Hybrid molecules based on 1,3,5-triazine as potential therapeutics: A focused review.

Majority of the representative drugs customarily interact with multiple targets manifesting unintended side effects. In addition, drug resistance and over expression of the cellular efflux-pumps render certain classes of drugs ineffective. With only a few innovative formulations in development, it is necessary to identify pharmacophores and novel strategies for creating new drugs. The conjugation of dissimilar pharmacophoric moieties to design hybrid molecules with an attractive therapeutic profile is an emerging paradigm in the contemporary drug development regime. The recent decade witnessed the remarkable biological potential of 1,3,5-triazine framework in the development of various chemotherapeutics. The appending of the 1,3,5-triazine nucleus to biologically relevant moieties has delivered exciting results. The present review focuses on 1,3,5-triazine based hybrid molecules in the development of pharmaceuticals.

New microbiological assay for determination of caspofungin in the presence of its degradation products and its measurement uncertainty.

Caspofungin is an echinocandin antifungal used in the treatment of invasive fungal infections. Several methods have been reported for the quantitative analysis of echinocandins; however, there is no microbiological assay for determination of caspofungin potency in the presence of its degradation products. This study aimed to develop and validate a microbiological method for quantitative analysis of caspofungin in lyophilized powder, evaluate the stability, and determinate the degradation kinetics of the drug when the finished product is submitted to heat stress. A procedure was established to estimate measurement uncertainty for routine analysis. The validation was performed as recommended in the current official guidelines. The agar diffusion method is based on the inhibitory effect of caspofungin on Candida albicans. Results showed selectivity, linearity, precision, and accuracy of the method. Statistical analysis demonstrated that method is linear (in the range 2.5 to 16 microg/mL, y= 15.73 + 6.4x, r2 = 0.9965), precise (intermediate precision: 2.54%), and accurate (recovery range: 95.01-102.46%). The proposed method allowed evaluation of the thermal stability of the drug at 80 degreesC for 120 min and determination of first order degradation kinetics. The variability of inhibition zone sizes was the most important source of uncertainty at about 87% of the overall uncertainty (103.0+/-1.7%). These results show that the proposed method is applicable to routine laboratory testing, and is sensitive to thermal degradation of caspofungin.

Effect of bixin and norbixin on the expression of cytochrome P450 in HepG2 cell line.

Bixin and norbixin are the main components of annatto, which is extracted from Bixa orellana and largely used as natural colorant in the food and pharmaceutical industries. Annatto can enhance CYP1A and CYP2B activity in rats; however, the inducer effect has not been investigated in human cell lines. In this study, the ability of bixin and norbixin to induce the cytochrome P450 (CYP) enzymes was assessed in HepG2 human hepatoma cell line. HepG2 cells were treated with bixin and norbixin, and the expression of the CYP genes quantified by real-time reverse transcription polymerase chain reaction (RT-PCR). Expression of CYP1A1 and CYP1A2 was significantly increased by bixin treatment, while CYP2B6, 2C9, 2E1 and 3A4 were unaffected. Cells were treated with norbixin showed no inducer effect. The results suggest that the inducer potential of annatto is attributed to bixin, but not to norbixin, despite their similarities in molecular structure.

Berberine-loaded engineered nanoparticles attenuate TGF-ß-induced remodelling in human bronchial epithelial cells.

Airway remodelling occurs in chronic respiratory diseases (CRDs) such as asthma and chronic obstructive pulmonary disease (COPD). It is characterized by aberrant activation of epithelial reparation, excessive extracellular matrix (ECM) deposition, epithelial-to-mesenchymal transition (EMT), and airway obstruction. The master regulator is Transforming Growth Factor-ß (TGF-ß), which activates tissue repair, release of growth factors, EMT, increased cell proliferation, and reduced nitric oxide (NO) secretion. Due to its fundamental role in remodelling, TGF-ß is an emerging target in the treatment of CRDs. Berberine is a benzylisoquinoline alkaloid with antioxidant, anti-inflammatory, and anti-fibrotic activities whose clinical application is hampered by poor permeability. To overcome these limitations, in this study, berberine was encapsulated in monoolein-based liquid crystalline nanoparticles (BM-LCNs). The potential of BM-LCNs in inhibiting TGF-ß-induced remodelling features in human bronchial epithelial cells (BEAS-2B) was tested. BM-LCNs significantly inhibited TGF-ß-induced migration, reducing the levels of proteins upregulated by TGF-ß including endoglin, thrombospondin-1, basic fibroblast growth factor, vascular-endothelial growth factor, and myeloperoxidase, and increasing the levels of cystatin C, a protein whose expression was downregulated by TGF-ß. Furthermore, BM-LCNs restored baseline NO levels downregulated by TGF-ß. The results prove the in vitro therapeutic efficacy of BM-LCNs in counteracting TGF-ß-induced remodelling features. This study supports the suitability of berberine-loaded drug delivery systems to counteract airway remodelling, with potential application as a treatment strategy against CRDs.

An overview of the use of central venous catheters impregnated with drugs or with inorganic nanoparticles as a strategy in preventing infections.

Central venous catheter (CVC) is a medical device widely used in therapeutics to avoid repetitive venipuncture. Although its use is advantageous, it is possible to highlight limitations, such as the risk of catheter-related bloodstream infections, caused by excessive manipulation and even the urgency at the time of insertion. These factors lead to an expensive treatment, often hampered by resistance to antimicrobial agents, exposing the patient the risk and even leading to death. The use of CVC impregnated with free drugs or incorporated with nanoparticles is a promising strategy for preventing the adherence of microorganisms in these devices and consequently in the prevention of the infections. Although most of the nanoparticles registered by the FDA for medical use are organic, several studies have reported the potential of inorganic nanoparticles for this purpose. Therefore, the present review seeks to highlight the current scenario of hospital infections related to the use of CVC and the importance of CVCs impregnated with drugs or incorporated with inorganic nanoparticles as an interesting strategy in combating infections assigned to the use of this medical device.

Tertiary Nanosystem Composed of Graphene Quantum Dots, Levofloxacin and Silver Nitrate for Microbiological Control.

BACKGROUND: Infectious diseases have the highest mortality rate in the world and these numbers are associated with scarce and/or ineffective diagnosis and bacterial resistance. Currently, with the development of new pharmaceutical formulations, nanotechnology is gaining prominence. METHODS: Nanomicelles were produced by ultrasonication. The particle size and shape were evaluated by scanning electron microscopy and confirmed by dynamic light scattering, also thermogravimetric analysis was performed to evaluate the thermal stability. Finally, antibacterial activity has been performed. RESULTS: The results showed that a rod-shaped nanosystem, with 316.1 nm and PDI of 0.243 was formed. The nanosystem was efficient against Staphylococcus aureus, Pseudomonas aeruginosa, and Bacillus subtilis subsp. spizizenii with MIC inferior to 0.98 and a synergistic effect between silver graphene quantum dots and levofloxacin was observed. CONCLUSION: The nanosystem produced may rise as a promising agent against the bacterial threat, especially regarding bacterial resistance.

Targeting mucus barrier in respiratory diseases by chemically modified advanced delivery systems.

Mucus gel constitutes of heavily cross-linked mucin fibers forming a viscoelastic, dense porous network that coats all the exposed epithelia not covered with the skin. The layer provides protection to the underlying gastrointestinal, respiratory, and female reproductive tracts, in addition to the organs such as the surface of eye by trapping the pathogens, irritants, environmental fine particles, and potentially hazardous foreign matter. However, this property of mucus gel poses a substantial challenge for realizing the localized and sustained drug delivery across the mucosal surfaces. The mucus permeating particles that spare the protective properties of mucus gel improve the therapeutic potency of the drugs aimed at the management of diseases, including sexually transmitted infections, lung cancer, irritable bowel disease, degenerative eye diseases and infections, and cystic fibrosis. As such, the mucoadhesive materials conjugated with drug molecules display a prolonged retention time in the mucosal gel that imparts a sustained release of the deliberated drug molecules across the mucosa. The contemporarily developed mucus penetrating materials for drug delivery applications comprise of a finer size, appreciable hydrophilicity, and a neutral surface to escape the entrapment within the cross-inked mucus fibers. Pertaining to the mucus secretion as a first line of defence in respiratory tract in response to the invading physical, chemical, and biological pathogens, the development of mucus penetrating materials hold promise as a stalwart approach for revolutionizing the respiratory drug delivery paradigm. The present review provides an epigrammatic collation of the mucus penetrating/mucoadhesive materials for achieving a controlled/sustained release of the cargo pharmaceutics and drug molecules across the respiratory mucus barrier.

Matrix-assisted laser desorption ionization-time of flight mass spectrometry for identification of bacteria isolated from pharmaceutical clean rooms.

INTRODUCTION: During the manufacturing of sterile drugs, it is of the utmost importance to meet the minimum requirements for asepsis recommended by the legislations on good manufacturing practices-based efficient environmental monitoring. AIMS AND METHODS: The availability of relatively simple to use matrix-assisted laser desorption ionization-time of flight mass spectromtomy (MALDI-TOF MS) devices in the last years has changed the laboratory workflows for the microbial identification, mainly in the clinical area. Thus, the objective of this work was to evaluate the suitability of the MALDI-TOF MS technique for the identification of bacteria isolated from the environment of clean rooms used in some stages of the production of a viral vaccine. Eighteen known bacterial species commonly isolated from clean rooms studied were identified by MALDI-TOF technique and by a biochemical technique (BBL Crystal® System). RESULTS: Performance of MALDI-TOF MS was better than biochemical technique for correct species identifications (88.89% and 38.89%, respectively) and produced less unreliable identification (5.55% and 22.22%). CONCLUSION: MALDI-TOF MS can be implemented for routine identification of bacteria in a pharmaceutical quality control laboratory, but as a database-dependent system, maybe some isolated not identified by this technique must be additionally studied and, if appropriate, added to an in-house database.

Tumor suppressor role of miR-503.

MicroRNAs (miRNAs) are non-coding RNAs of around 20-25 nucleotides in length with highly conserved characteristics. They moderate post-transcriptional silencing by precisely combining with 3' untranslated regions (UTRs) of target mRNAs at a complementary site. miR­503, an associate of the "canonical" miRNA-16 family, is expressed in numerous types of tumors such as breast cancer, prostate cancer, lung cancer, colorectal cancer, hepatocellular carcinoma, glioblastoma and several others. There is convincing evidence to show that miR­503 functions as a tumor suppressor gene through its effects on target genes that regulate cell proliferation, migration, and invasion in tumor cells. In this current assessment, we discuss the biology and tumor suppressor role of miR­503 in different cancers and elaborate on its mechanism of action.

A clinical update on metformin and lung cancer in diabetic patients.

Diabetes mellitus (DM) is frequently increased in many countries and become a serious health problem worldwide. Diabetes is associated with dysfunction of different organs such as heart, eyes, blood vessels, nerves, and kidneys. There is a strong connection between diabetes and cancer. Metformin is one of the most commonly prescribed oral antidiabetic medicines and it is suggested as the first-line therapy due to its comparatively safe, inexpensive, effective and well-tolerated. Some of the in vitro and in vivo investigations proved that metformin may have a direct anticancer action by preventing the proliferation of malignant cells and formations of the colony, inducing arrest of cell cycle and apoptosis and suppressing tumor growth. The antiproliferative mechanism of metformin alone or in combination with various chemotherapeutic agents is complex and involves several beneficial roles. In this regard, clinical studies are required to explain these roles. In the coming future, the use of metformin, alone or in combination with current chemotherapy, might be a conventional approach to effectually manage lung cancer. This mini-review provides a critical overview of currently available clinical trials investigating the effects of metformin in lung cancer.

Role of microRNAs (miRNAs) in the pathophysiology of diabetes mellitus.

Diabetes mellitus is becoming the critical problem among the entire world and it is difficult to understand the molecular mechanism representing the concept of diabetic pathology. Recently the knowledge of the involvement of genetics in type 2 diabetes mellitus (T2DM) susceptibility has sketched a great concentration towards the transcriptional activity of ß cells within the pancreas. This disease becomes the leading cause of death, so it is necessary to study the molecular pathogenesis, phenotypes, and characteristics to design the therapeutic parameters. Here in this review role of miRNA is being illustrated as it plays a crucial role in the pathogenesis, progression, and fate of beta cells of pancreas regulating the insulin secretion. Here in this review, we try to include the effects and pathophysiology of various miRNA in diabetes mellitus and on the various sites of the human body.

Peroxisome proliferator-activated receptor gamma: promising target in glioblastoma.

Glioblastoma, also known as glioblastoma multiforme, is the most common and worldwide-spread cancer that begins within the brain. Glioblastomas represent 15% of brain tumors. The most common length of survival following diagnosis is 12 to 14 months with less than 3% to 5% of people surviving longer than five years. Without treatment, survival is typically 3 months. Among all receptors, special attention has been focused on the role of peroxisome proliferator-activated receptors (PPARs) in glioblastoma. PPARs are ligand-activated intracellular transcription factors. The PPAR subfamily consists of three subtypes encoded by distinct genes named PPARα, PPARß/δ, and PPARγ. PPARγ is the most extensively studied subtype of PPAR. There has been interesting preliminary evidence suggesting that diabetic patients receiving PPARγ agonists, a group of anti-diabetics, thiazolidinedione drugs, have an increased median survival for glioblastoma. In this paper, the recent progresses in understanding the potential mechanism of PPARγ in glioblastoma are summarized.

Performance Survey and Comparison Between Rapid Sterility Testing Method and Pharmacopoeia Sterility Test.

The sterility test described in pharmacopoeial compendia requires a 14-day incubation period to obtain a valid analytical result. Therefore, the use of alternative methods to evaluate the sterility of pharmaceuticals, such as the BacT/Alert® 3D system, is particularly interesting, because it allows a reduced incubation period and lower associated costs. Considering that the BacT/Alert® 3D system offers several culture media formulations developed for this microbial detection system, the present study was aimed to evaluate and compare the performance of BacT/Alert® 3D with the pharmacopoeial sterility test. There was no significant difference between the ability of the culture media to allow detection of microbial contamination. However, the rapid sterility testing method allowed a more rapid detection of the challenge microorganisms, which indicates that the system is a viable alternative for assessing the sterility of injectable products.

Nanotechnology: Advancing the translational respiratory research.

Considering the various limitations associated with the conventional dosage forms, nanotechnology is gaining increased attention in drug delivery particularly in respiratory medicine and research because of its advantages like targeting effects, improved pharmacotherapy, and patient compliance. This paper provides a quick snapshot about the recent trends and applications of nanotechnology to various translational and formulation scientists working on various respiratory diseases, which can help paving a new path in developing effective drug delivery system.

Preparation and characterization of metoprolol tartrate containing matrix type transdermal drug delivery system.

The present study aimed to develop matrix-type transdermal drug delivery system (TDDS) of metoprolol tartrate using polyvinyl pyrrolidone (PVP) and polyvinyl alcohol (PVA). The transdermal films were evaluated for physical parameters, Fourier transform infrared spectroscopy analysis (FTIR), differential scanning calorimetry (DSC), in vitro drug release, in vitro skin permeability, skin irritation test and stability studies. The films were found to be tough, non-sticky, easily moldable and possess good tensile strength. As the concentration of PVA was increased, the tensile strength of the films was also increased. Results of FTIR spectroscopy and DSC revealed the absence of any drug-polymer interactions. In vitro release of metoprolol followed zero-order kinetics and the mechanism of release was found to be diffusion rate controlled. In vitro release studies of metoprolol using Keshary-Chein (vertical diffusion cell) indicated 65.5 % drug was released in 24 h. In vitro skin permeation of metoprolol transdermal films showed 58.13 % of the drug was released after 24 h. In vitro skin permeation of metoprolol followed zero-order kinetics in selected formulations. The mechanism of release was found to be diffusion rate controlled. In a 22-day skin irritation test, tested formulation of transdermal films did not exhibit any allergic reactions, inflammation, or contact dermatitis. The transdermal films showed good stability in the 180-day stability study. It can be concluded that the TDDS of MPT can help in bypassing the first-pass effect and will provide patient improved compliance, without sacrificing the therapeutic advantages of the drugs.

Hydrogel Based Drug Delivery Systems: A Review with Special Emphasis on Challenges Associated with Decontamination of Hydrogels and Biomaterials.

BACKGROUND: Many researches involving the development of new techniques and biomaterials to formulate a suitable drug delivery system and tissue engineering have been conducted. The majority of published literature from these researches emphasizes the production and materials characterization. The safety aspect of hydrogels and biomaterials is a major constraint in their biological applications. OBJECTIVE: The present review article aimed to summarize various literatures that encompass the difficulties encountered with decontamination and sterilization methods in the preparations of biomaterials and especially hydrogels for biological applications. METHOD: We searched for original and review articles from various indexed journals reporting applications of hydrogels and biomaterials in drug delivery systems and the importance of decontamination process for hydrogel containing preparations based on various patents evidences. RESULTS: Despite the vast literature available, limited information regarding the decontamination and sterilization processes related to hydrogels and biomaterials is reported. Sterilization processes to hydrogels are not yet fully explored. Researchers working on hydrogel based systems can consider decontamination of such biomaterial as an important tool to allow for commercialization within the chemical, herbal or pharmaceutical industries. CONCLUSION: Unfortunately, till date, limited papers are available which reported the challenges associated with decontamination methods to prepare hydrogels and biomaterials for biological applications. In conclusion, each case of biomaterial requires individual consideration to decontamination and/or sterilization. This must be submitted to a specific method, but more than one technique can be involved. Physicochemical and biological alterations must be avoided and evaluated by the appropriate assays method. Furthermore, it is also important to consider that each method must be validated depending upon the process variables.

Application of Chitosan and its Derivatives in Nanocarrier Based Pulmonary Drug Delivery Systems.

BACKGROUND: The respiratory tract as a non-invasive route of drug administration is gaining increasing attention in the present time on achieving both local and the systemic therapeutic effects. Success in achieving pulmonary delivery, requires overcoming barriers including mucociliary clearance and uptake by macrophages. An effective drug delivery system delivers the therapeutically active moieties at the right time and rate to target sites. A major limitation associated with most of the currently available conventional and controlled release drug delivery devices is that not all the drug candidates are well absorbed uniformly locally or systemically. METHODS: We searched and reviewed the literature focusing on chitosan and chitosan derivative based nanocarrier systems used in pulmonary drug delivery. We focused on the applications of chitosan in the development of nanoparticles for this purpose. RESULTS: Chitosan, a natural linear bio-polyaminosaccharide is central in the development of novel drug delivery systems (NDDS) including nanoparticles for use in the treatment of various respiratory diseases. It achieves this through its unique properties of biodegradability, biocompatibility, mucoadhesivity and its ability to enhance macromolecule permeation across membranes. It also achieves sustained and targeted effects, primary requirements for an effective pulmonary drug delivery system. This review highlights the applications and importance of chitosan with special emphasis on nanotechnology, employed in the management of respiratory diseases such as asthma, Chronic Obstructive Pulmonary Disease (COPD), lung cancer and pulmonary fibrosis. CONCLUSION: This review will be of interest to both the biological and formulation scientists as it provides a summary on the utility of chitosan in pulmonary drug delivery systems. At present, there are no patented chitosan based controlled release products available for pulmonary drug delivery and so this area has enormous potential in the field of respiratory science.

Dual crosslinked pectin-alginate network as sustained release hydrophilic matrix for repaglinide.

Repaglinide, an oral antidiabetic agent, has a rapid onset of action and short half-life of approximately 1h. Developing a controlled and prolonged release delivery system is required to maintain its therapeutic plasma concentration and to eliminate its adverse effects particularly hypoglycemia. The present study aimed to develop controlled release repaglinide loaded beads using sodium alginate and pectin with dual cross-linking for effective control of drug release. The prepared beads were characterized for size, percentage drug entrapment efficiency, in vitro drug release and the morphological examination using scanning electron microscope. For the comparative study, the release profile of a marketed conventional tablet of repaglinide (Prandin® tablets 2mg, Novo Nordisk) was determined by the same procedure as followed for beads. The particle size of beads was in the range of 698±2.34-769±1.43µm. The drug entrapment efficiency varied between 55.24±4.61 to 82.29±3.42%. The FTIR results suggest that there was no interaction between repaglinide and excipients. The XRD and DSC results suggest partial molecular dispersion and amorphization of the drug throughout the system. These results suggest that repaglinide did not dissolve completely in the polymer composition and seems not to be involved in the cross-linking reaction. The percent drug release was decreased with higher polymer concentrations. In conclusion, the developed beads could enhance drug entrapment efficiency, prolong the drug release and enhance bioavailability for better control of diabetes.

Norfloxacin and metronidazole topical formulations for effective treatment of bacterial infections and burn wounds.

INTRODUCTION: Our various previous findings have shown the suitability of norfloxacin in the treatment of bacterial infections and burn wounds in alone as well as in combination with Curcuma longa in various topical (ointments, gels, and creams) and transdermal drug delivery systems. AIMS AND METHODS: Keeping these facts in consideration, we have made an another attempt to prepare semisolid formulations containing 1% w/w of norfloxacin and metronidazole with different bases like Carbopol, polyethylene glycol, and hydroxypropylmethyl cellulose for effective treatment of bacterial infections and burn wounds. The prepared formulations were evaluated for physicochemical parameters, in vitro drug release, antimicrobial activity, and burn wound healing properties. RESULTS: The prepared formulations were compared with Silver Sulfadiazine cream 1%, USP. Antimicrobial activity of norfloxacin semisolid formulations was found to be equally effective against both aerobic and anaerobic bacteria in comparison to a marketed formulation of Silver Sulfadiazine 1% cream, USP. Based on the burn wound healing property, the prepared norfloxacin semisolid formulation was found to be in good agreement with marketed Silver Sulfadiazine 1% cream, USP. CONCLUSIONS: These findings suggest formulations containing norfloxacin and metronidazole may also prove as an effective alternative for existing remedies in the treatment of bacterial infections and burn wounds.