Current Drug Metabolism (v.18, #2)

Meet Our Editorial Board Member by Hiroshi Yamazaki (87-87).

Phage Display Technique: A Novel Medicinal Approach to Overcome An tibiotic Resistance by Using Peptide-Based Inhibitors Against β-Lactamases by Ghazala Muteeb, Md. Tabish Rehman, Saeedut Zafar Ali, Abdurrahman M. Al-Shahrani, Mohammad Amjad Kamal, Ghulam Md. Ashraf (90-95).
The emergence of antibiotic resistance in bacteria is a serious threat with enormous social and economic implications. The distribution of resistance genes/markers through horizontal gene transfer leads to the dissemination of resistant strains in different parts of the world. The resistant bacteria acquire the ability to overcome resistance by different modes amongst which the expression of β-lactamases is a major factor. The β-lactamase enzymes cleave the amide bond of the β-lactam antibiotics, which constitute about one-third of the antibiotics used all over the world. In a quest to control the spread of resistant bacteria, advanced generations of antibiotics are used either alone or in combination with inhibitors. However, these antibiotics and inhibitors also contain β-lactam ring in their structure and hence are prone to be hydrolyzed by β-lactamase enzymes in the near future. Thus, the severity of the problem is manifested due to the paucity of novel non-β-lactam core containing antibiotics in the drug development stage. One approach to overcome these shortcomings is to use peptide-based inhibitors. Here, we describe the potential use of phage display technique to screen commercially available libraries to pan against β-lactamase enzymes. The main advantage of using peptide-based inhibitors is that the bacteria will not be able to recruit pre-existing defense mechanisms and it will take a long time to evolve a new mechanism in its defense against peptide-based inhibitors.

A Current Perspective on the Inhibition of Cholinesterase by Natural and Synthetic Inhibitors by Anzer A. Shah, Tanveer A. Dar, Parvaiz A. Dar, Showkat A. Ganie, Mohammad A. Kamal (96-111).
Majority of the observed cognitive and behavioral changes in Alzheimer's disease are postulated to be due to the deficiencies in cholinergic pathways of the brain. Enhancement of cholinergic transmission may thus stimulate the cholinergic receptors or prolong the availability of acetylcholine in synaptic cleft and hence improve the Alzheimer's disease associated symptoms. Of these two, the inhibition of cholinesterases (Acetylcholinesterase and Butyrylcholinesterase) by cholinesterase inhibitors is suggested to be a promising strategy. In this regard, various agents both natural and non-natural have been evaluated for the inhibition of cholinesterases. Phytochemical studies of some of the medicinal plants have shown the presence of many valuable compounds that show a wide range of pharmacological activity against cholinesterase enzymes. Interestingly, a good number of potent synthetic inhibitors of cholinesterase enzymes reported so far are natural-product based. This article aims to provide a comprehensive overview of both natural and synthetic cholinesterase inhibitors reported so far. Presenting a comparative overview of synthetic and natural cholinesterase inhibitors may provide some leads for the synthesis of new cholinesterase inhibitors from medicinal plants. Structural activity relationship of the active cholinesterase inhibitors is also discussed with some insights from simulation studies. Insights for possible future research have also been highlighted.

Ginkgo biloba as an Alternative Medicine in the Treatment of Anxiety in Dementia and other Psychiatric Disorders by Sandeep Kumar Singh, George E. Barreto, Gjumrakch Aliev, Valentina Echeverria (112-119).
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.

A Review on Nano-Antimicrobials: Metal Nanoparticles, Methods and Mechanisms by Edris Hoseinzadeh, Pouran Makhdoumi, Parisa Taha, Hooshyar Hossini, John Stelling, Mohammad Amjad Kamal, Ghulam Md. Ashraf (120-128).
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.

Nanoparticles as a Carrier System for Drug Delivery Across Blood Brain Barrier by Alika Sarkar, Ismat Fatima, Qazi Mohammad Sajid Jamal, Usman Sayeed, Mohammad Kalim A. Khan, Salman Akhtar, Mohammad Amjad Kamal, Alvina Farooqui, Mohammad Haris Siddiqui (129-137).
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.

Potential of Plant Alkaloids as Antipyretic Drugs of Future by Imad Ahmad, Haroon Khan, Anwar-ul-Hassan Gilani, Mohammad Amjad Kamal (138-144).
Fever or Pyrexia means abnormal rise in body temperature above the usual range of normal in response to a variety of infectious, immunological and neoplastic stimuli. To normalize these febrile conditions, several synthetic agents are in clinical practice such as acetaminophen, ibuprofen, and aspirin. However, they are having many side effects which sometimes challenge their applications. The various sources are under investigation worldwide to overcome issues of unwanted effects and to better therapeutic response. In this scenario botanicals such as alkaloids, the most widely distributed and studied plant secondary metabolites, could effectively produce the molecules with better antipyretic effect and safety profile. The current review deals with 21 isolated alkaloids from 14 plants species having some antipyretic effect in preliminary screening/preclinical studies with the possible mechanism and structural edges. Therefore, these alkaloids of plant origin are candidates for further detail studies to ascertain their mechanism(s) and clinical utility or as lead compounds for future drugs.

Sonication-Assisted Nanoprecipitation in Drug Delivery by Anh Thi Ngoc Vo, Thinh Duc Luu, Minh Ngoc Uyen Nguyen, Toi Van Vo, Wei Duan, Phuong Ha-Lien Tran, Thao Truong-Dinh Tran (145-156).
Sonication-assisted nanoprecipitation provides an effective tool for nanomedicine engineering in therapeutic improvement. In the scope of this review, original works in interdisciplinary areas of using sonication with precipitation method for nanoparticulate drug delivery systems and its applications in management of different diseases are discussed. The use of sonication-assisted nanoprecipitation has been proved to improve drug bioavailability, which attracts tremendous interests as an effective strategy for drug delivery. However, many challenges still remain. To overcome these barriers, different approaches such as precipitation method, rational design, optimization and modification have been investigated. Accordingly, current knowledge of sonication-assisted nanoprecipitation proposes a broad perspective and optimization for the applications of nanotechnology in drug delivery.

Challenges Related to Glycemic Control in Type 2 Diabetes Mellitus Patients by Masoumeh Kheirandish, Hamidreza Mahboobi, Maryam Yazdanparast, Mohammad Amjad Kamal (157-162).
Diabetes mellitus (DM) is a chronic disease with long-term complications. Glycemic control is an important part in management of DM. The first line in treatment of type 2 DM (T2DM) is diet and life style change. Metformin is the first choice of medication in T2DM patients. Sulfonylureas have high risk of hypoglycemia. Glinides are associated with lower risk of hypoglycemia in comparison to sulfonylureas. Also, α-glucosidase inhibitors decrease the polysaccharides' digestion in small intestine and are less effective in comparison to metformin and sulfonylureas in lowering hemoglobin A1c (HbA1c). These have no risk for hypoglycemia, but gastrointestinal symptoms are common. Thiazolidinediones are known as insulin sensitizers and are effective for a longer duration in comparison to sulfonylureas, however, have side effects such as fluid retention, edema and heart failure. Incretin mimetics including exenatide and liraglutide act through increase in insulin secretion by pancreatic beta cells, in a glucose-dependent manner. Therefore, these are associated with no risk of hypoglycemia. Pramlintide is an amylin agonist which is also effective in lowering postprandial blood glucose. Sitagliptin and vildagliptin are dipeptidyl peptidase-4 inhibitors and have no risk of hypoglycemia when used as monotherapy. Canagliflozin and dapagliflozin decrease blood glucose level by increasing urinary glucose excretion and are associated with weight loss.

Glycosides as Possible Lead Antimalarial in New Drug Discovery: Future Perspectives by Marya, Haroon Khan, Gohar Mushtaq, Mohammad Amjad Kamal, Izhar Ahmad (163-171).
Malaria remains one of the major public health problems worldwide and it is responsible for a large number of morbidity and mortality. Especially, in the third world countries, it is still alarming. The development of drugresistant to Plasmodium falciparum strains has further degraded the overall situation. However, a limited number of effective drugs available emphasize how essential it is to establish new anti-malarial compounds. New antimalarial agents with distinctive structures and mechanism of action from the natural origin are thus immediately required to treat sensitive and drug-resistant strains of malaria. Over the years, phytopharmaceuticals have provided numerous lead compounds. Similarly, the success rate of botanicals in terms of clinical significance is also very high. Of them, glycoside is one of the most widely distributed and emerging class of plant secondary metabolites. This review provides an outlook to recently isolated glycosides from plants with marked antimalarial effects in an in-vitro and in-vivo protocols and thus ideal candidates for clinical trials to ascertain their clinical utility and or led compounds.