactive oxygen species (ROS) that ultimately leads to apoptosis. Conclusion The pathophysiology of CIPN is complicated as chemotherapeutic medications often involve combination of drugs. With these combinatorial therapies cancer survivors develop continuing effects of CIPN which require rehabilitation strategies for the recovery of patient's condition and quality of life.

Recent Advances in Drug Delivery of Polymeric Nano-Micelles.

Abstract: In clinical studies, drugs with hydrophobic characteristic usually reflect low bioavailability, poor drug absorption, and inability to achieve the therapeutic concentration in blood. The production of poor solubility drugs, in abundance, by pharmaceutical industries calls for an urgent need to find the alternatives for resolving the above mentioned shortcomings. Poor water solubility drugs loaded with polymeric micelle seem to be the best alternative to enhance drugs solubility and bioavailability. Polymeric micelle, formed by self-assembled of amphiphilic block copolymers in aqueous environment, functioned as solubilizing agent for hydrophobic drug. This review discusses the fundamentals of polymeric micelle as drug carrier through representative literature, and demonstrates some applications in various clinical trials. The structure, characteristic, and formation of polymeric micelle have been discussed firstly. Next, this manuscript focuses on the potential of polymeric micelles as drug vehicle in oral, transdermal routes, and anti-cancer agent. Several results from previous studies have been reproduced in this review in order to prove the efficacy of the micelles in delivering hydrophobic drugs. Lastly, future strategies to broaden the application of polymeric micelles in pharmaceutical industries have been highlighted.

Ginkgo biloba as an Alternative Medicine in the Treatment of Anxiety in Dementia and other Psychiatric Disorders.

Abstract: Background: Mental disorders are the most common health problems in the worldwide population. Current medicines against these conditions have undesired side effects or limited effectiveness. These disadvantageous pharmacological and therapeutic characteristics provoke a low adherence to treatment in an important percentage of patients with mental disorders. Since ancient times, ethnically different groups have been using plants extracts as medicines for the treatment of mental conditions including dementia, depression and anxiety disorders. Among them are extracts of Ginkgo biloba, a tree in the division Gingophyta, that has been used by millions of people worldwide. Objective: This review aims to discuss current scientific evidence of efficacy, neuroprotective and antioxidant effects as mechanism of action, side effects and potential interaction with other commonly prescribed anxiolytic drugs. Methods: A PubMed search of preclinical studies as well as individual clinical trials and meta-analysis were scrutinized. Results: Various preclinical and clinical studies have shown a positive effect of Ginkgo biloba to improve cognitive abilities in impaired individuals and reducing anxiety under pathological conditions. Conclusion: A more advanced clinical research is needed to confirm the efficacy of Gingko biloba for the treatment of anxiety in different health conditions.

Nanocarriers Mediated Topical Drug Delivery for Psoriasis Treatment.

Abstract: Background Psoriasis is a chronic autoimmune inflammatory skin disease affecting 2 to 3% of people worldwide. Topical therapy as first option in the management of psoriasis is an attractive strategy by delivering drugs efficiently into target sites of disease, minimizing systemic side effects of drugs and ensuring high patient compliance. However, the delivery of antipsoriatic agents via conventional topical formulations is limited due to their poor percutaneous penetration and targeting into deeper layers of the skin. Method In this review, an overview of skin structure and psoriatic skin as well as different approaches used for the treatment are provided. We discussed the topical nanocarriers including solid lipid nanoparticles, nanostructured lipid carriers, liposomes, niosomes, ethosomes, transfersomes, dendrimers and micelles used to deliver antipsoriatic drugs. We also summarized the 2011 onward research studies dealing with the application of nanocarriers for psoriasis treatment. Result In the last decades, numerous types of nanocarriers have been widely investigated as a novel delivery approach to reach effective antipsoriatic drug concentrations. These nanocarriers can enhance the therapeutic efficacy and minimize the toxicity of the drugs by lowering the dose. They also improve drug localization in the skin and achieve site-specific drug targeting. But, most of the available studies have lack of clinical outcome in psoriasis and required more focus on the clinical evaluation. Conclusion Nanocarriers could enhance deposition of antipsoriatic drugs in targeted sites of the skin. Nevertheless, still there is a need to develop more effective simulated models that provide realistic model for psoriasis.

Pharmacological and Toxicological Profile of Harmane-β-Carboline Alkaloid: Friend or Foe.

Abstract: Background The plant secondary metabolites have an outstanding therapeutic potential and success over the years. In fact, it is the foundation of numerous clinically used drugs. Similarly, these is a general perception that these products are inherent safety. However, such products might have toxic/unwanted lethal effects therefore, along with biological relevance, toxicological evaluation is equally important for clinical applications. Therefore, harmane- β-carboline alkaloid was investigated for both therapeutic and toxicological potential. Methods The literature related to the therapeutic/toxicological effects of the alkaloid was searched using various scientific data bases including Google, ScienceDirect, PubMed, SpringerLink, ASC. The peer reviewed articles were only selected. Results The harmane-β-carboline alkaloid has shown several pharmacological activities such as antianxiety, antidepressant, antiplatelet, antidiabetic, acetylcholinesterase and myeloperoxidase inhibition, antioxidant, antiparasitic, hypotensive, morphine withdrawal syndrome alleviation, and antinociceptive effects. On the other hand, it exhibited tremorogenic effect, for a symptom of Parkinson's disease. Adverse effect of the alkaloid on learning and memory have also been observed. Conclusions All together, it is, concluded in this review that harmane elicited marked pharmacological effects but simultaneously, it possessed some serious side effects that could be the primary hurdle in the way of its clinical testing.

Natural Products Combating Neurodegeneration: Parkinson's Disease.

Abstract: Parkinson's disease (PD) is characterized by neurodegeneration and a progressive functional impairment of the midbrain nigral dopaminergic neurons. The cause remains unknown; however, several pathological processes and central factors, such as protein aggregation, mitochondrial dysfunction, iron accumulation, neuroinflammation and oxidative stress, have been reported. The current treatment method primarily targets symptoms by using anti-Parkinson drugs such as levodopa, carbidopa, dopamine (DA) agonists, monoamine oxidase type B inhibitors and anticholinergics to replace DA. When drug therapy is not satisfactory, surgical treatments are recommended. Unfortunately, the existing conventional strategies that target PD are associated with numerous side effects and possess an economic burden. Therefore, novel therapeutic approaches that regulate the pathways leading to neuronal death and dysfunction are necessary. For many years, nature has provided the primary resource for the discovery of potential therapeutic agents. Remarkably, many natural products from medicinal plants, fruits and vegetables have been demonstrated to be efficacious anti-Parkinson agents. These products possess neuroprotective properties as a result of not only their wellrecognized anti-oxidative and anti-inflammatory activities but also their inhibitory roles regarding iron accumulation, protein misfolding and the maintenance of proteasomal degradation, as well as mitochondrial homeostasis. The aim of this review is to report the available anti-Parkinson agents based on natural products and delineate their therapeutic actions, which act on various pathways. Overall, this review emphasizes the types of natural products that are potential future resources in the treatment of PD as novel regimens or supplementary agents.

Reduction of Doxorubicin-Induced Cardiotoxicity Using Nanocarriers: A Review

Abstract: Background: Anthracycline antibiotic doxorubicin (DOX) is a very potent and extensively prescribed chemotherapeutic drug. It is widely utilized in the therapy of variety of haematological and solid tumours, although its administration is commonly accompanied with several severe side effects. The most serious one is a development of dose-dependent and cumulative cardiotoxicity. In the course of time, many strategies have been investigated in order to avoid or at least to diminish DOX-induced cardiac dysfunction; these include reduction of toxic effect by co-administration with iron chelators (dexrazoxane), trastuzumab, taxanes, statins, and ACE-inhibitors. However, the attenuation of cardiotoxic effect is still not satisfactory yet. Objective: This review represents an overall appraisal of studies concerning with the utilization of various doxorubicin-loaded nanoparticles in the cancer treatment with specific emphasis on those studies evaluating their influence on the reduction of heart tissue damage. Conclusion: Introduction of nanoscale drug delivery systems undoubtedly represents nowadays one of the most promising tools for lowering systemic toxicity. Nanoparticles enable to target the therapeutic payload directly towards the tumor tissue, thus leading to the increased accumulation of the drug in the desired tissue and simultaneously protecting surrounding healthy tissues.

Mirna Expression in Bladder Cancer and Their Potential Role in Clinical Practice

Abstract: Background To date more than 3000 miRNA sequences have been described in humans and registered at miRBase since their discovery However, the functions of only a few of these miRNAs have been experimentally determined using deep sequencing technology Aberrant miRNA expression has been associated with differentiation, invasion and metastasis in several cancers In this context, recent reports have suggested that miRNAs play important roles in the regulation of target genes by binding to complementary regions of messenger transcripts to repress their translation or regulate degradation In addition, the expression profiles of certain miRNAs can function biologically as oncogenes and tumor suppressor genes Method In this review, we summarize the relationship between miRNAs expression and Bladder Cancer (BC) A comprehensive review of the literature has shown a differential expression between malignant and normal tissues, and that miRNAs could be the driving molecules of the BC progression Similarly, the expression levels of miRNAs in urine and blood samples of BC patients have been demonstrated to be different from healthy people, a finding that might have diagnostic value Conclusion In conclusion, the understanding of miRNAs mechanisms and cell distribution provides new opportunities for diagnosis, prognostic, disease monitoring and personalized therapy of BC patients

Engineered Nanoparticles with Antimicrobial Property.

Abstract: BACKGROUND The urge for the development and manufacture of new and effective antimicrobial agents is particularly demanding especially in the present scenario of emerging multiple drug resistant microorganisms. A promising initiative would be to converge nanotechnology to develop novel strategies for antimicrobial treatment. These distinct nano scale properties confer impressive antimicrobial capabilities to nanomaterials that could be exploited. Nanotechnology particularly modulates the physicochemical properties of organic and inorganic nanoparticles, rendering them suitable for various applications related to antimicrobial therapy compared to their bulk counterparts. However, a major issue associated with such usage of nanomaterials is the safety concern on heath care system. Hence, a thorough put knowledge on biocompatible nanostructures intended for antimicrobial therapy is needed. METHODS A systematic review of the existing scientific literature is being attempted here which includes the properties and applications of a few nano structured materials for antimicrobial therapy and also the mechanism of action of nanomaterials as antimicrobial agents. Silver (Ag), Graphene, Quantum dots (QDs), Zinc oxide (ZnO) and chitosan nanoparticles are taken as representatives of metals, semiconductors, metal oxides and organic nanoparticles that have found several applications in antimicrobial therapy are reviewed in detail. RESULTS AND CONCLUSION An ideal anti microbial should selectively kill or inhibit the growth of microbes but cause little or no adverse effect to the host. Each of the engineered nanomaterials reviewed here has its own advantages and disadvantages. Nanomaterials in general directly disrupt the microbial cell membrane, interact with DNA and proteins or they could indirectly initiate the production of reactive oxygen species (ROS) that damage microbial cell components and viruses. Some like silver nanoparticles have broad spectrum antibacterial activity while others like cadmium containing QDs shows both antibacterial as well as antiprotozoal activity. Nano material formulations can be used directly or as surface coatings or as effective carriers for delivering antibiotics. Polycationic nature of Chitosan NPs helps in conjugation and stabilization of metallic nanoparticles which will enhance their effective usage in antimicrobial therapy.

Pancreatic Cancer Therapy Review: From Classic Therapeutic Agents to Modern Nanotechnologies.

Abstract: Pancreatic cancer remains one of the most lethal cancers worldwide, with an extremely poor prognosis. This cancer is considered the 5th leading cause of cancer related death. The median survival after diagnosis is generally 2-8 months and five-year survival rate is less than 5%. In recent years, nanotechnology is emerging as a rising approach for drug delivery since it has opened up new landscapes in medicine through introduction of smart nanocarrier systems that can selectively deliver the therapeutic agent in a specific region and in appropriate levels, reducing the adverse side effects. This review covers the main delivery systems developed so far for anticancer drug delivery to the pancreas over a period of 20 years, from polymeric to lipidic-based nanosystems, with a particular emphasis on albumin as core material.

Endogenous Biomarkers to Assess Drug-Drug Interactions by Drug Transporters and Enzymes.

Abstract: Background Drug-Drug Interactions (DDI) by modulation of drug transporters or drug metabolizing enzymes are common in multi-drug therapy. DDI potential of any new drug is assessed by conducting separate clinical studies using relevant probe substrates, which involves additional resource and cost. Recently, several endogenous compounds have been evaluated as substrates of transporters and enzymes that could be assessed as part of early clinical trials along with the assessment of drug pharmacokinetics, pharmacodynamics and safety studies. This enables an early readout on potential DDIs avoiding or minimally delaying the conduct of definitive DDI studies until later in clinical development. Method This review describes various endogenous biomarkers reported for drug transporters and metabolizing enzymes with their advantages and limitations. Conclusion Furthermore, the authors describe strategies to adopt while exploring a new endogenous biomarker, and factors to be considered in selection of biomarkers with the current challenges and opportunities.

Nanoparticles as a Carrier System for Drug Delivery Across Blood Brain Barrier.

Abstract: Brain, the centre of the nervous system and an integral part the body, is protected by two anatomical and physiological barriers- Blood-Brain Barrier (BBB) and Blood-Cerebrospinal Fluid Barrier (BCSFB). Blood-Brain Barrier is a very complex and highly organized multicellular structure that shields the brain from harmful substances and invading organisms from the bloodstream and thus offering protection against various brain diseases and injuries. However, it also impede the effective delivery of drug to the brain, thus, preventing treatment of numerous neurological disorders. Even though various traditional approaches such as Intra-Cerebro-Ventricular (ICV) injection, use of implants, disruption of BBB and use of prodrugs have achieved some success in overcoming these barriers, researchers are continuously working for promising alternatives for improved brain drug delivery. Recent breakthroughs in the field of nanotechnology provide an appropriate solution to problems associated with these delivery approaches and thus can be effectively used to treat a wide variety of brain diseases. Thus, nanotechnology promises to bring a great future to the individuals with various brain disorders. This review provides a brief overview of various brain drug delivery approaches along with limitations. In addition, the significance of nanoparticles as drug carrier systems for effective brain specific drug delivery has been highlighted. To show the complexity of the problems to be overcome for improved brain drug delivery, a concise intercellular classification of the BBB along with general transport routes across it is also included.

Targeting the Programmed Cell Death-1 Pathway in Genitourinary Tumors: Current Progress and Future Perspectives

Abstract: Immune checkpoint inhibitors have revolutionized the treatment many malignancies with over a dozen new United States Food and Drug Administration (FDA) approvals in the past six years Due to the combination of potent treatment success and potentially deadly adverse effects from immune checkpoint inhibitors, gathering prognostic and predictive information about FDA-indicated tumors is prudent PD-L1 expression is a poor prognostic factor and predictive of better responses from both PD-1 and PD-L1 inhibitors in a variety of tumor types including RCC and urothelial carcinoma Each FDA-approved PD-1/PD-L1 drug is paired with a PD-L1 immunohistochemistry (IHC) assay The majority of PD-1/PD-L1 inhibitor clinical trials use proprietary IHC antibodies with undefined validation data Thus, there is need for improved knowledge and application of PD-1/PD-L1 IHC biomarkers There is a wealth of recent publications using antibody clones to characterize tumor PD-1/PD-L1 expression profiles PD-1 is expressed on lymphocytes PD-L1 is expressed on both tumor cells and immune cells IHC staining appears in membranous fashion A cutoff of at least 5% tumor cell PD-L1 staining for positivity has worked for most studies Caution should be observed when employing tissue microarray techniques RCC has been the most studied of the genitourinary malignancies for PD-L1 expression The atezolizumab-approved ICH assay is unique in that only immune cell staining is quantified for the use of this assay in urothelial carcinoma With familiarity of the current FDA guidelines, published medical literature, and general immunohistochemical considerations, the use of immune checkpoint biomarkers can continue to flourish

Dabigatran - Metabolism, Pharmacologic Properties and Drug Interactions.

Abstract: BACKGROUND The superiority of dabigatran has been well proven in the standard dosing regimen in prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and extended venous thromboembolism (VTE) treatment. Dabigatran, an anticoagulant with a good safety profile, reduces intracranial bleeding in patients with atrial fibrillation and decreases major and clinically relevant non-major bleeding in acute VTE treatment. However, several important clinical issues are not fully covered by currently available directions with regard to dabigatran administration. The prominent one is reflected in the fact that dynamic impairment in renal function due to dehydratation may lead to haemorragic complications on the one hand, while on the other hand glomerular hyperfiltration may be a possible cause of dabigatran subdosing, hence reducing the drug's efficacy. Furthermore, limitations of the Cockcroft-Gault formula, considered a standard equation for assessing the renal function, may imply that other calculations are likely to obtain more accurate estimates of the kidney function in specific patient populations. Method and Conclusions: Although not routinely recommended, a possibility of monitoring dabigatran in special clinical settings adds to optimization of its dosage regimens, timely perioperative care and administration of urgently demanded thrombolytic therapy, therefore significantly improving this drug's safety profile. Despite the fact that dabigatran has fewer reported interactions with drugs, food constituents, and dietary supplements, certain interactions still remain, requiring considerable caution, notably in elderly, high bleeding risk patients, patients with decreased renal function and those on complex drug regimens. Additionally, upon approval of idarucizumab, an antidote to dabigatran solution, hitherto being a major safety concern, has been finally reached, which plays a vital role in life-threatening bleeding and emergency interventions and surgery.

Advances and Implications in Nanotechnology for Lung Cancer Management

Abstract: Background: Lung cancer is one of the most fatal chronic diseases in the field of respiratory medicine. The purpose of this paper is to address the side effects of conventional treatment strategies and to report the findings of till date drug nanocarriers researches performed for lung cancer therapy. This review also highlights the outstanding results of several researches employing pulmonary delivery system of nano-based drug formulations suitable for lung cancer. Objective: Summarizing the advances made in the field of nanotechnology-based lung cancer management. Methods: We systematically searched for research literature using a well-framed review question and presented data in the tabular forms for readers’ convenience. Results: Sixty-four papers were included in the review, the majority of which represent latest researches in the field of nanoparticle-based drug delivery for lung cancer therapy. Conventional treatment strategies for lung cancer lack specificity and are limited by undesirable toxicities in normal cells, as well as a high rate of recurrence. Intervention of nanotechnology has revolutionized the therapy of lung cancer upto a great extent by overcoming the current constraints in conventional therapies. Pulmonary delivery of nano-based drug formulations has resulted in potentially more effective and advanced lung cancer therapy. Conclusion: Several nanoscale drug delivery systems for lung cancer treatment are at present in clinical trials and some of them already exist in commercially available forms in the marketplace. However, although nanoscale drug carriers for lung cancer treatment have demonstrated stupendous therapeutic potential at both preclinical and clinical trials, but there are still many limitations to be solved.

Pharmacogenetics of Metabolic Genes of Anthracyclines in Acute Myeloid Leukemia.

Abstract: Background Anthracyclines in combination with cytarabine have been the standard therapy for acute myeloid leukemia (AML) for decades with high efficacy. However, the majority of patients will show initial resistance or will relapse after initial complete remission. Genetic variability in genes involved in anthracyclines metabolic pathway could be one of the causes of the interindividual differences in clinical outcomes. Methods A systematic review of published studies in AML cohorts was carried out in order to analyze the influence of polymorphisms in genes of anthracycline metabolism on efficacy and toxicity. Results Polymorphisms in the main enzymes of anthracyclines metabolism (CBR, AKR, NQO1, NOS3) have been related to lower enzymatic activity and higher cardiotoxicity. Moreover, variant alleles in the genes of carcinogens and chemotherapy neutralizing enzymes (GST, SULT, NADP(H) oxidase) have been associated with ROS generation and drug efficacy, influencing the survival rates and cardiac toxicities. In addition, genetic variability in the transporters of anthracyclines could affect the intake in cells, including influx (SLC28A3, SLC22A12, SLCO1B1) and efflux transporters (ABCB1, ABCC1, ABCC3, ABCG2). Conclusion The knowledge of the role of pharmacogenetics in anthracyclines metabolism could explain the differences observed in their disposition in leukemic cells. These genetic variants are proposed biomarkers in clinical practice in order to individualize chemotherapy schemes, potentially increasing the effectiveness and reducing the toxicities.

Recent Development and Future Prospects of Plant-Based Vaccines.

Abstract: Background Growing world population and continuous disease emergence have invited the development of more efficient new vaccines against a range of diseases. Conventional vaccines are being wildly used in the world but their production requires higher cost, more time and better infrastructure. Thus, the idea of plant-based edible vaccine technology has emerged and showed promising results with strong and effective protection against many diseases. Plants have been utilized since more than two decades as pharmaceuticals against many diseases. Methods Plant-based technology has great potential to express genes and produce clinically important compounds in the desired tissue. Plant biotechnology has played important role in the production of pharmaceutical compounds like vaccines, antibodies, antigens, sub-units, growth hormones and enzymes by utilizing genetic modification. It has also been opened a new approach for developing an edible vaccine as an oral delivery. Results Edible vaccines have been shown to induce both mucosal as well as systemic immunity. Currently, many pharmaceuticals proteins as an edible vaccine have been developed in different plant expression systems and evaluated against various life-threatening diseases and some of them have reached advanced phase of the clinical trial and exhibited promising results. Conclusion In this review, we have discussed about the molecular pharming, edible vaccines, plant base technology and current status of developed edible vaccines in the different plant tissue expression system, mechanism of action and clinical applications with clinical trials stage, significance, requirements, advantage and disadvantage of edible vaccines.