Conditions Of Clinical Use Research Articles

Nanoplatforms for Magnetic-Photo-Heating of Thermo-Resistant Tumor Cells: Singular Synergic Therapeutic Effects at Mild Temperature.

A self-assemble amphiphilic diblock copolymer that can incorporate iron oxide nanocubes (IONCs) in chain-like assemblies as heat mediators for magnetic hyperthermia (MHT) and tuneable amounts of IR780 dye as agent for photothermal therapy (PTT) is developed. MHT-heating performance of photobeads in viscous media have the same heat performances in water at magnetic field conditions of clinical use. Thanks to IR780, the photobeads are activated by infrared laser light within the first biological window (808nm) with a significant enhancement of photo-stability of IR780 enabling the raise of the temperature at therapeutic values during multiple PTT cycles and showing unchanged optical features up to 8 days. Moreover, the photobeads fluorescent signal is preserved once internalized by glioblastoma multiforme (GBM) cells. Peculiarly, the photobeads are used as toxic agents to eradicate thermo-resistant GBM cells at mild heat, as low as 41°C, with MHT and PTT both of clinical use. Indeed, a high U87 GBM cell mortality percentage is obtained only with dual MHT/PTT while each single treatment dose not provide the same cytotoxic effects. Only for the combined treatment, the cell death mechanism is assigned to clear sign of apoptosis as observed by structural/morphological cell studies and enhanced lysosome permeability.

The Development and Evaluation of an All-Purpose Bolus for Radiotherapy

The purpose of this study was to develop on a new bolus (HM bolus) which had tissue equivalence, transparency, reusability, and free shaping at approximately 40°C for excellent adhesion, and to evaluate its features could be satisfy ideal bolus conditions for clinical use. The newly developed HM bolus was controlled to prevent phase separation by adjusting the contents of ethylene propylene rubber, styrene, butadiene rubber, thermoplastic resin, temperature-sensitive adjuster, and silica. The element ratios (wt%) in the HM bolus are H: 10.2%, C: 63.5%, O: 17.1%, and Si: 9.2%. The density was adjusted to 0.96 g cm-3. We evaluated dose characteristics, a vinyl gel sheet bolus (Gel bolus) and HM bolus placed on a water-equivalent phantom were used to obtain the percent depth dose (PDD) of electron (6 MeV, 9 MeV) and photon (4 MV,6 MV) beams. The average dose difference of the HM bolus and Gel bolus was calculated. The Gel bolus, a soft rubber bolus (SR bolus), and HM bolus were placed in adherence to a pelvic phantom. CT images taken after shaping and 1, 2, and 3 weeks after shaping were used to evaluate the adhesion and reproducibility using air gap and dice similarity coefficient (DSC) metrics. The visibility of letters (maximum: 80 pt, minimum: 10 pt) through a plate-shaped bolus and the visibility of markers when each bolus was set up on the pelvic phantom under normal room lighting were evaluated. The average dose difference for electron beams was 0.16% ± 0.79% and photon beams was 0.06% ± 0.34%, both within 1% of the PDD results. The HM bolus showed the same build-up effect and dose characteristics as the Gel bolus. The mean air gap values for the Gel bolus, SR bolus, and HM bolus were 96.02 ± 43.77 cm3, 34.93 ± 21.44 cm3, and 4.40 ± 1.50 cm3 44, respectively. The mean DSC values for the Gel bolus, SR bolus, and HM bolus were 0.363 ± 0.035, 0.556 ± 0.042, and 0.837±0.018. The HM bolus showed the smallest air gap at all time points and the DSC closest to 1. Excellent adhesion was observed in the CT simulation and during the treatment period. The letter visibility through the HM bolus and Gel bolus was sufficient, and when the HM bolus was set up on the pelvic phantom, the markers that were completely invisible with the SR bolus were visible. We succeeded in developing an all-purpose bolus with unique characteristics for clinical use. The HM bolus had the same build-up effect and dose characteristics as a Gel bolus. Therefore, it can be used for CT simulation and dose calculation. The other advantages of the new bolus are tissue equivalence, transparency, reusability, and free shaping at approximately 40°C, providing excellent adhesion at each setup during the treatment period.

Stability of 10 Beta-Lactam Antibiotics in Human Plasma at Different Storage Conditions.

Recently, several studies have assessed the effects of therapeutic drug monitoring of frequently prescribed beta-lactam antibiotics, for which they were quantified in human plasma samples. Beta-lactams are considered unstable, leading to extra challenges in quantification. Therefore, to ensure sample stability and minimize sample degradation before analysis, stability studies are crucial. This study investigated the stability of 10 frequently used beta-lactam antibiotics in human plasma at relevant storage conditions for clinical use. Amoxicillin, benzylpenicillin, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, flucloxacillin, imipenem, meropenem, and piperacillin were analyzed using ultraperformance convergence chromatography tandem mass spectrometry and liquid chromatography tandem mass spectrometry. Their short-term and long-term stabilities were investigated by measuring quality control samples at low and high concentrations against freshly prepared calibration standards. Measured concentrations at each time point were compared with the concentrations at T = 0. Antibiotics were considered stable if recovery results were between 85% and 115%. Short-term stability results indicated ceftriaxone, cefuroxime, and meropenem to be stable up to 24 hours at room temperature. All evaluated antibiotics, except imipenem, were stable on ice in a cool box for 24 hours. Amoxicillin, benzylpenicillin, and piperacillin were stable for 24 hours at 4-6°C. Cefotaxime, ceftazidime, cefuroxime, and meropenem were stable at 4-6°C up to 72 hours. Ceftriaxone and flucloxacillin were stable for 1 week at 4-6°C. Long-term stability results showed that all antibiotics were stable up to 1 year at -80°C, except imipenem and piperacillin, which were stable for 6 months at -80°C. Plasma samples for amoxicillin, benzylpenicillin, cefotaxime, ceftazidime, flucloxacillin, and piperacillin may be stored for a maximum of 24 hours in a cool box. Refrigeration is suitable for plasma samples of amoxicillin, benzylpenicillin, meropenem, and piperacillin for up to 24 hours and cefotaxime, ceftriaxone, ceftazidime and cefuroxime for 72 hours. Plasma samples for imipenem should be frozen directly at -80°C. For long-term storage, plasma samples can be stored at -80°C for a maximum of 6 months for imipenem and piperacillin and 12 months for all other evaluated antibiotics.

Scale-up approach for the preparation of magnetic ferrite nanocubes and other shapes with benchmark performance for magnetic hyperthermia applications.

Magnetic nanoparticles are increasingly used in medical applications, including cancer treatment by magnetic hyperthermia. This protocol describes a solvothermal-based process to prepare, at the gram scale, ferrite nanoparticles with well-defined shape, i.e., nanocubes, nanostars and other faceted nanoparticles, and with fine control of structural/magnetic properties to achieve point-of-reference magnetic hyperthermia performance. This straightforward method comprises simple steps: (i) making a homogeneous alcoholic solution of a surfactant and an alkyl amine; (ii) adding an organometallic metal precursor together with an aldehyde molecule, which acts as the key shape directing agent; and (iii) reacting the mixture in an autoclave for solvothermal crystallization. The shape of the ferrite nanoparticles can be controlled by the structure of the aldehyde ligand. Benzaldehyde and its aromatic derivatives favor the formation of cubic ferrite nanoparticles while aliphatic aldehydes result in spherical nanoparticles. The replacement of the primary amine, used in the nanocubes synthesis, with a secondary/tertiary amine results in nanoparticles with star-like shape. The well-defined control in terms of shape, narrow size distribution (below 5%), compositional tuning and crystallinity guarantees the preparation, at the gram scale, of nanocubes/star-like nanoparticles that possess, under magnetic field conditions of clinical use, specific adsorption rates comparable to or even superior to those obtained through thermal decomposition methods, which are typically prepared at the milligram scale. Here, gram-scale nanoparticle products with benchmark features for magnetic hyperthermia applications can be prepared in ~10 h with an average level of expertise in chemistry.

Clickable Polymer Ligand-Functionalized Iron Oxide Nanocubes: A Promising Nanoplatform for 'Local Hot Spots' Magnetically Triggered Drug Release.

Exploiting the local heat on the surface of magnetic nanoparticles (MNPs) upon exposure to an alternating magnetic field (AMF) to cleave thermal labile bonds represents an interesting approach in the context of remotely triggered drug delivery. Here, taking advantages of a simple and scalable two-step ligand exchange reaction, we have prepared iron oxide nanocubes (IONCs) functionalized with a novel multifunctional polymer ligand having multiple catechol moieties, furfuryl pendants, and polyethylene glycol (PEG) side chains. Catechol groups ensure a strong binding of the polymer ligands to the IONCs surface, while the PEG chains provide good colloidal stability to the polymer-coated IONCs. More importantly, furfuryl pendants on the polymer enable to click the molecules of interest (either maleimide-fluorescein or maleimide-doxorubicin) via a thermal labile Diels-Alder adduct. The resulting IONCs functionalized with a fluorescein/doxorubicin-conjugated polymer ligand exhibit good colloidal stability in buffer saline and serum solution along with outstanding heating performance in aqueous solution or even in viscous media (81% glycerol/water) when exposed to the AMF of clinical use. The release of conjugated bioactive molecules such as fluorescein and doxorubicin could be boosted by applying AMF conditions of clinical use (16 kAm-1 and 110 kHz). It is remarkable that the magnetic hyperthermia-mediated release of the dye/drug falls in the concentration range 1.0-5.0 μM at an IONCs dose as low as 0.5 gFe/L and at no macroscopical temperature change. This local release effect makes this magnetic nanoplatform a potential tool for drug delivery with remote magnetic hyperthermia actuation and with a dose-independent action of MNPs.

The Osteoinductive Potential of Partially Demineralized Bone Matrix and the Possibility of Its Use in Clinical Practice

Today autografts are considered to be an optimal material for bone grafting. However, the collection of material and its clinical use is associated with several serious drawbacks, and therefore, in reconstructive surgery, a search for alternative treatment approaches is being conducted. A bone transplant from another person (allo-osteoplasty) is the most natural and logical option for replacing an autobone. Since 1965, allogeneic implants of a partially demineralized bone matrix combining osteoinductive and osteoconductive action have been used in clinical practice. However, the clinical results of the use of this material turned out to be ambiguous, which is due, first of all, to the significant variability of the osteoplastic potential of its various samples. For this reason, in clinical practice, sometimes preference is given to samples of non-demineralized allobone, which retain its structure longer. In this paper, we consider factors affecting the osteoinductive activity of a partially demineralized bone matrix, related both to the technological issues of its preparation and to the clinical conditions of use. Issues of the possible improvement of this material were discussed with a view to its further use in medical practice.

Manufacturing Therapeutic Exosomes: from Bench to Industry.

Exosome, a type of nanoparticles also known as small extracellular vesicles are gaining attention as novel therapeutics for various diseases because of their ability to deliver genetic or bioactive molecules to recipient cells. Although many pharmaceutical companies are gradually developing exosome therapeutics, numerous hurdles remain regarding manufacture of clinical-grade exosomes for therapeutic use. In this mini-review, we will discuss the manufacturing challenges of therapeutic exosomes, including cell line development, upstream cell culture, and downstream purification process. In addition, developing proper formulations for exosome storage and, establishing good manufacturing practice facility for producing therapeutic exosomes remains as challenges for developing clinical-grade exosomes. However, owing to the lack of consensus regarding the guidelines for manufacturing therapeutic exosomes, close communication between regulators and companies is required for the successful development of exosome therapeutics. This review shares the challenges and perspectives regarding the manufacture and quality control of clinical grade exosomes.

Fe3O4@Au@Cu2−xS Heterostructures Designed for Tri‐Modal Therapy: Photo‐ Magnetic Hyperthermia and 64Cu Radio‐Insertion

Here, the synthesis and proof of exploitation of three-material inorganic heterostructures made of iron oxide-gold-copper sulfide (Fe3 O4 @Au@Cu2- x S) are reported. Starting with Fe3 O4 -Au dumbbell heterostructure as seeds, a third Cu2- x S domain is selectively grown on the Au domain. The as-synthesized trimers are transferred to water by a two-step ligand exchange procedure exploiting thiol-polyethylene glycol to coordinate Au and Cu2- x S surfaces and polycatechol-polyethylene glycol to bind the Fe3 O4 surface. The saline stable trimers possess multi-functional properties: the Fe3 O4 domain, of appropriate size and crystallinity, guarantees optimal heating losses in magnetic hyperthermia (MHT) under magnetic field conditions of clinical use. These trimers have indeed record values of specific adsorption rate among the inorganic-heterostructures so far reported. The presence of Au and Cu2- x S domains ensures a large adsorption which falls in the first near-infrared (NIR) biological window and is here exploited, under laser excitation at 808nm, to produce photo-thermal heat alone or in combination with MHT obtained from the Fe3 O4 domain. Finally, an intercalation protocol with radioactive 64 Cu ions is developed on the Cu2- x S domain, reaching high radiochemical yield and specific activity making the Fe3 O4 @Au@Cu2- x S trimers suitable as carriers for 64 Cu in internal radiotherapy (iRT) and traceable by positron emission tomography (PET).

Production, characterization and biological evaluation of nanocapsules containing tricresol formalin and their comparison with the free form

Ethnopharmacological relevance: Tricresol formalin is composed of 90% formaldehyde and 10% cresols, highly volatile, has action at a distance, has been used in endodontics since the 20th century, and it remains widely used in Brazil in dental treatments, in necrotic teeth and with periapical lesions. However, there is still controversy regarding the biological compatibility under the conditions of clinical use of this drug, as the studies carried out on this substance and its components are not consistent with its clinical use. Formaldehyde is reported as a potential cytotoxic substance, because when in direct contact with cells it is responsible for a cytogenotoxic response, so an alternative to increase stability and ensure the safe administration of this compound in direct contact with cells would be nanoencapsulation. The use of nanomaterials provides numerous advantages, as the main interests are increased solubility and drug release control. Study objective: This study aimed to produce and characterize nanocapsules containing tricresol formalin as active, evaluating and comparing the in vitro cytotoxic effect of free and nanostructured forms.Materials and methods: a nanoparticle was produced, optimization of the preparation method and characterization of nanocapsules containing tricresol formalin. Were performed antimicrobiological tests, tests for cell viability through the tetrazolium method assay (MTT), free radical production, double strand DNA damage, and nitric oxide production. Results: The formulation used did not show toxic behavior against human peripheral blood mononuclear cells and showed a significant reduction in the toxicity of tricresol formalin in human fibroblast cells. The nanostructures showed values ​​similar to the free form for antimicrobial activity. The nanoparticles showed mean particle size of 192.3 ± 2.5 nm, PDI of 0.101 ± 0.013, zeta potencial of -17.7 ± 2.8 mV, and pH of 5.48 ± 0.3. Conclusion: Thus, it is evident that nanocapsules containing tricresol formalin can become a safer alternative for use within endodontics.

Co-loading of doxorubicin and iron oxide nanocubes in polycaprolactone fibers for combining Magneto-Thermal and chemotherapeutic effects on cancer cells

Among the strategies to fight cancer, multi-therapeutic approaches are considered as a wise choice to put in place multiple weapons to suppress tumors. In this work, to combine chemotherapeutic effects to magnetic hyperthermia when using biocompatible scaffolds, we have established an electrospinning method to produce nanofibers of polycaprolactone loaded with magnetic nanoparticles as heat mediators to be selectively activated under alternating magnetic field and doxorubicin as a chemotherapeutic drug. Production of the fibers was investigated with iron oxide nanoparticles of peculiar cubic shape (at 15 and 23 nm in cube edges) as they provide benchmark heat performance under clinical magnetic hyperthermia conditions. With 23 nm nanocubes when included into the fibers, an arrangement in chains was obtained. This linear configuration of magnetic nanoparticles resemble that of the magnetosomes, produced by magnetotactic bacteria, and our magnetic fibers exhibited remarkable heating effects as the magnetosomes. Magnetic fiber scaffolds showed excellent biocompatibility on fibroblast cells when missing the chemotherapeutic agent and when not exposed to magnetic hyperthermia as shown by viability assays. On the contrary, the fibers containing both magnetic nanocubes and doxorubicin showed significant cytotoxic effects on cervical cancer cells following the exposure to magnetic hyperthermia. Notably, these tests were conducted at magnetic hyperthermia field conditions of clinical use. As here shown, on the doxorubicin sensitive cervical cancer cells, the combination of heat damage by magnetic hyperthermia with enhanced diffusion of doxorubicin at therapeutic temperature are responsible for a more effective oncotherapy.

Encapsulation of human limbus-derived stromal/mesenchymal stem cells for biological preservation and transportation in extreme Indian conditions for clinical use

Human limbus-derived stromal/mesenchymal stem cells (hLMSC) can be one of the alternatives for the treatment of corneal scars. However, reliable methods of storing and transporting hLMSC remains a serious translational bottleneck. This study aimed to address these limitations by encapsulating hLMSC in alginate beads. Encapsulated hLMSC were kept in transit in a temperature-conditioned container at room temperature (RT) or stored at 4 °C for 3–5 days, which is the likely duration for transporting cells from bench-to-bedside. Non-encapsulated cells were used as controls. Post-storage, hLMSC were released from encapsulation, and viability-assessed cells were plated. After 48 and 96-hours in culture the survival, gene-expression and phenotypic characteristics of hLMSC were assessed. During transit, the container maintained an average temperature of 18.6 ± 1.8 °C, while the average ambient temperature was 31.4 ± 1.2 °C (p = 0.001). Encapsulated hLMSC under transit at RT were recovered with a higher viability (82.5 ± 0.9% and 76.9 ± 1.9%) after 3 (p = 0.0008) and 5-day storage (p = 0.0104) respectively as compared to 4 °C (65.2 ± 1.2% and 64.5 ± 0.8% respectively). Cells at RT also showed a trend towards greater survival-rates when cultured (74.3 ± 2.9% and 67.7 ± 9.8%) than cells stored at 4 °C (54.8 ± 9.04% and 52.4 ± 8.1%) after 3 and 5-days storage (p > 0.2). Non-encapsulated cells had negligible viability at RT and 4 °C. Encapsulated hLMSC (RT and 4 °C) maintained their characteristic phenotype (ABCG2, Pax6, CD90, p63-α, CD45, CD73, CD105, Vimentin and Collagen III). The findings of this study suggest that alginate encapsulation is an effective method of hLMSC preservation offering high cell viability over prolonged durations in transit at RT, therefore, potentially expanding the scope of cell-based therapy for corneal blindness.

Fluorescent and magnetic stellate mesoporous silica for bimodal imaging and magnetic hyperthermia

There is currently a crucial need of innovative multifunctional nanoparticles combining, in one formulation, imaging and therapy capacities allowing thus an accurate diagnosis and a therapy monitored by imaging. Multimodal imaging will ensure to speed up diagnosis, and to increase its sensitivity, reliability and specificity for a better management of the disease. Combined with a therapeutic action, it will also enable to treat the disease in a specific personalized manner in feedback mode. The mastered design of such bioprobes as well as the demonstration of their efficiency are still challenges to face in nanomedicine. In this work, novel fluorescent and magnetic core–shell nanocomposites have been designed to ensure, in one nanoformulation, bimodal fluorescence and MRI imaging coupled with therapy by magnetic hyperthermia. They consist in the coating of a magnetic iron oxide (IO) core (ca.18nm diameter to ensure magnetic hyperthermia) by an original large pore stellate mesoporous silica (STMS) shell to produce uniform and mono-core magnetic core–shell nanocomposites denoted IO@STMS NPs. To confer fluorescence properties, CdSe/ZnS quantum dots (QDs) NPs were grafted inside the large pores of the IO@STMS nanocomposites. To provide biocompatibility and opsonization-resistance, a tightly-bound human serum albumin (HSA) coating is added around the nanocomposite using an original IBAM-based strategy. Cellular toxicity and non-specific cell–nanomaterial interactions allowed to determine a concentration range for safe application of these NPs. Cellular endosomes containing spontaneously-uptaken NPs displayed strong and photostable QD fluorescence signals while magnetic relaxivity measurements confirm their suitability as contrast agent for MRI. HeLa cell-uptaken NPs exposed to a magnetic field of 100kHz and 357Gauss (or 28.5kAm−1) display an outstanding 65% cell death at a very low iron concentration (1.25μgFemL−1), challenging current magnetic hyperthermia nanosystems. Furthermore, at the particularly demanding conditions of clinical use with low frequency and amplitude field (100kHz, 117Gauss or 9.3kAm−1), magnetic hyperthermia combined with the delivery of a chemotherapeutic drug, doxorubicin, allowed 46% cell death, which neither the drug nor the NPs alone yielded, evidencing thus the synergistic effect of this combined treatment.

Stability and degradation products of imipenem applying high-resolution mass spectrometry: An analytical study focused on solutions for infusion.

Carbapenems show recognized instability in aqueous solutions; therefore some care must be taken in their handling and preparation and their use in the hospital environment. The stability and degradation products of imipenem were investigated from conditions that simulate its clinical use. For this, a simple stability-indicating method by HPLC-DAD was validated with a focus on the quantitation of drug concentration remaining from infusion solutions (sodium chloride 0.9% and glucose 5%). The degradation products formed were identified by high-resolution mass spectrometry (ESI-Q-TOF-MS/MS), with detection of the [M + H]+ ions at m/z 318 (DP-1), m/z 599 (DP-2) and m/z 658 (DP-3). The most probable elemental compositions were obtained with a high degree of confidence, where the error between the masses observed and calculated was 1.25 ppm for DP-1, -0.33 ppm for DP-2 and 1.82 ppm for DP-3. The DP-1 degradation product resulted from cleavage of the β-lactam ring; DP-2 corresponded to the drug dimer; and DP-3 was generated from the interaction between imipenem and cilastatin. The proposed method provides a safe and reliable alternative for the quantitation of imipenem, and the stability data obtained by ESI-Q-TOF help in understanding the drug behavior under the conditions of clinical use.

A crack-free anti-corrosive coating strategy for magnesium implants under deformation

Surface patterns can be used as a selective coating platform on metal surfaces, in particular, under various deformation conditions because they induce local strain gradients along with pattern geometry. In this study, hard and flexible coating materials were introduced to regions with small and large deformations, respectively, on patterned magnesium (Mg) surfaces. Despite significant deformation, a polymer-ceramic coating on patterned Mg maintained its protection, as opposed to a ceramic coating on a flat Mg surface. Our proposed approach can be implemented in various Mg-based medical-device platforms by optimizing surface patterns on Mg depending on their loading conditions for clinical use.

Oxidative stress does not play a primary role in the toxicity induced with clinical doses of doxorubicin in myocardial H9c2 cells.

The implication of oxidative stress as primary mechanism inducing doxorubicin (DOX) cardiotoxicity is still questionable as many in vitro studies implied supra-clinical drug doses or unreliable methodologies for reactive oxygen species (ROS) detection. The aim of this study was to clarify whether oxidative stress is involved in compliance with the conditions of clinical use of DOX, and using reliable tools for ROS detection. We examined the cytotoxic mechanisms of 2μM DOX 1day after the beginning of the treatment in differentiated H9c2 rat embryonic cardiac cells. Cells were exposed for 2 or 24h with DOX to mimic a single chronic dosage or to favor accumulation, respectively. We found that apoptosis was prevalent in cells exposed for a short period with DOX: cells showed typical hallmarks as loss of anchorage ability, mitochondrial hyperpolarization followed by the collapse of mitochondrial activity, and nuclear condensation. Increasing the exposure period favored a shift to necrosis as the cells preferentially exhibited early DNA impairment and nuclear swelling. In either case, measuring the fluorescence lifetime of 1-pyrenebutyric acid or the intensities of dihydroethidium or amplex red showed a consistent pattern in ROS production which was a slight increased level far from representative of an oxidative stress. Moreover, pre-treatment with dexrazoxane provided a cytoprotective effect although it failed to detoxify ROS. Our data support that oxidative stress is unlikely to be the primary mechanism of DOX cardiac toxicity in vitro.

Development and Justification of a Risk Evaluation Matrix To Guide Chemical Testing Necessary To Select and Qualify Plastic Components Used in Production Systems for Pharmaceutical Products.

An accelerating trend in the pharmaceutical industry is the use of plastic components in systems used to produce an active pharmaceutical ingredient or a finished drug product. If the active pharmaceutical ingredient, the finished drug product, or any solution used to generate them (for example, a process stream such as media, buffers, eluents, and the like) is contacted by a plastic component at any time during the production process, substances leached from the component may accumulate in the active pharmaceutical ingredient or finished drug product, affecting its safety and/or efficacy. In this article the author develops and justifies a semi-quantitative risk evaluation matrix that is used to determine the amount and rigor of component testing necessary and appropriate to establish that the component is chemically suitable for its intended use. By considering key properties of the component, the contact medium, the contact conditions, and the active pharmaceutical ingredient's or finished drug product's clinical conditions of use, use of the risk evaluation matrix produces a risk score whose magnitude reflects the accumulated risk that the component will interact with the contact solution to such an extent that component-related extractables will accumulate in the active pharmaceutical ingredient or finished drug product as leachables at levels sufficiently high to adversely affect user safety. The magnitude of the risk score establishes the amount and rigor of the testing that is required to select and qualify the component, and such testing is broadly grouped into three categories: baseline assessment, general testing, and full testing (extractables profiling). Production suites used to generate pharmaceuticals can include plastic components. It is possible that substances in the components could leach into manufacturing solutions and accumulate in the pharmaceutical product. In this article the author develops and justifies a semi-quantitative risk evaluation matrix that can be used to determine the amount and rigor of component testing that may be necessary and appropriate to establish that the component is suitable for its intended use. Use of the risk evaluation matrix allows a user of a component to determine the type and amount of testing that should be performed to establish the patient safety risk associated with using that component in order to manufacture an active pharmaceutical ingredient or a finished drug product.

La stimulation transcrânienne à courant continu (tDCS) dans la dépression : bilan de près d’une décennie de recherche clinique

Since 2006 transcranial direct current stimulation (tDCS) has been investigated in the treatment of depression. In this review, we discuss the implications and clinical perspectives that tDCS may have as a therapeutic tool in depression from the results reported in this domain. A comprehensive literature review has found nearly thirty articles - all in English - on this topic, corresponding to clinical studies, placebo-controlled or not, case reports and reviews. Several meta-analyses showed that the antidepressant effects of active tDCS are significant against placebo, but variable, mainly due to the heterogeneity of the patients included in the studies, for example regarding the resistance to antidepressant treatment. Specific recommendations for the use of tDCS in treating depression may not yet be available, but some elements of good practice can be highlighted. Of particular note is that anodal tDCS of the left prefrontal cortex at 2mA for 20 minutes per day has a potential therapeutic value without risk of significant side effects: tDCS offers safe conditions for clinical use in the treatment of depression.

Development of Automatic Brain Temperature Controller Based on Conditions of Clinical Use

A new automatic brain temperature controller was developed based on the conditions required for clinical use from the viewpoint of various aspects of feasibility, in particular an electric power consumption of less than 1500 W in an intensive care unit. An adaptive algorithm was employed to deal with individual time-varying characteristic changes of patients. The controller in water-surface cooling hypothermia requires significant power for frequent regulation of the water temperature of cooling blankets. Thus, in this study, the power consumption of the controller was checked by several kinds of tests involving simulated control of brain temperature with a mannequin that had thermal characteristics similar to those of adult patients. The required accuracy for therapeutic brain hypothermia, specifically a control deviation within ±0.1 °C, was experimentally confirmed in terms of the root mean square control error, even though the present controller consumes less energy than a conventional controller. It can maintain a reserve power margin of more than 300 W even during full operation. The clinically required water temperature was also confirmed within the limits of the power supply. Thus, its practical application is highly desirable, since it will reduce the physical burden on medical staff and will offer greater usability and better medical cost performance.

Regenerative Medicine for the Cornea

Regenerative medicine for the cornea provides a novel treatment strategy for patients with corneal diseases instead of conventional keratoplasty. Limbal transplantation has been performed in patients with a limbal stem cell deficiency. This procedure requires long-term immunosuppression that involves high risks of serious eye and systemic complications, including infection, glaucoma, and liver dysfunction. To solve these problems, ocular surface reconstruction using cultured limbal or oral mucosal epithelial stem cells has been successfully applied to patients. However, cell sheets must be fabricated in a cell processing center (CPC) under good manufacturing practice conditions for clinical use, and the expenses of maintaining a CPC are too high for all hospitals to cover. Therefore, several hospitals should share one CPC to standardize and spread the application of regenerative therapy using tissue-engineered oral mucosal epithelial cell sheets. Consequently, we developed a cell transportation technique for clinical trial to bridge hospitals. This paper reviews the current status of regenerative medicine for the cornea.

Should licking behavior be considered in the bioavailability evaluation of transdermal products?

Antiparasitic drugs, and especially macrocyclic lactones (MLs), are often formulated as pour-on products because of their ease of administration, convenience, and reduction of stress in treated animals. However, because of self- and allo-grooming, much of a drug administered transdermally may be systemically absorbed via the oral route, creating highly variable pharmacokinetic and pharmacodynamic response in treated (and untreated) animals. Testing bioequivalence (BE) of pour-on drugs in cattle under laboratory conditions (with restricted licking) ignores a major factor of drug disposition of these drugs and thus fails to predict therapeutic equivalence in the target population under clinical conditions of use. Therefore, the interanimal and intra-animal variability associated with licking behavior should be considered as a biological fact, rather than a noise that needs to be reduced or eliminated. As a result, it is recommended that the BE testing for pour-on products in cattle be conducted by evaluating both the mean and distribution of bioavailability parameters between the reference and test products when animals are not prevented from allo- and self-licking.