Current Drug Metabolism - Volume 18, Issue 11, 2017

Background: Recently, pharmaceutical research has focused on in vitro-in vivo correlation as a novel challenge, and in silico modeling has been an important component. As in silico models are highly representative of practical use, regulatory agencies such as the US Food and Drug Administration and European Medicines Agency have recognized and utilized in silico modeling as a useful tool; this allows pharmaceutical organizations to use Physiologically Based Pharmacokinetic (PBPK) models for decision-making, which may aid the financial efficiency of a clinical trial. However, some studies have shown differences of up to approximately 40% in pharmacokinetic parameters such as area under the curve or maximum serum concentration between observed and simulated data. Methods: Gastroplus™ was used to demonstrate current PBPK simulation. 46 research papers were compared with each other's applications of PBPK simulation. Results: To improve the accuracy of simulation, additional factors may need to be considered, such as precise volume of gastrointestinal sections, specific metabolism of the target drug, and physicochemical data of drug metabolites. Furthermore, the results of these simulations would be extremely valuable to the relevant applications. Simulation programs using Advanced Compartmental Absorption and Transit (ACAT)/PBPK modeling could be a powerful tool for companies performing pre-clinical experiments, and could provide a solution for the ethical issues and economic constraints of clinical trials. Conclusion: If in silico modeling produced more precise results that could closely match clinical data, it could be more readily used to screen drug pharmacodynamics in bodily systems, and the efficiency of clinical trials would be improved. However, simulation programs are currently limited in their accuracy of pharmacodynamic predictions. In developing new drugs, pharmaceutical companies should address this issue in order to improve in silico/PBPK modeling in the future.

Background: Nanostructured material is a solid substance with at least one face is in the range of 1-100 nm. Manipulations in the characteristics and effects of nanostructures can invent new procedures and technologies, as the physical and chemical properties of nanomaterials are noticeably dissimilar from those of a single atom or its bulk phase. This difference in the properties is due to different spatial arrangements and shapes, changes in phase, energetics, electronic structure, chemical reactivity, and catalytic properties of huge, finite systems, and their assemblages. Theranostic involves the study of compounds which associates the modalities of curative and investigative purposes. Objective: The aim of this review was to highlight the possible uses of nanoparticles as therapeutic and diagnostic agents. As is evident by the latest applications of nanoparticles in the development of sensitive biosensors as well as in MRI and drug delivery systems. The most important theranostic application of nanoparticles involves the treatment of cancer. In most of the cases, the late diagnosis of the disease is responsible for increasing the mortality rate. Moreover, the toxic effect of the chemotherapeutic drugs on the normal cells of the body seems to be another major drawback of the treatment. Therefore, theranostics appears to be very helpful and realistic area in the diagnosis and targeted drug delivery of this particular disease. Methods: We systematically searched for research literature using well-framed review questions and presented data in both the text as well as tabular forms for readers' convenience. The present review collected the data from the published reviews as well as original research papers. The manuscripts considered in this article were taken from the databases and search engines comprising NCBI, PubMed, Google scholar, directory of open access journals, ScienceDirect and local library searches. The properties of the selected articles were analyzed, and a rational quantitative and qualitative content were used for the outcome and inference of the study applying a conceptual foundation. Results: Two hundred seventeen papers were included in the review. Most of the papers were from developed countries (163) and the rest from developing countries (54). Seventy four articles dealt with both the diagnostic as well as therapeutic study of nanomaterials, fifty seven manuscripts included only therapeutic approach and twenty seven papers included only diagnostic approach. The rest of the articles included the data on the synthesis and characterization of surface modified nanomaterials which could be applied in this area. Forty five papers dealt with both in vitro and in vitro studies, sixteen manuscripts involved studies on clinical trials, fifty nine articles gave data on the basis of in vitro experiments and twenty seven articles on the basis of in vivo studies only while 2 papers included in situ data. In the manuscripts considered for the review, the data on both the solid tumors as well as cancers were taken. Almost all types of cancers are being studied using nanomaterials but the most studied cancer for therapeutic and diagnostic approach on the basis of literature is breast cancer. Conclusion: By the help of surface modification of the nanomaterials specific targeting properties towards specific molecules and receptors in various types of cells could be achieved. It has been suggested that the delivered drugs require low amount to achieve the synergy between both the drugs delivered to cancer cells and tissues. Moreover, the toxic effect of the chemotherapeutic drugs on the normal cells of the body is another major drawback of the treatment. Upon further improvement and optimization of these nanoparticle-based strategies, it will ultimately lead to the prediction of patient's response towards a specific molecular therapy and it will be helpful to observe their responses to personalized therapy. Therefore, theranostics appears to be very helpful and realistic area in the diagnosis and targeted drug delivery of this particular disease.

Background: More than 60% of the active pharmaceutical ingredients, which are classified as Biopharmaceutics Classification System class II. The limited solubility of these drug may lead to low therapeutic effects. Methods: Nanoprecipitation presents some advantages because it is a straightforward method with low-cost equipment that is easy to scale up. Results: However, there are two technical issues of concern related to this method. First, the two solvents used for this approach must be miscible; concomitantly, the drug has to be soluble enough in a solvent but not in the antisolvent. Second, the particle growth needs to be adjusted by surfactant addition. Conclusion: In this review, nanoprecipitation methods and solvent removal techniques for poorly water soluble drugs will be discussed.

Background: Efficient colon-specific drug delivery has been demonstrated recently in the treatment of various diseases, including Crohn's disease, ulcerative colitis (inflammatory bowel disease), and colorectal cancer. Methods: Of all strategies, the conjugation of a model drug to a carrier (with or without spacers) has been recognized as promising for targeting the colon. Results: This is because the conjugation method releases large amounts of the drug while reducing the amount of the drug released in the stomach and small intestine. Conclusion: This review focuses on the design of linkage conjugates that carry out specific delivery to the colon. The types of conjugation for application in colorectal cancer therapy will be discussed as well.

Background: Recently the decoration of graphene with metallic nanoparticles by a synchronized reduction of graphene oxide (GO) and synthesis of metallic nanoparticles has gained momentum. Metal-decorated carbon substrates, for example, carbon nanotubes and graphene oxide have been of interest to the scientific group all through the past three decades on account of different potential applications. The utilization of graphene oxide as the nano scale substrates for the formation of nanocomposites with metal oxides is a novel thought to acquire a hybrid which would show both the properties of GO as an interesting paper-shape material and the elements of single nanosized metal particles. Methods: Graphene is a carbon allotrope of sp2 hybridized carbon atoms in a honeycomb lattice. It has attracted unique properties and potential applications. It has been synthesized and modified through various methods, and composites have been made with other nanomaterials, such as metals, metal oxides, and some complex oxides. Results: Grapheme-metal oxide composites are gaining attention as a viable alternative to boost the efficiency of various catalytic, storage reactions in energy conversion, anticancer and drug delivery applications. Nevertheless, by combining the superior physical/chemical properties of GO themselves and the versatile nanomaterials that can decorate with GO, GO based materials have a bright future in the anticancer, drug delivery, energy, and environmental applications. Conclusion: This review article has described the recent publications in the development of Decoration of Graphene Oxide such as metals, metal oxides and their nanocomposites based materials. We anticipate this active field will continue growing rapidly, leading eventually to a variety of mature materials and devices that would benefit the society. Finally, the applications of composites are at their initial stages. They need to be studied systematically from both theoretical and experimental aspects.

Background: The first-line TB antibiotic isoniazid (INH) serves as a central component of combined first-line anti-tuberculosis drug therapy. However, resistance to INH has hindered the functioning of this drug. Resistance is caused by several known and unknown mutations in genes/regions in Mycobacterium tuberculosis (M. tuberculosis), followed by selection of these mutants in the presence of the drug. INH resistance can be categorised as either “high-level” (minimum inhibitory concentration (MIC) of > 1μg/mL to INH) or “low-level” (MIC between 0.1-1.0 μg/L) resistance and is dependent on the specific mutation acquired. The level of resistance is relevant, as INH resistance is often considered to be the first step in development of Multi-Drug Resistant (MDR) and extremely resistant (XDR) TB. Isoniazid is a pro-drug in which first pass metabolism happens via N-acetyltransferase and is fast, intermediate or slow, depending on the genetics of the host. Thus, low-level INH resistance, particularly in the presence of fast metabolism, could allow additional mutations, development of high-level resistance and progression to multi-drug resistance. Methods: A structured search of bibliographic databases for peer-reviewed research literature was performed. Set parameters and specific inclusion criteria were used to filter the literature, based on our specified review questions. The quality and relevance of included papers was deduced using standard tools. The relevant content of cited papers was described, and an inferential qualitative content analysis methodology was utilised to analyse the inferences and findings of included studies using a conceptual framework. Results: Seventy-eight papers were included in the review, of which a sub-set (36) of the papers describe how different genetic mutations result in low or high-level resistance to INH. These papers were also used to set up a diagram detailing how each mutation affects INH functionality in order to visualise the interactome of INH and M.tuberculosis A further twenty-eight out of the seventy-eight papers detail the methods for testing for INH resistance, current treatment regimens and factors that influence treatment outcome in order to better understand the role of INH within the current anti-tuberculosis treatment therapy and how its use can be optimised. Conclusion: The findings of this review suggest that low-level INH resistance, in the presence of fast-acetylation, is an underrated component of the global TB epidemic worldwide, and may be a significant problem in terms of treatment outcome and progression to antibiotic resistance. Thus, more research must be done to test whether personalised diagnostics and targeted high dose treatment with INH will reduce the incidence of isoniazid mono-resistant and multi-drug resistant (MDR) tuberculosis.

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.

Background: Gold nanoparticles have been exploited for nanobiotechnology applications for the last two decades. New insights of the nanomaterials as promising agent for cancer diagnosis and therapy have just started to emerge. Due to the size- and shape-dependent optical, electrical and thermal properties, gold nanoparticles are being developed as diagnostic reagents, drug carriers, contrast agents, photothermal agents and radiosensitisers. This review aims to summarize the latest advances of gold nanoparticles in cancer treatment. Methods: We undertook a systematical search for research literatures using a well-framed review question and presented the applications in different fields, including early cancer diagnosis, imaging, radiotherapy, chemotherapy, gene therapy and photothermal therapy, which were fully described, filtered, combined and analyzed in order to provide documented proofs on the applications of gold nanoparticles in current cancer treatments. Results: One hundred and sixty papers were included in the review, the majority of which represent latest researches in the field of gold nanoparticle-based diagnosis and therapy for cancer. Conventional treatment strategies for cancer cannot identify normal and cancer cells. While due to the high surface area to volume ratio and rich surface functionalization chemistry, gold nanoparticle can greatly enhance the targeting with adverse side effects of traditional treatment on normal tissues being avoided. Conclusion: Gold nanoparticles have greatly improved the traditional treatment due to their unique properties. However, their size-dependent toxicity, distribution and clearance need further studies to make them a clinical reality.