Implantable cardioverter defibrillator pocket infection caused by Klebsiella pneumonia

Like any other foreign bodies, implanted cardiac devices can become infected. Staphylococcus aureus and coagulase-negative Staphilococci are the most common causes of infections of pacemaker and defibrillator systems. In this case an implantable cardioverter defibrillator pocket infection caused by an extremely rare microorganism, Klebsiella pneumonia, is presented.     

Sustained release of antibiotic from poly(2-hydroxyethyl methacrylate) to prevent blinding infections after cataract surgery

Intraocular lens implantation after opacified natural lens removal is the primary treatment for cataracts in developed countries. Cataract surgery is generally considered safe, but entails significant risks in countries where sophisticated sterile operating theaters are not widely available. Post-operative infection (endophthalmitis) is a potential blinding complication. Infection often results from bacterial colonization of the new lens implant and subsequent antibiotic-tolerant biofilm formation. To combat this risk, we developed a polymeric hydrogel system that can deliver effective levels of antibiotic over an extended period of time within the globe of the eye. Norfloxacin™ antibiotic was loaded into cross-linked poly(2-hydroxyethyl methacrylate) (pHEMA) gels, which were subsequently surface-modified with octadecyl isocyanate to produce a hydrophobic rate-limiting barrier controlling norfloxacin release. Octadecyl surface modification was characterized using scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). A 15-min modification leads to a uniform surface coating and near zero order release of norfloxacin from the matrix. Norfloxacin released from coated pHEMA kills Staphylococcus epidermidis in suspension and on a simulated medical implant surface. With these data, we demonstrate a new and effective system for sustained drug release from a hydrogel matrix with specific application for intraocular lens surgery.     

抗生素-多孔玻璃陶瓷（A-PGC）药物释放系统（DDS）的研制

目的 研制抗生素多孔玻璃陶瓷(A-PGC)药物释放系统(DDS)为骨髓炎治疗提供一种新方法。方法将两种多孔玻璃陶瓷(PGC)浸于抗生素(含庆大霉素和头孢唑林钠)溶液，真空吸附，制得A-PGC。同法制得抗生素多孔羟基磷灰石陶瓷(A-PHA)作对照。测定其体外、体内释放抗生素的药物浓度及持续时间。结果A-PGC体外释放有效浓度的庆大霉素达42天以上，而APHA为28天。三种陶瓷洗脱液中头孢唑林浓度均低于庆人霉素浓度。A-PGC在兔股骨中维持有效浓度庆大霉素达8周以上且有良好的骨传导作用。结论 A-PGC可望成为治疗骨髓炎的一种新方法。     

抗生素—多孔玻璃陶瓷(A-PGC)药物释放系统(DDS)的研制

目的研制抗生素多孔玻璃陶瓷(A-PGC)药物释放系统(DDS)为骨髓炎治疗提供一种新方法.方法将两种多孔玻璃陶瓷(PGC)浸于抗生素(含庆大霉素和头孢唑林钠)溶液,真空吸附,制得A-PGC.同法制得抗生素多孔羟基磷灰石陶瓷(A-PHA)作对照.测定其体外、体内释放抗生素的药物浓度及持续时间.结果A-PGC体外释放有效浓度的庆大霉素达42天以上,而A-PHA为28天.三种陶瓷洗脱液中头孢唑林浓度均低于庆大霉素浓度.A-PGC在兔股骨中维持有效浓度庆大霉素达8周以上且有良好的骨传导作用.结论A-PGC可望成为治疗骨髓炎的一种新方法.     

Design of an implantable active microport system for patient specific drug release

We present a novel concept of an implantable active microport based on micro technology that incorporates a high-resolution volumetric dosing unit and a drug reservoir into the space of a conventional subcutaneous port. The controlled release of small drug volumes from such an "active microport" is crucial e.g. for innovative methods in cancer treatment or pain therapy. Our microport system delivers a flow rate in the range of 10-1,000 mul/h and enables a patient-specific release profile. The core of our device is a two-stage piezoelectric micropump. It features a backpressure-independent volumetric dosing capability i.e. a stable flow rate is ensured up to a backpressure of 30 kPa. The stroke volume and hence the resolution of the mircopump is voltage controlled and can be preset between 10 and 200 nl. A miniaturized high-performance electronic control unit enables freely programmable dosing profiles. This electronic circuit is optimized for both energy consumption and weight which are both essential for a portable device. The data of an implemented pressure sensor are used to permanently monitor the dosing process and to detect a potential catheter occlusion. A polyurethane soft lithography process is introduced for the fabrication of the prototype. Therewith, a compact multilayer system has been developed which measures only 50 x 35 x 25 mm(3).     

Generation of nanovesicles with sliced cellular membrane fragments for exogenous material delivery

We propose a microfluidic system that generates nanovesicles (NVs) by slicing living cell membrane with microfabricated 500 nm-thick silicon nitride (Si_xN_y) blades. Living cells were sliced by the blades while flowing through microchannels lined with the blades. Plasma membrane fragments sliced from the cells self-assembled into spherical NVs of ∼100–300 nm in diameter. During self-assembly, the plasma membrane fragments enveloped exogenous materials (here, polystyrene latex beads) from the buffer solution. About 30% of beads were encapsulated in NVs, and the generated NVs delivered the encapsulated beads across the plasma membrane of recipient cells, but bare beads could not penetrate the plasma membrane of recipient cells. This result implicates that the NVs generated using the method in this study can encapsulate and deliver exogenous materials to recipient cells, whereas exosomes secreted by cells can deliver only endogenous cellular materials.     

Polymers to treat brain tumours

Brain tumours are difficult to treat by conventional methods. A biodegradable polymer, poly-[bis(p-carboxyphenoxy) propane sebacic acid] with a nitrosourea, carmustine, has been demonstrated to be biocompatible in the brains of experimental animals and to release drugs in a predictable sustained manner. Carmustine impregnated in polymers appears to be more effective than when delivered by standard methods. A Phase I clinical study has demonstrated the safety of this approach in treating brain tumours and a Phase III placebo-controlled study is currently underway. Other applications of the polymer in the treatment of brain diseases are discussed.     

Implantable measurement technique dedicated to the monitoring of electrode-nerve contact in bladder stimulators

A fully integrated electrode-nerve contact monitoring circuit intended to increase safety and reliability in implantable bladder stimulators is described. The proposed integrated circuit converts a measurement of the impedance of two electrode-nerve contacts into frequency. The measurement is derived from a test current generated by the stimulation current source. The obtained result is the frequency of a square wave signal. This frequency is then converted into 8-bit data, which are serially transmitted to an external controller through an inductive link. The whole circuit can be set in idle mode during stimulation, ensuring low energy consumption. It is fully testable, and an internal calibration technique makes it possible to reduce errors due to temperature and process variations. The total area of the proposed monitoring circuit is 0.1 mm² when fabricated with a 0.35μm technology, including a digitally controlled, current source. The design has been fabricated and successfully tested.     

Mesoporous silica/apatite nanocomposite: special synthesis route to control local drug delivery

Synthetic hydroxyapatite is widely used in medicine and dentistry due its notable biocompatibility and bioactivity properties. The hydroxyapatite incorporation into silica has demonstrated excellent bioactivity or biodegradability, according to the content of calcium ions. Procedures to obtain ordered mesoporous silicates rely on the micelle-forming properties of a surfactant, whose chemical composition, size and concentration control the structural dimensions of the final material. This paper reports the synthesis of two types mesoporous materials: pure MCM-41 and a nanocomposite of apatite and mesoporous silica, MCM-41-HA. The samples were charged with atenolol as a model drug and in vitro release essays were carried out. The bioactivity behavior was investigated as a function of soaking time in simulated body fluid. The materials were characterized by X-ray diffraction, N₂ adsorption, FTIR spectroscopy, scanning electron microscopy, dispersive energies spectroscopy, and transmission electron microscopy. The influence of the release rate of atenolol molecules from pure MCM-41 mesoporous and containing hydroxyapatite was demonstrated, since it results in a very slowly drug delivery from the nanocomposite system.     

利塞膦酸对硅酸钙骨水泥材料性能影响及体外释放机理的研究

目的探讨利塞膦酸对硅酸钙骨水泥材料性能的影响及其体外缓释的机理。方法将不同浓度的利塞膦酸(0.1%、0.5%和1.0%)与硅酸钙骨水泥粉末混合后进行水化反应,观察骨水泥固化时间及3天和7天后的抗压强度,并利用X射线衍射仪和Rietveld数字模拟精修方法定性与定量分析水化后骨水泥的相组成。同时,将固化后载药骨水泥样本放入磷酸盐缓冲液中,利用高效液相色谱仪检测利塞膦酸28天内的释放曲线。结果固化速度及3天和7天后力学强度均受到利塞膦酸的影响,且随着利塞膦酸含量的增加,固化速度减慢,力学性能下降。X射线衍射的定性分析与Rietveld定量分析表明,利塞膦酸强有力附着在硅酸钙水化后产物硅酸钙水凝胶表面,阻碍水化反应进一步发生,从而延长固化时间并减少骨水泥的力学强度。体外药物释放曲线表明,利塞膦酸在浸泡后2周内达到释放峰值,在其后的14天中,并无明显释放,证明硅酸钙骨水泥作为利塞膦酸载药系统具有缓释及控释的效果。吸附与脱附实验及Higuchi方程分析表明,利塞膦酸在水化时形成不溶性钙盐,因此药物释放速度受到制约。结论硅酸钙骨水泥作为利塞膦酸缓释系统具有缓释和控释的效果,有利于合并骨质疏松症患者的骨折修复与重铸。     

Multi-layered nanoparticles for combination gene and drug delivery to tumors

Drug resistance and toxicity are major obstacles in cancer chemotherapy. Combination therapies can overcome resistance, and synergies can minimize dosing. Polymer nanocarriers are interesting vehicles for cancer therapeutics for their delivery and tumor targeting abilities. We synthesized a multi-layered polymer nanoparticle (MLNP), comprising of poly(lactic-co-glycolic acid) with surface polyethyleneimine and functional peptides, for targeted drug and gene delivery. We confirmed the particle's ability to inhibit tumor growth through synergistic action of the drug and gene product. MLNPs achieved transfection levels similar to lipofectamine, while maintaining minimal cytotoxicity. The particles delivered camptothecin (CPT), and plasmid encoding TNF related apoptosis inducing ligand (pTRAIL) (CT MLNPs), and synergistically inhibited growth of multiple cancer cells in vitro. The synergy of co-delivering CPT and pTRAIL via CT MLNPs was confirmed using the Chou-Talalay method: the combination index (CI) values at 50% inhibition ranged between 0.31 and 0.53 for all cell lines. Further, co-delivery with MLNPs resulted in a 3.1–15 fold reduction in CPT and 4.7–8.0 fold reduction in pTRAIL dosing. CT MLNPs obtained significant HCT116 growth inhibition in vivo compared to monotherapy. These results support our hypothesis that MLNPs can deliver both small molecules and genetic agents towards synergistically inhibiting tumor growth.     

Plasmonic nanobubble-enhanced endosomal escape processes for selective and guided intracellular delivery of chemotherapy to drug-resistant cancer cells

Cancer chemotherapies suffer from multi drug resistance, high non-specific toxicity and heterogeneity of tumors. We report a method of plasmonic nanobubble-enhanced endosomal escape (PNBEE) for the selective, fast and guided intracellular delivery of drugs through a self-assembly by cancer cells of separately targeted gold nanoparticles and encapsulated drug (Doxil). The co-localized with Doxil plasmonic nanobubbles optically generated in cancer cells released the drug into the cytoplasm thus increasing the therapeutic efficacy against these drug-resistant cells by 31-fold, reducing drug dose by 20-fold, the treatment time by 3-fold and the non-specific toxicity by 10-fold compared to standard treatment. Thus the PNBEE mechanism provided selective, safe and efficient intracellular drug delivery in heterogeneous environment opening new opportunities for drug therapies.     

Systematic in vitro and in vivo study on porous silicon to improve the oral bioavailability of celecoxib

Mesoporous materials are promising candidates for improving dissolution rate of poorly water-soluble drugs in vitro and their bioavailability in vivo. In the present study, sixteen batches of celecoxib-loaded PSi particles with pore sizes ranging from 17 to 58 nm and celecoxib content from 5 to 36 w-% were prepared and a detailed physicochemical characterization of the drug was performed by several methods. Interaction between co-culture of Caco-2/HT29-MTX cells and unloaded PSi particles was tested in toxicity assays, and increased toxicity for particles with large pore size was observed. Dissolution rate of celecoxib was improved in vitro by lowering the drug loading degree which hindered the recrystallization of celecoxib on the external surface of the particles. The fastest permeation of loaded celecoxib through the co-culture monolayer as well as the highest bioavailability in rats was observed with the particles with small pore size and low loading degree. New insights were obtained on how various parameters of the mesoporous delivery system affect the state of the drug inside the pores and its release in vitro and in vivo.     

An in situ forming biodegradable hydrogel-based embolic agent for interventional therapies

We present here the characteristics of an in situ forming hydrogel prepared from carboxymethyl chitosan and oxidized carboxymethyl cellulose for interventional therapies. Gelation, owing to the formation of Schiff bases, occurred both with and without the presence of a radiographic contrast agent. The hydrogel exhibited a highly porous internal structure (pore diameter 17 ± 4 μm), no cytotoxicity to human umbilical vein endothelial cells, hemocompatibility with human blood, and degradability in lysozyme solutions. Drug release from hydrogels loaded with a sclerosant, tetracycline, was measured at pH 7.4, 6 and 2 at 37 °C. The results showed that tetracycline was more stable under acidic conditions, with a lower release rate observed at pH 6. An anticancer drug, doxorubicin, was loaded into the hydrogel and a cumulative release of 30% was observed over 78 h in phosphate-buffered saline at 37 °C. Injection of the hydrogel precursor through a 5-F catheter into a fusiform aneurysm model was feasible, leading to complete filling of the aneurysmal sac, which was visualized by fluoroscopy. The levels of occlusion by hydrogel precursors (1.8% and 2.1%) and calibrated microspheres (100–300 μm) in a rabbit renal model were compared. Embolization with hydrogel precursors was performed without clogging and the hydrogel achieved effective occlusion in more distal arteries than calibrated microspheres. In conclusion, this hydrogel possesses promising characteristics potentially beneficial for a wide range of vascular intervention procedures that involve embolization and drug delivery.     

Targeting Drugs to Combinations of Receptors: A Modeling Analysis of Potential Specificity

Targeting drugs to specific cells by conjugating the drug to an antibody or ligand for a cell surface receptor currently requires that the receptor be uniquely over-expressed by the target cell (the target cell over-expresses a particular receptor in comparison with untargeted cells, which do display this receptor type but a lesser number of them). Here we develop a mathematical model to predict the behavior of multivalent ligand–drug constructs containing two different ligands for two different receptors, which would allow targeting cells that do not uniquely over-express any receptor. In this model, target cells express both receptors at a high level; whereas, untargeted cells express one receptor type at the high level but the other at a lower level. The model predicts that these heterovalent conjugates (containing two different types of ligands) can achieve specificity even when the target cell does not uniquely over-express any one receptor type. Using the current approach, constructs in which only one ligand type is used will bind as much to untargeted cells as to the target cells. Therefore, this combination strategy can enormously expand the number of applications for which cell surface receptor targeting of drugs is an appropriate option.     

Body distribution of fully biodegradable [C]-poly(lactic acid) nanoparticles coated with albumin after parenteral administration to rats

Fully biodegradable polylactic acid (PLA) nanoparticles (90–250 nm) coated with human serum albumin (HSA) were prepared by high-pressure emulsification and solvent evaporation, using the protein as surfactant. A new analytical tool was developed, based on Mie's law and size exclusion chromatography, to establish that, after evaporation of the solvent, the protein saturates the surface of the nanoparticles, masking the PLA core. According to this technique, no HSA is encapsulated in the polymer matrix. A radiolabelled [¹⁴C]-PLA₅₀ was synthesized to follow the fate of this new drug carrier after i.v. administration to rats. The time necessary to clear the albumin-coated nanoparticles from the plasma was significantly longer than for the uncoated ones but not extended enough to target cells other than mononuclear phagocytes. As deduced from whole-body autoradiography and quantitative distribution experiments, the ¹⁴Cl-abelled polymer is rapidly captured by liver, bone marrow, lymph nodes, spleen and peritoneal macrophages. Nanoparticle degradation was addressed following ¹⁴C excretion. The elimination of the ¹⁴C was quick on the first day (30% of the administered dose) but then slowed down. In fact, if the metabolism of the PLA proceeds to lactic acid which is rapidly converted into CO₂ via the Krebs cycle (80% of the total excretion was fulfilled by the lungs), anabolism from the lactic acid may also have taken place leading to long-lasting radioactive remnants, by incorporation of ¹⁴C into endogenous compounds.     

How to: prophylactic interventions for prevention of Clostridioides difficile infection

BackgroundClostridioides difficile infection (CDI) remains the leading cause of healthcare-associated diarrhoea, despite existing guidelines for infection control measures and antimicrobial stewardship. The high associated health and economic burden of CDI calls for novel strategies to prevent the development and spread of CDI in susceptible patients.ObjectivesWe aim to review CDI prophylactic treatment strategies and their implementation in clinical practice.SourcesWe searched PubMed, Embase, Emcare, Web of Science, and the COCHRANE Library databases to identify prophylactic interventions aimed at prevention of CDI. The search was restricted to articles published in English since 2012.ContentA toxin-based vaccine candidate is currently being investigated in a phase III clinical trial. However, a recent attempt to develop a toxin-based vaccine has failed. Conventional probiotics have not yet proved to be an effective strategy for prevention of CDI. New promising microbiota-based interventions that bind and inactivate concomitantly administered antibiotics, such as ribaxamase and DAV-132, have been developed. Prophylaxis of CDI with C. difficile antibiotics should not be performed routinely and should be considered only for secondary prophylaxis in very selected patients who are at the highest imminent risk for recurrent CDI (R-CDI) after a thorough evaluation. Faecal microbiota transplantation (FMT) has proved to be a very effective treatment for patients with multiple recurrences. Bezlotoxumab provides protection against R-CDI, mainly in patients with primary episodes and a high risk of relapse.ImplicationsThere are no proven effective, evidenced-based prophylaxis options for primary CDI. As for secondary prevention, FMT is considered the option of choice in patients with multiple recurrences. Bezlotoxumab can be added to standard treatment for patients at high risk for R-CDI. The most promising strategies are those aimed at reducing changes in intestinal microbiota and development of a new effective non-toxin-based vaccine.     

Cancer stem cell therapy using doxorubicin conjugated to gold nanoparticles via hydrazone bonds

Nanoparticle-mediated delivery of chemotherapies has demonstrated enhanced anti-cancer efficacy, mainly through the mechanisms of both passive and active targeting. Herein, we report other than these well-elucidated mechanisms, rationally designed nanoparticles can efficiently deliver drugs to cancer stem cells (CSCs), which in turn contributes significantly to the improved anti-cancer efficacy. We demonstrate that doxorubicin-tethered gold nanoparticles via a poly(ethylene glycol) spacer and an acid-labile hydrazone bond mediate potent doxorubicin delivery to breast CSCs, which reduces their mammosphere formation capacity and their cancer initiation activity, eliciting marked enhancement in tumor growth inhibition in murine models. The drug delivery mediated by the nanoparticles also markedly attenuates tumor growth during off-therapy stage by reducing breast CSCs in tumors, while the therapy with doxorubicin alone conversely evokes an enrichment of breast CSCs. Our findings suggest that with well-designed drug delivery system, the conventional chemotherapeutic agents are promising for cancer stem cell therapy.     

Principles of strategic drug delivery to the brain (SDDB): development of anorectic and orexigenic analogs of leptin

The blood-brain barrier (BBB) presents a tremendous challenge for the delivery of drugs to the central nervous system (CNS). This includes drugs that target brain receptors for the treatment of obesity and anorexia. Strategic drug delivery to brain (SDDB) is an approach that considers in depth the relations among the BBB, the candidate therapeutic, the CNS target, and the disease state to be treated. Here, we illustrate principles of SDDB with two different approaches to developing drugs based on leptin. In normal body weight humans and in non-obese rodents, leptin is readily transported across the BBB and into the CNS where it inhibits feeding and enhances thermogenesis. However, in obesity, the transport of leptin across the BBB is impaired, resulting in a resistance to leptin. As a result, it is difficult to treat obesity with leptin or its analogs that depend on the leptin transporter for access to the CNS. To treat obesity, we developed a leptin agonist modified by the addition of pluronic block copolymers (P85-leptin). P85-leptin retains biological activity and is capable of crossing the BBB by a mechanism that is not dependent on the leptin transporter. As such, P85-leptin is able to cross the BBB of obese mice at a rate similar to that of native leptin in lean mice. To treat anorexia, we developed a leptin antagonist modified by pegylation (PEG-MLA) that acts primarily by blocking the BBB transporter for endogenous, circulating leptin. This prevents blood-borne, endogenous leptin from entering the CNS, essentially mimicking the leptin resistance seen in obesity, and resulting in a significant increase in adiposity. These examples illustrate two strategies in which an understanding of the interactions among the BBB, CNS targets, and candidate therapeutics under physiologic and diseased conditions can be used to develop drugs effective for the treatment of brain disease.