Treating Polymicrobial Infections in Chronic Diabetic Wounds.

This review provides a comprehensive summary of issues associated with treating polyclonal bacterial biofilms in chronic diabetic wounds. We use this as a foundation and discuss the alternatives to conventional antibiotics and the emerging need for suitable drug delivery systems. In recent years, extraordinary advances have been made in the field of nanoparticle synthesis and packaging. However, these systems have not been incorporated into the clinic for treatments other than for cancer or severe genetic diseases. We present a unifying perspective on how the field is evolving and the need for an early amalgamation of engineering principles and a biological understanding of underlying phenomena in order to develop a therapy that is translatable to the clinic in a shorter time.

The Landscape of Early Clinical Gene Therapies outside of Oncology.

The field of cell and gene therapy (GT) is expanding rapidly and there is undoubtedly a wave of enthusiasm and anticipation for what these treatments could achieve next. Here we assessed the worldwide landscape of GT assets currently in early clinical development (clinical trial phase 1/2 or about to enter clinical trial). We included all gene therapies, i.e., strategies that modify an individual's protein make-up by introducing exogenous nucleic acid or nucleic acid modifiers, regardless of delivery. Unmodified cell therapies, oncology therapies (reviewed elsewhere), and vaccine programs (distinct therapeutic strategy) were not included. Using a December 31, 2018 cutoff date, we identified 336 gene therapies being developed for 138 different indications covering 165 genetic targets. In all, we found that the early clinical GT landscape comprises a very disparate group of drug candidates in terms of indications, organizations, and delivery methods. We also highlight interesting trends, revealing the evolution of the field toward in vivo therapies and adeno-associated virus vector-based delivery systems. It will be interesting to witness what proportion of this current list effectively translates into new medicines.

Development of Human Target Validation Classification that Predicts Future Clinical Efficacy.

Fewer new medicines have become available to patients during the last decades. Clinical efficacy failures in late-phase development have been identified as a common cause of this decline. Improved ways to ensure early selection of the right drug targets when it comes to efficacy is therefore a highly desirable goal. The aim of this work was to develop a strategy to facilitate selection of novel targets already in the discovery phase that later on in clinical development would demonstrate efficacy. A cross-functional team at AstraZeneca with extensive experience in drug discovery and development participated in several workshops to identify the critical elements that contribute to building human target validation [(HTV); the relevance of the target from a human perspective]. The elements were consolidated into a 10-point HTV classification system that was ranked from lowest to highest in terms of perceived impact on future clinical efficacy. Using 50 years of legacy research and development data, the ability of the 10-point HTV classification to predict future clinical efficacy was evaluated. Drug targets were classified as having low, medium, or high HTV at the time of candidate drug selection. Comparing this HTV classification with later clinical development efficacy data showed that HTV classification was highly predictive of future clinical efficacy success. This new strategy for HTV assessment provides a novel approach to early prediction of clinical efficacy and a better understanding of portfolio risk.

Physical Medicine Devices; Reclassification of Iontophoresis Device Intended for Any Other Purposes. Final order.

The Food and Drug Administration (FDA) is issuing a final order to reclassify iontophoresis devices intended for any other purposes, which are preamendments class III devices (regulated under product code EGJ), into class II (special controls) and to amend the device identification to clarify that devices intended to deliver specific drugs are not considered part of this regulatory classification.

Advanced drug delivery nanosystems: perspectives and regulatory issues.

This chapter deals with the classification of Drug Delivery nano Systems (DDnSs) with a Modulatory Controlled Release profile (MCR) denoted as Modulatory Controlled Release nano Systems (MCRnSs). Conventional (c) and advanced (a) DDnSs are denoted by the acronyms cDDnSs and aDDnSs, and can be composed of a single or more than one biomaterials, respectively. The classification was based on their characteristics such as surface functionality (f), the nature of biomaterials used, and the kind of interactions between biomaterials. The aDDnSs can be classified as Hybridic (Hy-) or Chimeric (Chi-) based on the nature-same or different, respectively-of biomaterials and inorganic materials used. The nature of the elements used for producing advanced biomaterials is of great importance and medicinal chemistry contributes effectively to the production of aDDnSs.

Smart stimuli-responsive drug delivery systems based on cyclodextrin: A review.

Stimulated by researches in materials chemistry and medicine fields, drug delivery has entered a new stage of development. Drug delivery systems have been extensively studied according to the differences in the drug therapeutic environment such as pH, light, temperature, magnet, redox, enzymes, etc. Cyclodextrin is a smart tool that has been proven to be used in the preparation of drug delivery, and has become a new area of concern in recent years. In this review, we discuss recent research advances in smart stimuli-responsive cyclodextrin-based drug delivery. First, different stimuli-responsive drug delivery systems based on cyclodextrin are introduced and classified. Then, the characteristics of different types of stimuli-responsive drug delivery systems are described, and their applications are emphasized. Finally, current challenges and future development opportunities of smart stimuli-responsive drug delivery systems based on cyclodextrin are discussed.

Pharmacokinetic-pharmacodynamic crossover comparison of two levodopa extension strategies.

Controlled-release carbidopa and levodopa (CL-CR) and the combination of carbidopa, levodopa, and entacapone (CLE) are used for extending levodopa (L-dopa) effects. In a randomized, open-label crossover study of 17 PD subjects with wearing-off responses, we compared 8-hour L-dopa pharmacokinetics (PK) and clinical effects after two doses of CL-CR (50 and 200 mg, respectively) and CLE (37.7, 150, 200 mg, respectively). PK analysis revealed the anticipated near-equivalent mean L-dopa area-under-the-concentration-curve values (639,490 ng min/mL for two doses of CLE, and 662,577 for CL-CR, P = 0.86). The mean hourly fluctuation index for L-dopa concentration was 235% for CLE and 196% for CL-CR (P = 0.004). The mean maximal concentration for the first CLE dose was 1,926 +/- 760 ng/mL and for CL-CR, 1,840 +/- 889 (P = 0.33). During the PK studies, the mean time that L-dopa concentration was > or =1,000 ng/mL for CLE was 291 +/- 88 minutes and for CL-CR, 306 +/- 86 (P = 0.33). The mean percent-time in "off" state was 18% for CLE and 28% for CL-CR (P = 0.017), "on state without dyskinesia" was 64% for CLE and 65% for CL-CR (P = 0.803), and "on state with nontroublesome dyskinesia" was 18% for CLE and 7% for CL-CR (P = 0.03). Despite less "off" time with CLE, both formulations demonstrated similar mean PK values and marked intersubject PK variability.

Pharmacological onomastics: what's in a name?

Drugs are named for their primary receptor target and overt action (agonism, antagonism) but the observation of multiple or collateral efficacies emanating from drugs activating a single receptor target is posing a challenge for drug classification and nomenclature. With increasing abilities to detect alteration in cellular function has come the identification of efficacies that are not necessarily manifest in obvious changes in cell response. Specifically, some agonists selectively activate cellular pathways, demonstrate phenotypic behaviour associated with cell type and some antagonists actively induce receptor internalization without activation. In addition, the effects of allosteric modulators can be linked to the nature of the co-binding ligand posing a similar complication in classification and naming. Thus, accurate labels for this new generation of selective drugs may require identification of receptor partners (G-protein type, beta-arrestin) or pathway or, in the case of allosteric modulators, identification of co-binding ligands. The association of distinct phenotypic behaviours with molecules opens the opportunity to better associate clinical effects with distinct pharmacological properties.

Encapsulation of 9-nitrocamptothecin, a novel anticancer drug, in biodegradable nanoparticles: factorial design, characterization and release kinetics.

This study was aimed at developing a polymeric drug delivery system for a new and potent antitumor drug, 9-nitrocamptothecin (9-NC), intended for both intravenous administration and improving the therapeutic index of the drug. To achieve these goals, 9-NC loaded poly(DL-lactide-co-glycolide) (PLGA) nanoparticles were prepared by nanoprecipitation method and characterized. The full factorial experimental design was used to study the influence of four different independent variables on response of nanoparticle drug loading. Analysis of variance (ANOVA) was used to evaluate optimized conditions for the preparation of nanoparticles. The physical characteristics of PLGA nanospheres were evaluated using particle size analyzer, scanning electron microscopy, differential scanning calorimetry and X-ray diffractometry. The results of optimized formulations showed a narrow size distribution with a polydispersity index of 0.01%, an average diameter of 207+/-26 nm, and a drug loading of more than 30%. The in vitro drug release profile showed a sustained 9-NC release up to 160 h indicating the suitability of PLGA nanoparticles in controlled 9-NC release. Thus prepared nanoparticles described here may be of clinical importance in both stabilizing and delivering camptothecins for cancer treatment.

Classification of plastic eye dropper tips using Harkins and Brown's factor.

In this work, the weights of drops produced by seven commercially available eye drop dispensing systems were investigated using benzalkonium chloride solutions in concentration range of 0-0.02%. The effect of the surface tension, the effective diameter of the dropper tip, and the dropper bottle volume on the drop weights was studied at the vertical position. Based on the principle of Tate's law, the theoretical maximal weights of drops were expressed. In all cases, the lower the surface tension, the lower drop weights were noted. Simultaneously, effect of both the effective diameter of the dropper tip and the dropper bottle volume on the drop weights could be described. A regression equation characterized a significantly negative linear interaction of both variables. Comparing the theoretical drop weights with those measured experimentally, Harkins and Brown's factors, FHB, were received. The mean drop weights obtained for the Traube's stalagmometer were 62% that of the theoretical values. FHB values detected for the plastic dropper tips were significantly greater ranging from 0.66 to 0.76. In contrast to the obvious characterization of dropper tips by geometrical parameters, a classification of dropper tips with Harkins and Brown's factor is proposed.

A combined approach to data mining of textual and structured data to identify cancer-related targets.

BACKGROUND: We present an effective, rapid, systematic data mining approach for identifying genes or proteins related to a particular interest. A selected combination of programs exploring PubMed abstracts, universal gene/protein databases (UniProt, InterPro, NCBI Entrez), and state-of-the-art pathway knowledge bases (LSGraph and Ingenuity Pathway Analysis) was assembled to distinguish enzymes with hydrolytic activities that are expressed in the extracellular space of cancer cells. Proteins were identified with respect to six types of cancer occurring in the prostate, breast, lung, colon, ovary, and pancreas. RESULTS: The data mining method identified previously undetected targets. Our combined strategy applied to each cancer type identified a minimum of 375 proteins expressed within the extracellular space and/or attached to the plasma membrane. The method led to the recognition of human cancer-related hydrolases (on average, approximately 35 per cancer type), among which were prostatic acid phosphatase, prostate-specific antigen, and sulfatase 1. CONCLUSION: The combined data mining of several databases overcame many of the limitations of querying a single database and enabled the facile identification of gene products. In the case of cancer-related targets, it produced a list of putative extracellular, hydrolytic enzymes that merit additional study as candidates for cancer radioimaging and radiotherapy. The proposed data mining strategy is of a general nature and can be applied to other biological databases for understanding biological functions and diseases.

A new classification system of anticancer drugs - based on cell biological mechanisms.

The arrival of a great number of new anticancer agents has made it necessary to reclassify all of them. We established a new classification system based on cell biological mechanisms. Anticancer drugs were grouped as cytotoxic drug and modifier, which could regulate the interaction of tumor, host and drugs. The modifiers were subdivided into three groups: cell biological modifier which reverses the abnormal biological behaviour of tumor cells, biological response modifier which regulates the host response of tumor and biochemical modulator which affects the host's metabolic pathway of cytotoxic drug to enhance the chemosensitivity or reduce the adverse reaction. Combination with cell biological modifiers and cytotoxic drugs play a double role of killer and rectifier for tumor cells, whereas biological response modifiers and cytotoxic drugs are combined to regulate the tumor-host interaction. Biochemical modulators and cytotoxic drugs are combined to enhance the chemosensitivity or improve the dose of cytotoxic drugs.

Recent Aspects of Osmotic Pump Systems: Functionalization, Clinical use and Advanced Imaging Technology.

BACKGROUND: Osmotic pump drug delivery systems are one of the most promising and widely developed systems. They are based on the principle of osmosis and are characterized by a zero-order release pattern independent of the physicochemical properties of the drug involved and some physiological factors. In the past 30 years, a series of difficulties, such as the very wide solubility range of different drugs, have been resolved accompanied by the development of various types of osmotic pumps. Furthermore, more advanced designs have been proposed according to practical requirements. METHODS: We started a systematic references collection on osmotic pump systems through different available databases. Then these information were analyzed and divided according to different subjects. Finally, we made clear our thought and begun to write it in a logical way. RESULTS: This review mainly concentrates on five kinds of functional osmotic pumps including technology combined, targeted, chronotherapy- based, ascending and compound osmotic pumps, involving ways to improve bioavailability and reduce side effects. Special attention is paid to the application of advanced imaging technologies to study osmotic pumps including the coating process, processing steps, polymer hydration and changes in the internal structure. CONCLUSIONS: Present-day osmotic pumps not only produce a constant release, but also have the ability to produce adjustable release according to practical requirements. Hence, technology combined, targeted, chronotherapy-based, ascending and compound osmotic pumps are a positive development. These latest advances offer various advantages compared with the classic osmotic pump, and enable them to meet the new needs for clinical use with fewer side effects and improved safety. In addition, following the improvements in the versatility and complexity of the novel osmotic pump system, conventional assessing parameters may fail to meet the increasing demand for information. Hence, novel imaging and monitoring technologies have been employed to monitor osmotic pumps from the coating process, processing steps, and polymer hydration to the changes in polymeric internal structure, which are associated with the different performance offered by the in vivo action of similar products.

Submicron Emulsions and Their Applications in Oral Delivery.

A "submicron emulsion" is an isotropic mixture of drug, lipids, and surfactants, usually with hydrophilic cosolvents and with droplet diameters ranging from 10 to 500 nm. Submicron emulsions are of increasing interest in medicine due to their kinetic stability, high solubilizing capacity, and tiny globule size. Because of these properties, they have been applied in various fields, such as personal care, cosmetics, health care, pharmaceuticals, and agrochemicals. Submicron emulsions are by far the most advanced nanoparticulate systems for the systemic delivery of biologically active agents for controlled drug delivery and targeting. They are designed mainly for pharmaceutical formulations suitable for various routes of administration like parenteral, ocular, transdermal, and oral. This review article describes the marked potential of submicron emulsions for oral drug delivery owing to their numerous advantages like reduced first pass metabolism, inhibition of P-glycoprotein efflux system, and enhanced absorption via intestinal lymphatic pathway. To overcome the limitations of liquid dosage forms, submicron emulsions can be formulated into solid dosage forms such as solid self-emulsifying systems. This article covers various types of submicron emulsions like microemulsion, nanoemulsion, and self-emulsifying drug delivery system (SEDDS), and their potential pharmaceutical applications in oral delivery with emphasis on their advantages, limitations, and advancements.

Delivery options for contraceptives.

Although a steady increase in contraceptive use has been observed in developed and less-developed countries, the contraceptive needs of a significant proportion of couples have not yet been met, resulting in an increase in unplanned pregnancies. Several new contraceptive products have reached the market during the past few years. Among these are new implants, a medicated intrauterine device, contraceptive vaginal rings, transdermal patches and several new regimen of combined oral contraceptives. These new or improved methods have been developed to expand the contraceptive choices available to women and men as well as to respond to the unmet need for contraceptives with long-term activity. New targets are being identified both in the ovary and the testes for a more specific non-hormonal contraception. This futuristic approach still keeps in mind the need for better access to existing contraceptive methods, as well as the discovery of new contraceptives that are simple to use, safe, reversible and inexpensive. In recent years, there has been great interest in agents that provide dual protection against pregnancy and sexually transmitted infections (STI), especially human immunodeficiency virus (HIV). A contraceptive method providing dual medical benefits might increase motivation for consistent use, thus reducing contraceptive failures and unwanted pregnancies.

Trends in exploration of therapeutic targets.

Lead discovery against a preselected therapeutic target is a key component in modern drug development. Continuous effort and increasing interest has been directed at the search for new targets, which has led to the identification of a growing number of them. Data from the therapeutic target database, at http://bidd.nus.edu.sg/group/cjttd/ttd.asp, show that, as of July 2004, the number of documented targets of marketed and investigational drugs has reached 1,174 distinct proteins (including subtypes) and 27 nucleic acids, 239 of which are targets of the marketed drugs. Analysis of these targets, particularly those of recently approved drugs and patented investigational agents, provide useful hints about general trends of target exploration and current focus in drug discovery for the treatment of high impact diseases needing effective or more treatment options.

Colloidal drug delivery systems: current status and future directions.

In this paper, we provide an overview an extensive range of colloidal drug delivery systems with special focus on vesicular and particulates systems that are being used in research or might be potentially useful as carriers systems for drug or active biomolecules or as cell carriers with application in the therapeutic field. We present some important examples of commercially available drug delivery systems with applications in research or in clinical fields. This class of systems is widely used due to excellent drug targeting, sustained and controlled release behavior, higher entrapment efficiency of drug molecules, prevention of drug hydrolysis or enzymatic degradation, and improvement of therapeutic efficacy. These characteristics help in the selection of suitable carrier systems for drug, cell, and gene delivery in different fields.

Ligand-Appended BBB-Targeted Nanocarriers (LABTNs).

Delivering therapeutics across the blood brain barrier (BBB) remains the rate-limiting step in brain medicine research. Three main categories of endogenous transportation at BBB that can be used for targeting brain are carrier-mediated transport, active efflux transport, and receptor-mediated transport. Various approaches using nanocarriers such as liposomes, niosomes, micelles, and nanoparticles with manifested surface modifications using either covalent or noncovalent methods to append suitable ligands are being intensively explored to achieve drug delivery to the brain. Harvested ligands include peptide, glutathione, transferrin, and transferrin antibody, lectins, lactic acid, cholera toxin B, etc. In this review, we present recent insights into the development of safe and efficient brain drug delivery as well as recent advances in BBB targeting tactics including antibody-directed enzyme prodrug therapy, a biotin-avidin conjugated system, and chimeric peptides. This review serves as an excellent source of knowledge for budding brain researchers.

Controlled release of paclitaxel from microemulsion containing PLGA and evaluation of anti-tumor activity in vitro and in vivo.

The main objective of this study was to develop an optimal paclitaxel microemulsion prepared by self-microemulsifying drug delivery system (SMEDDS) which is a mixture of paclitaxel, tetraglycol, Cremophor ELP, and Labrafil 1944 and a paclitaxel microemulsion containing poly(D,L-lactide-co-glycolide) (PLGA) in order to offer controlled release of paclitaxel. To achieve this goal, paclitaxel and PLGA were dissolved by solubilizer like tetraglycol. There was not observed any change in molecular weight of PLGA after being solubilized by tetraglycol. The droplet size for all of the formulation of microemulsion was found in the range of 45-270nm by dynamic light scattering (DLS). It was observed that the droplet size of microemulsion without PLGA was smaller than that of microemulsion containing PLGA by transmission electron microscopy (TEM). The droplet of microemulsion containing PLGA was almost of spherical shape with smooth surface and there was no aggregation or adhesion among droplet of microemulsion by atomic force microscopy (AFM). The release behaviour of paclitaxel from microemulsion containing PLGA having various molecular weights (8K, 33K, and 90K) exhibited a biphasic pattern characterized by a fast initial release during the first 48h, followed by a slower and continuous release for 144h, in contrast that the release of paclitaxel from microemulsion without PLGA was finished during 24h. This result was identical with the result of anti-tumor activity in vitro of paclitaxel from microemulsion containing PLGA against human breast cancer cell line MCF7 and this formulation enhanced anti-tumor activity in vivo compared with microemulsion without PLGA against SKOV-3 human ovarian cancer cells bearing nude mice model.

Clinical evaluation of new designs for intraoral fluoride-releasing systems.

PURPOSE: Intraoral fluoride-releasing (IFR) devices provide elevated levels of fluoride in the mouth for extended periods of time. However, retention and protection of the devices have posed major challenges for clinical applications. The objectives of this study were to develop new methods for retaining and protecting IFR devices in the mouth and to assess their effects on salivary fluoride levels and distribution in adolescents. METHODS: Four different IFR systems (combinations of an IFR device and its retainer) were evaluated in four groups of 10 adolescents each, 12-15 years of age, for a period of six months. Each child wore two IFR systems of a given type affixed to the buccal surface of each permanent maxillary first molar. Unstimulated saliva samples were collected at each clinical examination and analyzed for fluoride. RESULTS: A significant increase in salivary fluoride concentration from a baseline mean of 0.07-0.69 microgram/mL was observed on day 14 postinsertion. IFR system retention was 85% after 6 months and, of the systems retained, 100% were functional. CONCLUSIONS: These findings suggest that IFR devices can be successfully protected and retained in the mouth for prolonged periods of time.