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\"Create embedded projects for personal and professional application. Join the Internet of Things revolution with a project-based approach to building embedded Java applications. Written by recognized Java experts, this Oracle Press guide features a series of low-cost, DIY projects that gradually escalate your development skills. Learn how to set up and configure your Raspberry Pi, connect external hardware, work with the NetBeans IDE, and write and embed powerful Java applications. Raspberry Pi with Java: Programming the Internet of Things (IoT) covers hobbyist as well as professional home and industry applications.\" --Back cover.

Teriparatide is one of several generic peptides named in a recent Food and Drug Administration (FDA) guidance (FDA-2017-D-5767-0002), which outlines a potential strategy to inform immunogenicity risk assessment for synthetic generic peptides without requiring clinical studies. Specifically, the guidance states that for abbreviated new drug applications (ANDAs), once the sameness of the active pharmaceutical ingredient (API) between the generic product and the reference listed drug is established, developers can mitigate the residual risk of unwanted immunogenicity response by using and tools to characterize differences in product- and process-related impurities between the reference and generic drug products. Regarding product-related impurities, a stated concern is that sequence modifications may create new T-cell epitopes capable of driving unwanted immune responses. Specifically, the guidance sets limits for the relative abundance of each impurity and requests that any new impurity above a certain concentration threshold be evaluated for potential T-cell-driven immunogenicity using orthogonal methods that assess both human leukocyte antigen (HLA) binding and the capacity to elicit a T-cell response. One such orthogonal immunogenicity risk assessment approach was applied to teriparatide (TPT) and several theoretical or observed product-related impurities in the case study described here. First, the immunogenic potential of TPT and selected impurities was assessed using three tools: EpiMatrix, ClustiMer, and JanusMatrix. Second, an method was used to evaluate the binding affinity of TPT and the selected TPT impurities to different class II HLA-DRs . Third, a human peripheral blood mononuclear cell (PBMC) T-cell assay compared T-cell proliferation in response to individual impurities or the reference teriparatide drug product, Forteo , . The orthogonal approaches identified multiple impurities as more immunogenic than TPT. In a novel finding, the analysis revealed a potentially tolerogenic sequence in TPT, which correlated with lower-than-expected immune responses to TPT . The analysis and methods described in this case study may help assess the relative risk of impurities and help identify those with the potential to increase the immunogenicity risk of a generic peptide.

Use the JavaFX platform to create rich-client Java applications and discover how you can use this powerful Java-based UI platform, which is capable of handling large-scale data-driven business applications for PC as well as mobile and embedded devices. The expert authors cover the new more modular JavaFX 9 APIs, development tools and best practices, as well as providing code examples that explore the exciting new features provided with JavaFX 9, part of Oracle's Java 9 release.

Advances in synthetic peptide synthesis have enabled rapid and cost-effective peptide drug manufacturing. For this reason, peptide drugs that were first produced using recombinant DNA (rDNA) technology are now being produced using solid- and liquid-phase peptide synthesis. While peptide synthesis has some advantages over rDNA expression methods, new peptide-related impurities that differ from the active pharmaceutical ingredient (API) may be generated during synthesis. These impurity byproducts of the original peptide sequence feature amino acid insertions, deletions, and side-chain modifications that may alter the immunogenicity risk profile of the drug product. Impurities resulting from synthesis have become the special focus of regulatory review and approval for human use, as outlined in the FDA’s Center for Drug Evaluation and Research guidance document, “ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin,” published in 2021. This case study illustrates how in silico and in vitro methods can be applied to assess the immunogenicity risk of impurities that may be present in synthetic generic versions of the salmon calcitonin (SCT) drug product. Sponsors of generic drug abbreviated new drug applications (ANDAs) should consider careful control of these impurities (for example, keeping the concentration of the immunogenic impurities below the cut-off recommended by FDA regulators). Twenty example SCT impurities were analyzed using in silico tools and assessed as having slightly more or less immunogenic risk potential relative to the SCT API peptide. Class II human leukocyte antigen (HLA)-binding assays provided independent confirmation that a 9-mer sequence present in the C-terminus of SCT binds promiscuously to multiple HLA DR alleles, while T-cell assays confirmed the expected T-cell responses to SCT and selected impurities. In silico analysis combined with in vitro assays that directly compare the API to each individual impurity peptide may be a useful approach for assessing the potential immunogenic risk posed by peptide impurities that are present in generic drug products.

Background As nanoparticles (NPs) become more prevalent in the pharmaceutical industry, questions have arisen from both industry and regulatory stakeholders about the long term effects of these materials. This study was designed to evaluate whether gold (10 nm), silver (50 nm), or silica (10 nm) nanoparticles administered intravenously to mice for up to 8 weeks at doses known to be sub-toxic (non-toxic at single acute or repeat dosing levels) and clinically relevant could produce significant bioaccumulation in liver and spleen macrophages. Results Repeated dosing with gold, silver, and silica nanoparticles did not saturate bioaccumulation in liver or spleen macrophages. While no toxicity was observed with gold and silver nanoparticles throughout the 8 week experiment, some effects including histopathological and serum chemistry changes were observed with silica nanoparticles starting at week 3. No major changes in the splenocyte population were observed during the study for any of the nanoparticles tested. Conclusions The clinical impact of these changes is unclear but suggests that the mononuclear phagocytic system is able to handle repeated doses of nanoparticles.

Following a decision to require label warnings for concurrent use of opioids and benzodiazepines and increased risk of respiratory depression and death, the US Food and Drug Administratioin (FDA) recognized that other sedative psychotropic drugs may be substituted for benzodiazepines and be used concurrently with opioids. In some cases, data on the ability of these alternatives to depress respiration alone or in conjunction with an opioid are lacking. A nonclinical in vivo model was developed that could detect worsening respiratory depression when a benzodiazepine (diazepam) was used in combination with an opioid (oxycodone) compared to the opioid alone based on an increased arterial partial pressure of carbon dioxide (pCO2). The current study used that model to assess the impact on respiration of non‐benzodiazepine sedative psychotropic drugs representative of different drug classes (clozapine, quetiapine, risperidone, zolpidem, trazodone, carisoprodol, cyclobenzaprine, mirtazapine, topiramate, paroxetine, duloxetine, ramelteon, and suvorexant) administered alone and with oxycodone. At clinically relevant exposures, paroxetine, trazodone, and quetiapine given with oxycodone significantly increased pCO2 above the oxycodone effect. Analyses indicated that most pCO2 interaction effects were due to pharmacokinetic interactions resulting in increased oxycodone exposure. Increased pCO2 recorded with oxycodone‐paroxetine co‐administration exceeded expected effects from only drug exposure suggesting another mechanism for the increased pharmacodynamic response. This study identified drug‐drug interaction effects depressing respiration in an animal model when quetiapine or paroxetine were co‐administered with oxycodone. Clinical pharmacodynamic drug interaction studies are being conducted with these drugs to assess translatability of these findings.

A critical step to evaluate the potential in vivo antiviral activity of a drug is to connect the in vivo exposure to its in vitro antiviral activity. The Anti–SARS‐CoV‐2 Repurposing Drug Database is a database that includes both in vitro anti–SARS‐CoV‐2 activity and in vivo pharmacokinetic data to facilitate the extrapolation from in vitro antiviral activity to potential in vivo antiviral activity for a large set of drugs/compounds. In addition to serving as a data source for in vitro anti–SARS‐CoV‐2 activity and in vivo pharmacokinetic information, the database is also a calculation tool that can be used to compare the in vitro antiviral activity with in vivo drug exposure to identify potential anti–SARS‐CoV‐2 drugs. Continuous development and expansion are feasible with the public availability of this database.

Objective: Employ the hollow fiber infection model (HFIM) to study sequential antibiotic administration (ampicillin, ciprofloxacin and fosfomycin) using human pharmacokinetic profiles to measure changes in the rate of antibiotic resistance development and compare this to simultaneous combination therapy with the same antibiotic combinations. Methods: Escherichia coli CFT073, a clinical uropathogenic strain, was exposed individually to clinically relevant pharmacokinetic concentrations of ampicillin on day 1, ciprofloxacin on day 2 and fosfomycin on day 3. This sequence was continued for 10 days in the HFIM. Bacterial samples were collected at different time points to enumerate total and resistant bacterial populations. The results were compared with the simultaneous combination therapy previously studied. Results: Sequential antibiotic treatment (ampicillin-ciprofloxacin-fosfomycin sequence) resulted in the early emergence of single and multi-antibiotic-resistant subpopulations, while the simultaneous treatment regimen significantly delayed or prevented the emergence of resistant subpopulations. Conclusion: Sequential administration of these antibiotic monotherapies did not significantly delay the emergence of resistant subpopulations compared to simultaneous treatment with combinations of the same antibiotics. Further studies are warranted to evaluate different sequences of the same antibiotics in delaying emergent resistance.

The U.S. Food and Drug Administration (FDA) Division of Applied Regulatory Science (DARS) moves new science into the drug review process and addresses emergent regulatory and public health questions for the Agency. By forming interdisciplinary teams, DARS conducts mission-critical research to provide answers to scientific questions and solutions to regulatory challenges. Staffed by experts across the translational research spectrum, DARS forms synergies by pulling together scientists and experts from diverse backgrounds to collaborate in tackling some of the most complex challenges facing FDA. This includes (but is not limited to) assessing the systemic absorption of sunscreens, evaluating whether certain drugs can convert to carcinogens in people, studying drug interactions with opioids, optimizing opioid antagonist dosing in community settings, removing barriers to biosimilar and generic drug development, and advancing therapeutic development for rare diseases. FDA tasks DARS with wide ranging issues that encompass regulatory science; DARS, in turn, helps the Agency solve these challenges. The impact of DARS research is felt by patients, the pharmaceutical industry, and fellow regulators. This article reviews applied research projects and initiatives led by DARS and conducts a deeper dive into select examples illustrating the impactful work of the Division.

On the cusp of widespread permeation of nanomedicine, academia, industry, and government have invested substantial financial resources in developing new ways to better treat diseases. Materials have unique physical and chemical properties at the nanoscale compared with their bulk or small-molecule analogs. These unique properties have been greatly advantageous in providing innovative solutions for medical treatments at the bench level. However, nanomedicine research has not yet fully permeated the clinical setting because of several limitations. Among these limitations are the lack of universal standards for characterizing nanomaterials and the limited knowledge that we possess regarding the interactions between nanomaterials and biological entities such as proteins. In this review, we report on recent developments in the characterization of nanomaterials as well as the newest information about the interactions between nanomaterials and proteins in the human body. We propose a standard set of techniques for universal characterization of nanomaterials. We also address relevant regulatory issues involved in the translational process for the development of drug molecules and drug delivery systems. Adherence and refinement of a universal standard in nanomaterial characterization as well as the acquisition of a deeper understanding of nanomaterials and proteins will likely accelerate the use of nanomedicine in common practice to a great extent.