Current Pharmaceutical Biotechnology - Volume 18, Issue 5, 2017

Background: Up to 25% of diabetic patients will develop a diabetic foot ulcer. Chronic wounds such as diabetic foot ulcers often fail to heal with conventional therapies. In recent years, it has been identified that chronic wounds are usually associated with elevated level of matrix metalloproteinases (MMPs). Doxycycline, a cheap tetracycline antibiotic, has been shown to inhibit MMPs both in vitro and in vivo independent of its antimicrobial property. Methods: We undertook a search through PUBMED for peer-reviewed research literature with doxycycline, chronic wound, diabetes, MMPs as key words. Results: Seventy papers were included in the review. This review identified doxycycline is a very promising drug to be used in patients with diabetic foot ulcers because higher efficacy even in a very low dosage, little side effects in a lower dosage, inhibition of MMP as well as prevention/treatment of infection in the ulcers, beneficial to cardiovascular complications and cheap to manufacture. Conclusion: In this review, we provide an overview of the roles of MMPs in the pathogenesis of chronic wounds and explore the potential application of doxycycline as a treatment option in managing chronic wounds such as diabetic foot ulcers.

Background: The clinical application of cells and the development of new delivery systems have allowed significant advances in the field of cell therapy and encapsulation in recent years. The ability to combine cells and biocompatible matrices in the encapsulation of cells providing long-term delivery has provides new therapeutic alternatives in the development of new therapies. Methods: A structured search of bibliographic databases was carried out to determine the entire methodology related to cell encapsulation with clinical application. Results: Cell encapsulation provides increased retention time in the target tissue improving its therapeutic efficacy. This technology involves the development of a physical barrier (natural or synthetic matrix surrounded by a semipermeable membrane) to isolate and protect cells from the host's immune system maintaining the microenvironment of embedded cells, their viability and their capacity of differentiation, improving their function in vivo, and reducing side effects associated with the use of immunosuppressive therapy. Conclusion: The purpose of this review is to discuss the different technologies of cell encapsulation and the different materials utilized from both, natural and synthetic origin, and provide an overview of current therapeutic applications of cell encapsulation, as well as, the perspectives for their clinical application including as a novelty the current application in clinical trials.

Background: The indications for Allergen immunotherapy (AIT) in patients suffering from House Dust Mite (HDM)-related allergic diseases are presently based on incomplete data. This is essentially based on the fact that HDM allergy is difficult to evaluate in clinical trials, due to the largely variable allergen exposure and symptoms, and to the long periods of observation needed to assess the effects. In addition, at variance with pollen allergy, in HDM allergy asthma is more prevalent. However, several AIT products have been approved for HDM-induced allergic rhinitis, according to their ascertained clinical efficacy, tolerability and safety profile, particularly in the sublingual form (SLIT). Objective: We reviewed herein the available data on AIT in patients with HDM-induced allergic diseases, with a particular attention to the new product MK-8237 HDM-SLIT tablets, concerning its efficacy and safety profile. Method: In the recent years, several randomized placebo-controlled clinical trials have been performed in Europe, North America and Japan to evaluate the efficacy of HDM-sublingual tablets in patients with HDM-induced allergic asthma and allergic rhinitis, mainly assessing the reduction of symptoms, exacerbations and corticosteroid intake. Results: The results of the published clinical trials were encouraging and led to the approval and commercialization of MK-8237 HDM-SLIT tablet. Conclusion: The favorable efficacy and safety profile of MK-8237 HDM-SLIT tablets provided a consolidated therapeutic option for patients with HDM-induced allergic rhinitis and asthma.

Background: Aurones are a sub-set of the flavone family that possess a number of biological activities, including anti-cancer, anti-inflammatory, anti-microbial, anti-parasitic and anti-viral. Due to their high availability, simple synthesis, and generally low toxicity, aurones could be attractive candidates for safer cancer drugs. This study aims to evaluate the anti-proliferation and anti-metastasis activity of a series of synthesized aurone derivatives. Methods: A series of aurone derivatives with simple unsubstituted coumaranone (benzofuranone) fragments and a range of alkylidene fragments have been prepared and tested for anti-proliferation activity against human cancer cell lines A549 (lung), BT20 (breast) and MCF7 (breast), and antimetastasis activity against A549. Results: Several of these compounds displayed significant levels of activity and high levels of selectivity for the inhibition of the growth of cancerous cell lines versus the corresponding normal cell lines. This growth inhibition was found to be associated with the induction of apoptosis in cancer cells. Moreover, several aurone derivatives showed remarkable inhibition on the motility of lung cancer cells A549 at a concentration as low as 6.25 μM. Analysis of the structure-activity relationship revealed that the aurone derivatives based upon five-membered heteroaromatic rings exhibited the most significant anti-cancer activity. Conclusion: Aurone derivatives devoid of the unusual oxygenation found in the coumaranone fragment are potential leads for new anti-cancer agents.

Background: PS916, chitosan derivative with shown activities in atherosclerotic and fatty liver, is being investigated as an anti-atherosclerotic agent in clinical trials in China. Methods: Fluorescein-labeled PS916 (PS916-FTC) was prepared by the reaction with fluorescein isothiocyanate. The pharmacokinetics and bio-disposition of PS916-FTC were studied in rats after oral or intravenous administration. Results: Analysis of the plasma, urine, fecal and tissue samples collected at intervals up to 72 h revealed that PS916-FTC exhibited moderate volume of distribution (Vss, 0.650~0.748 L/kg), and low clearance (60.9~107 mL/h/kg) after intravenous administration. The pharmacokinetics of PS916-FTC was characterized by low bioavailability (8.40%) after oral administration. The average accumulation ratio for PS916-FTC exposure after steady-state administration was 1.04. A two-compartmental pharmacokinetics model was employed. The urinary route was the major pathway (54.4%), and the fecal route was a minor pathway (6.29%) for PS916-FTC elimination after intravenous administration; the fecal route was the major pathway (79.0%) for PS916-FTC elimination after oral administration. Conclusion: PS916-FTC was widely distributed to most tissues in rats; relatively high levels of PS916-FTC in kidney and liver were observed after intravenous or oral administration. These findings supported the understanding of pharmacokinetics and bio-disposition of PS916 in rats and provide relevant information for future design of clinical studies. Highlights: 1) Fluorescein-labeled PS916 was successfully synthesized. 2) A rapid and sensitive analytical method of PS916-FTC was validated. 3) The pharmacokinetic of PS916-FTC in rats was investigated. 4) The bio-distribution of PS916-FTC in rats was investigated.

Background: Enterotoxigenic Escherichia coli (ETEC) is the main cause of fatal diarrhea in piglets during the first week of life and over the time of weaning. Pathogenesis of ETEC-causing diarrhea involves intestinal colonization mediated by fimbriae. Although, both IgY and egg yolk phosvitin (PV) possess antimicrobial activity, their combined activity has not been explored. A combination of IgY specific for ETEC and metal-chelating PV may show synergistic effect in reducing the growth of ETEC by inhibiting bacterial proliferation and stipulating protection against ETEC infection. Objective: The goal of this study was to determine the effects of anti-ETEC IgY and PV on in vitro growth inhibition of ETEC strains possessing K88 and K99 fimbriae prevalent in the porcine population. Methods: Anti-K88 and -K99 IgY antibodies were obtained from egg yolks of 23-week-old Single- Comb White Leghorn hens immunized with K88 and K99 fimbriae of ETEC, respectively, with high titres sustained over 6 to 8 weeks of the immunization period. Specific IgY, PV, and PV-hydrolysate from alcalase-hydrolysis under high hydrostatic pressure (PVH-Alc-HHP) alone or in combination, were used to treat ETEC K88 and K99 cultures at optimal concentrations of 100 μg/mL, 1 mg/mL, and 1 mg/mL, respectively, for 24 h. Results: PVH-Alc-HHP demonstrated the highest degree of hydrolysis, 38.9%. Combined use of IgY and PVH-Alc-HHP showed the highest bactericidal effect resulting in ETEC K88 and K99 growth inhibition of 2.8 and 2.67 log CFU/mL, respectively. Conclusion: Combined IgY-PVH effectively control ETEC, therefore holds a great potential for microbial control in veterinary pharmaceutical industry.

Background: Microemulsions are attractive delivery systems for therapeutic proteins and peptides due to their ability to enhance bioavailability. Although different proteins and peptides have been successfully delivered through such ternary systems, no information can be found about protein loading and the formulation stability when such microemulsions are prepared with pharmaceuticallyapproved oils and surfactants. The aim of this work was to optimise a ternary system consisting of water/ ethyl oleate/Span® 80-Tween® 80 and to determine its protein loading capacity and stability, using bovine serum albumin (BSA) as a model of biomolecule. Methods: The optimization was carried out using a Central Composite Design and all the prepared formulations were characterised through dynamic light scattering, rheology, optical and polarized microscopy. Subsequently, the maximum loading capacity was determined and the stability of the final microemulsion with the highest content of protein was followed over six months. To investigate the structural features of the protein, BSA was recovered from the microemulsion and analysed through fluorescence spectroscopy. Results: After incorporation of the protein in the microemulsion, a decrease of its aqueous solubility was observed. However, the formulation remained stable over six months and the native-like state of the recovered protein was demonstrated by fluorescence spectroscopy Conclusion: This study demonstrated the feasibility of preparing microemulsions with the highest content of protein and their long-term stability.

Background: Angiogenesis is critical for the growth of tumor by supplying nutrients and oxygen that exacerbates the metastasis and progression of cancer. Noninvasive imaging of angiogenesis during the tumor therapeutic processes may provide novel opportunities for image-guided tumor management. Objective: Here, we want to develop a mouse animal model for assessing cancer progression and angiogenesis in the same individuals by molecular imaging. Methods: Breast cancer model was developed with mouse breast cancer cell line 4T1 carrying a reporter system encoding a triple fusion (TF) reporter gene consisting of renilla luciferase (Rluc), red fluorescent protein (RFP) and herpes simplex virus truncated thymidine kinase (HSV-ttk) in transgenic mice, which expressed firefly luciferase (Fluc) under the promoter of vascular endothelial growth factor receptor 2 (Vegfr2-luc). The mice were subsequently treated with ganciclovir (GCV) and the tumor angiogenesis was tracked by Fluc imaging and the growth status of tumor was monitored by imaging of Rluc simultaneously. Conclusion: Overall, this traceable breast cancer model can simultaneously image the tumor growth and angiogenesis in single individual, which may facilitate a better understanding the mechanisms of angiogenesis in the progression and regression of tumor.

Background: The renewable feedstock derived biodegradable plastics are important in various industries such as packaging, agricultural, paper coating, garbage bags and biomedical implants. The increasing water and waste pollution due to the available decomposition methods of plastic degradation have led to the emergence of biodegradable plastics and biological degradation with microbial (bacteria and fungi) extracellular enzymes. The microbes utilize biodegradable polymers as the substrate under starvation and in unavailability of microbial nutrients. Microbial enzymatic degradation is suitable from bioremediation point of view as no waste accumulation occurs. Methods: It is important to understand the microbial interaction and mechanism involved in the enzymatic degradation of biodegradable plastics under the influence of several environmental factors such as applied pH, thermo-stability, substrate molecular weight and/or complexity. To study the surface erosion of polymer film is another approach for hydrolytic degradation characteristion. Results: The degradation of biopolymer is associated with the production of low molecular weight monomer and generation of carbon dioxide, methane and water molecule. This review reported the degradation study of various existing biodegradable plastics along with the potent degrading microbes (bacteria and fungi). Patents available on plastic biodegradation with biotechnological significance is also summarized in this paper. Conclusion: This paper assesses that new disposal technique should be adopted for the degradation of polymers and further research is required for the economical production of biodegradable plastics along with their enzymatic degradation.