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It is a problem that the environment is often seen and treated as a reservoir of resources awaiting human use. How did this outlook arise? This essay analyzes a formative moment in the constitution of the environment as a buffet of goods to be consumed: seventeenth-century efforts by agricultural improvers, including John Locke, to eradicate waste. Locke’s theory of property prohibits the wasteful spoilage of food and charges mankind with a responsibility to cultivate, incorporate, and thereby appropriate earth’s nonhuman eatables—what I call his “partition of the digestible.” But eating both underwrites and unhinges Lockean property rights, for all food contains materials that cannot be used by the body and must be excreted from it. Poop and pee serve as visible (and smelly) reminders that consumption is inhabited by, and thus cannot resolve, waste. Even the improvers’ ostensible solution of repurposing excrement as manure to produce more food just creates more waste: this “peristaltic circle,” as I describe it, is voracious and expansive. Circular waste-eradication projects are best understood as enabling preconditions for the wastefulness of linear, take-make-waste political economies, not their antidote.

Background In 2016, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use updated its efficacy guideline for good clinical practice and introduced quality tolerance limits (QTLs) as a quality control in clinical trials. Previously, TransCelerate proposed a framework for QTL implementation and parameters. Historical data can be important in helping to determine QTL thresholds in new clinical trials. Methods This article presents results of historical data analyses for the previously proposed parameters based on data from 294 clinical trials from seven TransCelerate member companies. The differences across therapeutic areas were assessed by comparing Alzheimer’s disease (AD) and oncology trials using a separate dataset provided by Medidata. Results TransCelerate member companies provided historical data on 11 QTL parameters with data sufficient for analysis for parameters. The distribution of values was similar for most parameters with a relatively small number of outlying trials with high parameter values. Medidata provided values for three parameters in a total of 45 AD and oncology trials with no obvious differences between the therapeutic areas. Conclusion Historical parameter values can provide helpful benchmark information for quality control activities in future trials.

The concept of going 'green' and 'cold' has led to utilizing renewable resources for the synthesis of microbial biosurfactants that are both patient and eco-friendly. In this review, we shed light on the potential and regulatory aspects of biosurfactants in pharmaceutical applications and how they can significantly contribute to novel concepts for the Coronavirus 2019 (COVID-19) vaccine and future treatment. We emphasize that more specific guidelines should be formulated to regulate the approval of biosurfactants for human use. It is also crucial to implement a risk-based approach from the early research and development (R&D) phase in addition to establishing more robust standardized techniques and assays to evaluate the characteristics of biosurfactants.

This « Magnum Opus » emphasizes that serendipity is a corner stone in research. The paths of discovery and innovation often result from the interdisciplinarity of scientific areas that are a priori disconnected from each other. In the 1970s, fundamental discoveries in cell biology led to unexpected advances in galenic pharmacy with the emergence of nanotechnologies for the intracellular delivery of non diffusing molecules. As well, fluorescein-loaded polyacrylamide nanocapsules were shown to deliver this fluorescent agent precisely into cellular lysosomes which represented a seminal observation. However, due to the lack of biodegradability of this carrier polymer, this approach was still far from therapeutic application. The use of cyanoacrylates as surgical glue inspired us to use this material in the design of the first biodegradable nanoparticles for human use. Capable of transporting compounds with anti-tumor activity, these polyalkylcyanoacrylate nanoparticles demonstrated the unexpected property of overcoming multi-drug resistance. This discovery led to the development of a nanomedicine that has completed phase III clinical trials for the treatment of resistant hepatocarcinoma. Going beyond the state-of-the art, a step ahead in the nanomedicine field was the drug « squalenoylation » technology, which represents a shift from the « physical » to the « chemical » encapsulation paradigm. The bioconjugation of anticancer and other drugs to squalene, a natural and biocompatible lipid, enabled a dramatic increase in drug payload, and eliminated the so-called « burst release » of drug: Two major drawbacks commonly associated with drug nanoencapsulation. The drug « squalenoylation » approach resulted in a generic nanomedicine platform with broad pharmacological applications.

Sob o viés arqueológico denominado archaeogaming (Reinhard, 2018), este artigo tem por objetivo central colaborar com a metodologia de análise de jogos eletrônicos em ambientes digitais a partir do produto Detroit: Become Human, lançado em 2018 pela desenvolvedora francesa Quantic Dream. Serão objetos de análise as paisagens arqueológicas extra e intra-jogo, buscando os tecnofósseis que corroboram a inserção do jogo, enquanto mídia física, no debate sobre o Antropoceno; e, enquanto mídia digital, na recente hipótese de datação geológica, elencada pelo químico e ambientalista James Lovelock denominada Novaceno (Novacene). Pretende-se, assim, apresentar não uma Arqueologia Digital, mas, sim, uma Arqueologia do Digital, escavando e trazendo à luz vestígios que permitam, ao mesmo tempo, o entendimento do uso humano de máquinas cibernéticas, bem como a representação dessas máquinas a partir de códigos de programação intra-jogo escritos por humanos.

Introduction: The main purpose of this study was comparing median time (TTR, time to reimbursement) between the first Agenzia Italiana del Farmaco (AIFA) pricing and reimbursement (P&R) dossier’s evaluation and patient access in Italy and to observe the key P&R negotiation results for all new active substances approved by the European Medicines Agency (EMA)’s Committee for Medicinal Products for Human Use between January 2014 and December 2019. We analysed the different factors influencing TTR. Methods: A panel of medicines for human use approved by the EMA in the period 2014-2019 was considered. All information about authorisation and reimbursement in Italy, including timelines and results from the negotiation, were gathered through EMA and Italian Official Journal databases. Results: Of 213 new active substances approved from January 2014 to December 2019, 137 obtained reimbursement in Italy, with a median TTR of 7.6 months (228 days). Even if orphan designation, oncology indication, application of Managed Entry Agreements (MEAs; both outcome and financial based) or a discount did not show an impact on TTR, recognition of full innovativeness (n = 27; 20%) was associated with a reduction of 1 month in median TTR. Interestingly, drugs reimbursed with a lower price/daily defined dose showed a reduced TTR (−22%). Conclusions: Even if the lack of impact of some negotiation conditions was predictable (e.g. oncology indication or orphan status) or the application of a MEA helped to manage possible uncertainties, it did not lead to a quicker completion of the negotiation procedure. Likewise, full innovative drugs showed a shorter TTR underlying the AIFA commitment in recognising, promoting and rewarding innovation.

Background: An estimated 1 million patients require cardiac implantable electronic devices (CIEDs) but go without annually. This disparity exists in low-to-middle-income nations largely owing to the cost of CIED hardware. Humanitarian reuse of CIEDs has been shown to be safe and feasible. However, recent publications have raised concern that promotion of CIED reuse may foster a CIED “black market,” to the dismay of manufacturers, regulators, and clinicians alike. Objective: To determine if unregulated CIED sales for potential human use is a real issue by investigating unregulated public online CIED sale listings in the United States of America. Methods: An observational study was undertaken over 6 months using multiple internet search engines from May 1 to November 1, 2019. We cataloged usable CIEDs (still in packaging, manufactured

ObjectiveTo identify the presence of unapproved pharmaceutical drugs in over-the-counter dietary supplements marketed to improve memory and cognitive function.MethodsSupplements were identified by searching 2 supplement databases for products labeled as containing omberacetam, aniracetam, phenylpiracetam, or oxiracetam, 4 drugs not approved for human use in the United States. Products were purchased online and analyzed using nontargeted liquid chromatography-quadrupole time-of-flight mass spectrometry methods.ResultsIn the 10 products tested, omberacetam and aniracetam were detected along with 3 additional unapproved drugs (i.e., phenibut, vinpocetine and picamilon). By consuming recommended serving sizes, consumers could be exposed to pharmaceutical-level dosages of drugs including a maximum of 40.6 ± 0.4 mg omberacetam (typical pharmacologic dose of 10 mg), 502 ± 0.8 mg of aniracetam (typical pharmacologic dose 200–750 mg), 15.4 ± 0.3 mg of phenibut (typical pharmacologic dose 250–500 mg), 4.3 ± 0.1 mg of vinpocetine (typical pharmacologic dose 5–40 mg), and 90.1 ± 0.7 mg of picamilon (typical pharmacologic dose 50–200 mg). Several detected drugs were not declared on the label, and several declared drugs were not detected in the products. For those products with drug quantities provided on the labels, 75% (9/12) of declared quantities were inaccurate. Consumers could be exposed to up to four-fold greater than pharmaceutical dosages and as many as 4 unapproved drugs when using individual products.ConclusionsOver-the-counter cognitive enhancement supplements may contain multiple unapproved drugs. The health effects of consuming untested combinations of unapproved drugs at unpredictable dosages without clinician oversight in supplements are unknown.

Clinical trials of drug candidates intended to treat neurological conditions often fail because of the poor correlation between outcomes in humans and other animal models. Microphysiological systems offer a potential alternative to or a synergetic approach with animal testing by using human cells assembled in three-dimensional morphologies that are representative of human tissues and organs. The recent advances in microphysiological models of neurological disorders are reviewed here in terms of models used to quantify drug distribution and drug engagement and function. We find that the complexity of microphysiological models continues to increase, but only few neurological conditions have been modeled with the purpose of testing pharmacological traits of candidate drugs. Much more effort appears to have been devoted to models that recapitulate drug distribution, particularly across vascular barriers, and models involving barrier modifications as a result of patient-specific neurological conditions have started to emerge. Based on the current trend, microphysiological models of neurological disorders have the capacity to become a useful tool in the preclinical testing of drugs for human use.

Street furniture is an independent discipline. It addresses detailed solutions of products designed for human use in an exterior environment. Based on present-day studies, senior citizens constitute the fastest growing segment of the population. The sample element with defined ergonomic parameters has been defined by analyzing the standard and most used component of street furniture - bench, by the comparison of used materials and chosen construction. During the comparison and the subsequent conclusions, a great emphasis was placed on the functionality and durability of the individual components. The categories of street furniture have been based on the study of production programs of mainstream furniture manufacturers in Europe, and on the research of factors influencing street furniture. With the basic material of the supporting structure, the sitting and leaning sections and based on the measurements and defining of materials, a sample construction design has been proposed, and supporting element of concrete, steel and wooden constructions including their surface treatment has been described. info:eu-repo/semantics/openAccess

The aim of present review is to provide an insight on FDA updates in it’s own words on coronavirus disease 2019. The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

A vaccine is an immunogen, the administration of which is intended to stimulate the immune system to result in the prevention, amelioration, or therapy of any disease or infection (US Food and Drug Administration. Guidance for Industry: content and format of chemistry, manufacturing, and controls information and establishment description information for a vaccine or related product). A vaccine may be a live attenuated preparation of microorganisms, inactivated (killed) whole organisms, living irradiated cells, crude fractions, or purified immunogens, including those derived from recombinant DNA in a host cell, conjugates formed by covalent linkage of components, synthetic antigens, polynucleotides (such as the plasmid DNA vaccines), living vectored cells expressing specific heterologous immunogens, or cells pulsed with immunogen. Vaccines are highly complex products that differ from small molecule drugs because of the biological nature of the source materials such as those derived from microorganisms as well as the various cell substrates from which some are derived. Regardless of the technology used, because of their complexities, vaccines must undergo extensive characterization and testing. Special expertise and procedures are needed for their manufacture, control, and regulation. The Food and Drug Administration (FDA) is the National Regulatory Authority (NRA) in the United States responsible for assuring quality, safety, and effectiveness of all human medical products, including vaccines for human use.The Center for Biologics Evaluation and Research (CBER) within the US FDA is responsible for overseeing the regulation of therapeutic and preventative vaccines against infectious diseases. Authority for the regulation of vaccines resides in Section 351 of the Public Health Service Act and specific sections of the Federal Food, Drug, and Cosmetic Act (FD&C). Vaccines are regulated as biologics and licensed based on the demonstration of safety and effectiveness. The vaccine development process can be divided into two major categories: those events that are not under the regulatory authority of the FDA and are exploratory in nature and those events that are subject to regulatory authority by the FDA. Exploratory events or research and development cover basic research drug discovery processes that occur before the sponsor submits an investigational new drug application (IND) to the FDA. There are four main stages of vaccine development under the purview of regulatory authorities: preclinical, clinical (IND), licensing, and post-licensure. Throughout their life cycle from preclinical evaluation to post-licensure lot release testing, vaccines are subject to rigorous testing and oversight by manufacturers and NRAs. In this chapter an overview of the regulatory evaluation and testing requirements for vaccines is presented.

Dose is one of the parameters that any pharmacologist seriously considers when studying the effects of a drug. If the necessary dose to achieve a desired pharmacological effect is in a toxic or very toxic range for human use, the drug will probably fall out from further research. The concentration that a drug can reach at its target organ or cell is a direct consequence of the administered dose and its pharmacodynamic properties. Basic researchers investigate at the cellular level or eventually with xenografts. They use different concentrations of the drug in order to determine its cellular effects. However, in many cases, these concentrations require doses that are in the toxic range or well beyond any clinically achievable level. Therefore, in these cases, research is in the realm of Toxicology rather than therapeutics. This paper will show some examples about this exercise in futility which is time and resource consuming but that pullulates the pages of many prestigious journals. Many seasoned researchers seem to have forgotten the Paracelsus Paradox.

RESUMEN Introducción: Según la Organización Mundial de la Salud, el desecho de medicamentos es la eliminación de todos aquellos productos farmacéuticos que han expirado, derramado o contaminado y medicamentos que no son de utilidad y necesitan disponerse de forma adecuada. Objetivo: Caracterizar los medicamentos desechados en Costa Rica durante el 2019, con el sistema de recolección de una empresa de recolección de medicamentos en desuso. Materiales y métodos: Se realizó un estudio observacional, descriptivo-analítico y de corte transversal. El estudio se desarrolló en las instalaciones de la empresa MPD en Curridabat, San José, donde se almacenan los contenedores de la empresa. Los datos obtenidos se depositaron en una base de datos elaborada en Excel 2016. Resultados: En su mayoría los medicamentos encontrados vencidos eran de uso humano, especialmente para adultos, la forma farmacéutica más común fue la enteral, procedentes de los sectores privado y público. Existe una relación significativa entre la condición de los medicamentos y su origen, así como entre el origen y la forma farmacéutica. No existe relación significativa entre la forma farmacéutica de los medicamentos y la condición de estos, tampoco entre la nacionalidad y la condición. Conclusiones: La condición de desuso fue la que más prevaleció dentro de los medicamentos desechados. El principio activo más desechado fue el paracetamol y el principal grupo farmacológico encontrado en los productos desechados fue el de los analgésicos. SUMMARY Introduction: According to the World Health Organization, the disposal of medicines is the elimination of all those pharmaceutical products that have expired, spilled, or contaminated and medicines that are not useful and need to be disposed of properly. Objective: To characterize the medicines discarded in Costa Rica during 2019, with the collection system of a company that collects disused medicines. Materials and methods: An observational, descriptive-analytical, and cross-sectional study was carried out. The study was carried out at the facilities of the MPD Company in Curridabat, San José, where the company's containers are stored. The data obtained was deposited in a database elaborated in Excel 2016. Results: Most of the expired drugs were for human use, especially for adults, the most common pharmaceutical form was enteral, from the private and national sectors. There is a significant relationship between the condition of the drugs and their origin, as well as between the origin and the pharmaceutical form. There is no significant relationship between the pharmaceutical form of the drugs and their condition, nor between nationality and condition. Conclusions: The condition of disuse was the most prevalent among the discarded drugs. The most discarded active principle was paracetamol and the main pharmacological group found in discarded products was analgesics. RESUMO Introdução: De acordo com a Organização Mundial da Saúde, o descarte de medicamentos é a eliminação de todos os produtos farmacêuticos vencidos, derramados ou contaminados e os medicamentos que não são úteis e precisam ser descartados de maneira adequada. Objetivo: Caracterizar os medicamentos descartados na Costa Rica durante o 2019, com o sistema de coleta de uma empresa que coleta medica mentos fora de uso. Materiais e métodos: foi realizado um estudo observacional, descritivo-analítico e transversal. O estudo foi realizado nas instalações da empresa MPD em Curridabat, San José, onde estão armazenados os contentores da empresa. Os dados obtidos foram depositados em banco de dados elaborado no Excel 2016. Resultados: A maioria dos medicamentos vencidos era para uso humano, principalmente para adultos, a forma farmacêutica mais comum foi a enteral, do setor privado e nacional. Existe uma relação significativa entre o estado dos medicamentos e sua origem, bem como entre a origem e a forma farmacêutica. Não existe relação significativa entre a forma farmacêutica dos medicamentos e o seu estado de saúde, nem entre a nacionalidade e o estado de saúde. Conclusões: A condição de desuso foi a mais prevalente entre os medicamentos descartados. O princípio ativo mais descartado foi o paracetamol e o principal grupo farmacológico encontrado nos produtos descartados foram os analgésicos.

The COVID-19 pandemic has accelerated the need to identify new antiviral therapeutics at pace, including through drug repurposing. We employed a Quadratic Unbounded Binary Optimization (QUBO) model, to search for compounds similar to Remdesivir, the first antiviral against SARS-CoV-2 approved for human use, using a quantum-inspired device. We modelled Remdesivir and compounds present in the DrugBank database as graphs, established the optimal parameters in our algorithm and resolved the Maximum Weighted Independent Set problem within the conflict graph generated. We also employed a traditional Tanimoto fingerprint model. The two methods yielded different lists of lead compounds, with some overlap. While GS-6620 was the top compound predicted by both models, the QUBO model predicted BMS-986094 as second best. The Tanimoto model predicted different forms of cobalamin, also known as vitamin B12. We then determined the half maximal inhibitory concentration (IC50) values in cell culture models of SARS-CoV-2 infection and assessed cytotoxicity. We also demonstrated efficacy against several variants including SARS-CoV-2 Strain England 2 (England 02/2020/407073), B.1.1.7 (Alpha), B.1.351 (Beta) and B.1.617.2 (Delta). Lastly, we employed an in vitro polymerization assay to demonstrate that these compounds directly inhibit the RNA-dependent RNA polymerase (RdRP) of SARS-CoV-2. Together, our data reveal that our QUBO model performs accurate comparisons (BMS-986094) that differed from those predicted by Tanimoto (different forms of vitamin B12); all compounds inhibited replication of SARS-CoV-2 via direct action on RdRP, with both models being useful. While Tanimoto may be employed when performing relatively small comparisons, QUBO is also accurate and may be well suited for very complex problems where computational resources may limit the number and/or complexity of possible combinations to evaluate. Our quantum-inspired screening method can therefore be employed in future searches for novel pharmacologic inhibitors, thus providing an approach for accelerating drug deployment.

Human pharmaceuticals are extensively studied and assessed before marketing approval. Since 2006, this also includes an assessment of environmental risks. In the European Union, this is based on the guideline on the environmental risk assessment of medicinal products for human use (EMEA/CHMP/SWP/4447/00 corr 2), which is currently under revision. For Germany, the German Environment Agency (UBA) is tasked with the evaluation of environmental risks of human pharmaceuticals. Applicants seeking approval of medicinal products need to submit fate and effect data, in case predicted environmental concentrations (PECs) exceed 10 ng/L in surface waters, or the substance is of specific concern through its mode of action or physico-chemical characteristics.Over the last decade, this regulatory work resulted in an internal agency database containing effect data on approximately 300 active pharmaceutical ingredients (APIs). A considerable part of this data is currently not publicly available due to property rights held by the respective applicants. The database was evaluated to draw conclusions on how the current assessment approach may be improved.The evaluation of aquatic effect data shows considerable variation in ecotoxic effect concentrations, but supports the current use of 10 ng/L as PEC action limit. For endocrine-active substances and antibiotics, a clear sensitivity profile was observed, which allows a more targeted assessment in the future. The conclusions drawn from terrestrial effect data are less clear, as the database itself is biased because information is only available for substances with high sorption. Further adaptations of the terrestrial assessment strategy, including action triggers, appear necessary. Fate data show a high persistence of many APIs: approximately 43% of all APIs are classified as very persistent; 12% of these show DT50 values in a range where abiotic or biotic degradation is not expected.Overall, the evaluation has shown that improvements of the current guideline are possible.

The method of prohibiting khamar in the Qur'an is a way of educating a society by using a gradual approach. The first stage of the Qur'an provides an overview of the human use of dates and grapes, the second stage, the Qur'an in more detail Describes the advantages and disadvantages of drinking khamar. At these two stages, the Qur'an implements the concept of self-cultivation with logic, similarly on the resolving of game addiction. The stage that can be done by parents is to begin to explain to the child about what benefits and what the losses that children get from the game he played. Parents then make a deal with the child about the consequences of his actions in the form of rewards and punishment.

For the handling of active pharmaceutical ingredients (APIs) and production of medicinal products in shared facilities, the European Medicines Agency (EMA) has introduced the determination of permitted daily exposure (PDE) values to provide limits for cross-contamination. APIs have a desired pharmacological effect in the patient who intendedly uses a certain medicinal product. However, this effect is undesired in a patient that receives this API unintendedly as a cross-contamination of another medicinal product. In particular, for approved APIs for human use, a multitude of data is available on the pharmacological activity as well as adverse effects, which have to be taken into account in PDE setting. Thus, the setting of PDEs for APIs needs a structured scientific evaluation of all properties and identification of the most critical effect, which is the basis for PDE calculation. In this publication, we provide guidance on points for consideration when setting PDEs for APIs, or when evaluating the quality of documents describing the derivation of PDEs received, e.g. by third parties.

In the development of quality biopharmaceutical drugs, it is the level of knowledge gained, not the volume of data, which provides the basis for science-based submissions and their regulatory evaluation [International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q8 (R2)]. The identification of critical quality attributes (CQAs) is important as the initial step for quality by design (QbD) strategies. The impact of each potential critical attribute (pCQA) is assessed by using a systematic and scientific approach with respect to bioactivity, pharmacokinetics (PK)/pharmacodynamics (PD), immunogenicity, and safety of the biopharmaceutical drugs. The purpose of this section is to introduce a strategy for identifying CQA, and new analytical methods for CQA assessment.

Drugs re-purposing due to COVID-19 virus has declared a number of useful candidates for treatment and prevention of the virus. Ivermectin (IVM) has gained much popularity due to a strong background of magical applications against a broad spectrum of pathogens. The in- vitro studies of ivermectin have shown promise, the thorough clinical trials of its efficacy in the treatment and prevention of SARS-CoV-2 are still warranted. Useful strategies for analyzing projected use of IVM in human coronaviruses might be developed. It may be done by concluding ongoing clinical trials and culturing lessons from IVM usage in veterinary practice. The potential toxicity and careful dosage analyses are urgently required before declaring it as an anti-SARS-CoV-2 drug candidate. This manuscript overviews the background and potential threats associated with the off-label use of IVM as prophylactic drug or treatment option against COVID-19 virus., Graphical abstract Image, graphical abstract

The oral explanation (OE) is a critical event during new marketing authorisation procedures in the European Union (EU). The primary objective of the present study was to investigate how many procedures, having an OE in front of the Committee for Medicinal Products for Human Use (CHMP), resulted in a regulatory approval for oncology products. Procedures for new marketing authorisation applications (MAAs) and Type II variations (new indication) for oncology products with at least one OE (with or without a Scientific Advisory Group (SAG) meeting) and for which the outcome took place between 31 January 2016 to 31 January 2020 were included in the analysis. Publicly available agendas/meeting minutes and assessment reports were used to obtain information on the products. An OE occurred in about 20% of procedures (n = 28/150) for oncology products during the review period. The majority of procedures having an OE (61%), with or without any SAG meeting, led to MAA/Type II variation approval in the Centralised Procedure. It was also observed that in 41% of the cases a successful outcome was contingent upon willingness of the applicant to restrict the indication. A majority of oncology procedures that had an OE resulted in a positive outcome suggesting that such agency interaction is an important opportunity for the applicant to have a last chance to resolve any outstanding issues at the final stage of the procedure.

Producción Científica, Advanced therapy medicinal products (ATMPs) are a group of innovative and complex biological products for human use that comprises somatic cell therapy medicinal products, tissue engineered products, gene therapy medicinal products, and the so-called combined ATMPs that consist of one of the previous three categories combined with one or more medical devices. During the last few years, the development of ATMPs for the treatment of eye diseases has become a fast-growing field as it offers the potential to find novel therapeutic approaches for treating pathologies that today have no cure or are just subjected to symptomatic treatments. Therefore, it is important for all professionals working in this field to be familiar with the regulatory principles associated with these types of innovative products. In this review, we outline the legal framework that regulates the development of ATMPs in the European Union and other international jurisdictions, and the criteria that each type of ATMP must meet to be classified as such. To illustrate each legal definition, ATMPs that have already completed the research and development stages and that are currently used for the treatment of eye diseases are presented as examples., Department of Education, Castilla y León Regional Government (Grant VA168P18 FEDER, EU) Spain; Ministry of Science and Innovation (Grant PID2019-105525RB-100, MICINN/FEDER, EU), Spain; Institute of Health Carlos III, CIBER-BBN (CB06/01/003 MICINN/FEDER, EU), Spain; Regional Center for Regenerative Medicine and Cell Therapy of Castilla y León, Spain.

This review focuses on four new product categories of food supplements: pre-workout, fat burner/thermogenic, brain/cognitive booster, and hormone/testosterone booster. Many food supplements have been shown to be contaminated with unauthorized substances. In some cases, the ingredients in the new categories of dietary supplements were medicinal products or new synthetic compounds added without performing clinical trials. Some of the new ingredients in dietary supplements are plant materials that are registered in the pharmacopoeia as herbal medicines. In other cases, dietary supplements may contain plant materials that have no history of human use and are often used as materials to 'camouflage' stimulants. In the European Union, new ingredients of dietary supplements, according to European Food Safety Authority or unauthorized novel food. Furthermore, selected ingredients in dietary supplements may be prohibited in sports and are recognized as doping agents by World Anti-Doping Agency.

Abstract:: Conventional delivery of antidiabetic drugs faces many problems like poor absorption, low bioavailability, and drug degradation. Nanoemulsion is a unique drug technology, which is very suitable for the delivery of antidiabetic drugs. In recent years, the flaws of delivering anti-hypoglycaemic drugs have been overcome by choosing nanoemulsion drug technology. They are thermodynamically stable and also provide the therapeutic agent for a longer duration. Generally, nanoemulsions are made up of either oil-in-water or water-in-oil and the size of the droplets is from fifty to thousand nanometer. Surfactants are critical substances that are added in the manufacturing of nanoemulsions. Only the surfactants which are approved for human use can be utilized in the manufacturing of nanoemulsions. Generally, the preparation of emulsions includes mixing of the aqueous phase and organic phase and using surfactant with proper agitation. Nanoemulsions are used for antimicrobial drugs, and they are also used in the prophylaxis of cancer. Reduction in the droplet size may cause variation in the elastic and optical behaviour of nanoemulsions.

The rapid increase in the use of ethical generic pharmaceutical formulations in Japan emphasizes the importance of measures to ensure the quality of pharmaceutical distribution. This short review discusses the contributions of the Japanese Pharmacopoeia (JP) to pharmaceutical quality control. Numerous monographs have defined specifications and tests for multiple active pharmaceutical ingredients and excipients. Standardized methods of performing general tests and reference standards allow efficient, reliable evaluation of pharmaceutical quality during development processes and commercial manufacturing. Some new methods of characterizing the structure and performance of nonbiological complex drugs have been included in recent editions. An introduction to general tests and general information regarding the control of impurities in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines should significantly reduce the safety risks of pharmaceuticals.

In the late 1980s, Professor of Immunology Ana Soto accidentally discovered the presence of synthetic estrogens in her lab equipment. Her lab had designed an experiment to test the effect of estrogen on the proliferation of human breast cancer cells (MCF7). Based on previous findings, Soto and her research partner Carlos Sonnenschein believed that, contrary to popular wisdom, the introduction of estrogen would not directly induce the proliferation of the cells, but would instead interfere with a naturally occurring inhibitor in the blood. But the control setup containing positive and negative controls (used in the past without problem) was now producing odd readings: although no estrogenic compound had been introduced, the cancer cells were still proliferating. Soto and Sonnenschein methodically removed each item in the control setup that might be producing the estrogen-like result. When they discovered that the estrogenic activity leached from the plastic centrifuge tubes used to store components of the cell culture medium, they called the manufacturer to find out what could have changed. The manufacturer let them know that the constituent materials of the tubes had recently been modified in order to reduce the possibility of breakage during centrifugation but declined to reveal what specific changes had been made. So Soto’s lab turned to studying the tubes themselves. After a year of further research, they concluded that the estrogenic activity was due to the additive that had been introduced by the manufacturer—nonylphenol, an antioxidant used in numerous other applications, some of which are meant for human use (e.g., spermicide) and the synthesis of detergents. Soto and Sonnenschein’s assay is called E-SCREEN and has been enormously influential; in fact, most of the environmental estrogens discovered in the 1990s rely on it. Conducted by Gracen Brilmyer at UCLA during the Chemical Entanglements Symposium, this 2017 interview with Soto highlights her experiences of sexism in the sciences and how those experiences have shaped her thinking on language, science, and scholarship

Cardiovascular Magnetic Resonance (CMR), a non-invasive and nonionizing imaging technique, plays a major role in research and clinical cardiology. The strength of CMR lies in its high temporal resolution, superior contrast, and unique tissue characterization capabilities. Contrast agents have been used to improve sensitivity and specificity of CMR in detecting and evaluating various pathologies. Much effort has been made to develop more efficient contrast reagents to detect cardiovascular diseases at an asymptomatic stage, which has led to a plethora of products in animal studies. However, very few of the developed contrast agents are currently approved for human use. Major obstacles are high dosages, toxicity, body clearance rate and long-term immunogenicity. In this review, we critically assess recent developments in the field of the contrast agents for CMR, highlighting both benefits and current drawbacks. A clearer insight regarding the challenges facing the development of improved contrast agents may help collaborative work to enhance images contrast, decrease toxicity and accelerate their translation into clinical use.

The term quality of pharmaceutical products is frequently used in the literature interchangeably with safety and efficacy without a clear description. The lack of clarity and relevant use of these terminologies appear not only to cause confusion, but currently they also seriously hinder the development and assessment of pharmaceutical products, such as tablets and capsules. It is highly unlikely that improvements in the manufacturing practices of pharmaceuticals and their assessment, including associated regulatory standards and assessments, are possible without clearly understanding these terms and their interrelationships. The purpose of this chapter is to help explain the term product quality, in particular for tablet and capsule products, considering the underlying scientific concepts. A critical assessment of current practices along with regulatory standards and requirements for quality assessment of such products is provided, followed by suggestions for addressing the issues to facilitate improved product development and assessment.

In recent years, there is renewed interest in the study of various hallucinogens for their potential therapeutic effects. In the United States of America (USA), the abuse potential assessment of a drug is carried out as part of the general safety and efficacy evaluation of a drug. Additionally, the abuse potential assessment is taken under consideration in determining if a drug needs to be subject to controls to minimize the abuse of the drug once on the market. This assessment is conducted for all new drugs with central nervous system (CNS) activity, that are chemically or pharmacologically similar to other drugs with known abuse potential, or drugs that produce psychoactive effects predictive of abuse, such as euphoria and hallucinations. This paper describes the regulatory framework for evaluating the abuse potential of new drugs, with emphasis on hallucinogens. The paper discusses the role of the United States Food and Drug Administration (FDA) in the evaluation of the abuse potential of drugs and its role in drug control, and provides an overview of the controlled status of hallucinogens and the requirements to conduct research with Schedule I substances in the USA. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

Small and medium-sized enterprises (SMEs) are an important source of innovative medicines. Compared with their larger counterparts, they experience challenges as a result of insufficient human and financial resources that can hamper drug development and regulatory compliance. This analysis reviews the profile of major objections raised in marketing authorisation applications for medicines for human use submitted by SMEs to the European Medicines Agency (EMA) between 2011 and 2015 and their impact on the outcome of applications. It showed that SMEs experience challenges in the quality (e.g. manufacturing process validation and control and/or characterisation data of drug substance or drug product) and clinical sections of marketing authorisation applications (e.g. analysis or robustness of pivotal data or selection of submitted studies, study design issues and marginal or no clinical relevant efficacy), with deficiencies in demonstrating clinical efficacy representing the major eventual hurdles to authorisation.

Scientists suggest we are entering a new geological epoch called the Anthropocene. It is an epoch that signals an altogether more unpredictable and unstable period in Earth’s geological history compared to the state of relative Earth system stability, resilience and harmony that have hitherto prevailed in the Holocene. The Anthropocene’s imagery reveals the socio-ecological impacts occasioned by the ever-expanding project of human development the world over, including humans’ ability to change biogeochemical cycles; unprecedented species loss and species extinction; appropriation of non-human resources for exclusive human use; wide-spread land use conversion; alteration of evolutionary processes and outcomes; and changing the climate through the release of massive amounts of carbon into the atmosphere.

Purpose As part of the approval process, regulatory authorities often require postauthorization studies that involve patient registries; it is unknown, however, whether such registry studies are adequately completed. We investigated whether registry studies for new drugs were performed as agreed at time of approval. Methods This study reviewed protocols and follow-up reports for 73 registry studies that were proposed for 43 drugs approved by the Committee for Medicinal Products for Human Use in Europe in the period 2007 to 2010. Results The data lock point of January 1, 2016, was taken to allow a 5-year follow-up period for each drug after approval. At that time, 2 studies (3%) in registries had been finalized, 19 registries (26%) had not enrolled any patients, and 52 studies (71%) were ongoing. The median enrollment was 31% (interquartile range [IQR], 6–104) of the required number of patients for 41 registry studies that had a predefined sample size, 30% (IQR, 2–101) for nonimposed registries, and 61% (IQR, 18–144) for imposed registries. Implications Enrollment of patients into postapproval registries is poor, although the results for imposed registries seem better. Currently, registries only have a limited impact on resolving gaps in the knowledge of a drug’s benefits and risks at time of marketing authorization.

Listening has a fundamental function of life including the preschoolers. Human use more time of listening activities for about 50%, while the rest 50% are used for speaking, reading, and writing. Listening activities should begin early for children in all situations. But,it is not in line with the listening ability of group A children in Kindergarten SitiKhodijahPucukLamongan. They have some difficulties when being asked by the teacher to listen to information given. Listening is a tedious activity for children, especially preschoolers. It is necessary to have similar material and interesting way to practice listening skills in preschoolers.According to the problem, the research questions are formulated as follows (1) How the application of storytelling method to improve the listening ability of children group A in Kindergarten SitiKhodijahPucukLamongan?, (2) How to improve the listening ability through the storytelling method of group Achildren in Kindergarten SitiKhodijahPucukLamongan? The purpose of this study are (1) To find out how the application of storytelling method to improve the listening ability in children group A in Kindergarten SitiKhodijahPucukLamongan, (2) To know the improvement of listening ability through storytelling method of group A in Kindergarten SitiKhodijahPucukLamongan.This study uses a Classroom Action Research in which there are actions of teachers in two cycles. On the first cyclethe percentage of children who are able based on criteria of Exponential Developing Criteria (BSH) reaches 33.33% while in the second cyclethe percentage of children who are able increases to 83.33%. Based on the result of this study, it can be concluded that the method of storytelling can improve the listening ability of children group A in Kindergarten SitiKhodijahPucukLamongan.

Hepatoprotectors are one of the important categories of drugs prescribed to patients with acute and severe conditions accompanied by impairment of the liver function. In view of the importance of this problem, at the end of 2017 the Government of the Russian Federation approved a new list of vital and essential medicinal products for human use for 2018, which included the original drug developed by the Russian researchers - the infusion hepatoprotector Remaxol®.

Intense human use and high construction density in coastal areas are stressors to sandy beaches. Pollution by marine debris is a major problem on beaches worldwide. This study pioneered an assessment of marine debris characterization over time on beaches with different levels of access. In two periods and seasons, marine debris was sampled on nine sandy beaches of Rio de Janeiro, grouped by levels of access. The general marine debris density has decreased over time, accompanied by an improvement in public cleaning mechanisms. The most important predictor for the majority of marine debris items is related to accessibility; beaches with restricted access showed a reduction in the abundance of most items. High marine debris densities, even on beaches with restricted access, showed that all evaluated beaches can be sinks for marine debris circulating in marine waters. Beach cleaning strategy improvements will be inefficient unless integrated marine debris management is implemented.

Introduction: In 2019, the Italian Supreme Court established that hemp cannot be commercialized for human use, when the “psychotropic effect” of the product or its “offensiveness” can be demonstrated. The aim of the present study is to assess Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) blood concentrations after smoking cannabis with a low percentage of Δ9-THC, also referred as “light cannabis”, and its effects on young adults’ vigilance, cognitive and motor skills. Materials and methods: Eighteen young adults consumed three light cannabis cigarettes containing 400 mg of inflorescences each, with a percentage of 0.41% of Δ9-THC and of 12.41% of CBD. Blood samples were collected before the experiment (t0), after each light cannabis cigarette (t1→t3), 60 (t4) and 120 (t5) minutes after the beginning of the experiment. Five performance tasks and a subjective scale were employed for measuring cognitive and psychomotor performances the day before the experiment (TT0) and after the third cigarette (TT1). Results: Mean (SD) concentrations (ng/ml) were 1.0 (0.8) in t1, 1.2 (0.9) in t2, 1.0 (0.8) in t3, 0.6 (0.4) in t4 and 0.3 (0.3) in t5 for Δ9-THC; 10.5 (10.3) in t1, 10.3 (13.2) in t2, 15.1 (14.8) in t3, 9.9 (9.2) in t4 and 5.7 (5.7) in t5 for CBD. No significant differences were observed between TT0 and TT1 for all performed psychomotor performance task. None of the subjects declared to feel “high” after the experiment. Discussion: All study participants reported that a higher number of cigarettes, corresponding in this study to 1200 mg of herbal product, could hardly be consumed by smoking in a recreational setting. Δ9-THC and CBD concentrations showed a high inter-subject variability, and the average concentrations were lower than those previously reported. Toxicological results showed a decrease of Δ9-THC and CBD after the third light cannabis cigarette, and a Δ9-THC /CBD ratio always

Nowadays, an exciting challenge in the drug chemistry and technology research is represented by the development of methods aimed to protect molecular integrity and therapeutic activity of drugs from effects of light. The photostability characterization is ruled by ICH (The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use), which releases details throughout basic protocols of stability tests to be performed on new medicinal products for human use. The definition of suitable photoprotective systems is fundamental for pharmaceutical manufacturing and for human healthy as well, since light exposure may affect either drugs or drug formulations giving rise even to allergenic or mutagenic by-products. Here, we summarize and discuss the recent studies on the formulation of photosensitive drugs into supramolecular systems, capable of entrapping the molecules in a hollow of their structure by weak noncovalent interactions and protecting them from light. The best known supramolecular matrices belong to the ‘auto-assembled’ structures, of which liposomes are the most representative, and the ‘host-guest’ systems, of which cyclodextrins represent the most common ‘host’ counterpart. A relevant number of papers concerning the use of both liposomes and cyclodextrins as photoprotection systems for drugs has been published over the last 20 years, demonstrating that this topic captures interest in an increasing number of researchers.

The aim of this study was to identify trends in deficiencies raised during the EU evaluation of the quality part of dossiers for marketing authorisation applications of biosimilar medicinal products. All adopted day 120 list of questions on the quality module of 22 marketing authorisation applications for biosimilars submitted to the European Medicines Agency and concluded by the end of October 2015 was analysed. Frequencies of common deficiencies identified were calculated and summarised descriptions included. Frequencies and trends on quality deficiencies were recorded and presented for 22 biosimilar applications. Thirty-two 'major objections' for 9 products were identified from 14 marketing authorisation applications with 15 raised for drug substance and 17 for drug product. In addition, 547 'other concerns' for drug substance and 495 for drug product were also adopted. The frequencies and trends of the identified deficiencies together with their impact were discussed from a regulatory perspective and how these impact key manufacturing processes and key materials used in the production of biosimilars. This study provides an insight to the regulatory challenges prospective companies need to consider when developing biosimilars; it also helps elucidate common pitfalls in the development and production of biosimilars and in the submission of dossiers for their marketing authorisations. The results are expected to be of interest to pharmaceutical companies but also to regulators to obtain consistent information on medicinal products based on transparent rules safeguarding the necessary pharmaceutical quality of medicinal products.

In 2015, the International Agency for Research on Cancer of the World Health Organisation published a monograph stating that glyphosate, the active ingredient in Roundup, Monsanto’s leading herbicide, was ‘probably carcinogenic to humans’. Shortly after this, the European Food Safety Authority re-assessed glyphosate’s licence for use in the European Union, and deemed it to be safe for human use. Both of these expert advisory bodies faced condemnation and accusations of political bias as a result of these assessments. Employing Jasanoff’s ‘three-body problem’, this article examines the conflicting conclusions of the International Agency for Research on Cancer and the European Food Safety Authority, exploring what the contested assessments of glyphosate reveal about the entangled relationship between scientific expertise and law-making.

The significance of historic places often depends on their use by people. The Anderson Ferry, an historic river crossing in the Eastern United States, is an extreme example; arguably the on-going human use of the crossing is its only significant characteristic. The National Mall in Washington DC also exemplifies the importance of on-going human use. However, such places are often managed as though on-going human use were irrelevant and even damaging to their historic significance; again the National Mall offers a case in point. At least part of this disconnect may result from the documentation instruments used in recognising and designating such places as historic; these instruments tend to focus attention on architectural details and past events, at the expense of contemporary roles and values. We suggest that the forms and guidelines used in historic place designation should be rethought with an eye toward recognising that service as a living part of community life and development is an importan...

The world needs to know the facts as to how the FDA “protects” the public health by assuring the safety, effectiveness, and security of human drugs and biological products for human use. Recent uproar has surfaced over the FDA’s approval process on the unproven Duchenne Muscular Dystrophy (DMD) drug, Exondys 51 (Sarepta Therapeutics, Cambridge, MA, USA), but what many people do not know are the unlawful events that occurred nearly two decades ago on a proven and promising treatment for DMD.

Among the several new provisions foreseen by the EU Regulation (R) 2014/536 on Clinical Trials (CTs) repealing Directive (D) 2001/20/EC, this article focuses on the identification of possible critical points leading to potential incongruences regarding Good Clinical Practice (GCP). EU D foresees the obligation to be in compliance with GCP detailed guidelines, while the R foresees the obligation to be in compliance only with the GCP principles. Many of the GCP detailed aspects have been transposed in the R and the R provides to be in compliance with GCP quality standards. Nevertheless, other GCP aspects, which have direct or indirect ethical implication in CTs, will not be mandatory in the EU.

Background The complex regulatory framework for the quality of herbal medicinal products, in particular with regard to potential contaminants, consists of legal provisions including Pharmacopoeia requirements, relating to limits as well as in most cases to methods for determination. Objective This review intends to provide an overview on the legal requirements for testing potential contaminants in herbal drugs used for the production of herbal medicinal products. Methodology The following issues are described and discussed: For the assessment of pesticide residues, Chapter 2.8.13 of the European Pharmacopoeia and Regulation (EC) 396/2005 applies, for heavy metals the general Pharmacopoeia monograph as well as the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q3D guideline on elemental impurities. The Pharmacopoeia also includes limits and acceptance criteria for microbiological purity and aflatoxins, respectively. Polycyclic aromatic hydrocarbons are mentioned in Regulation (EC) 1881/2006 for food as well as in a Reflection Paper on herbal medicinal products. For several years, a potential contamination with pyrrolizidine alkaloids was discussed which led to measures being imposed on industry and health authorities. Results Various examples demonstrate that the evaluation of data from daily analytical practice is extremely useful to gain an overview on the occurrence of residues and/or contaminants in herbal drugs and herbal preparations. Such evaluations might assist manufacturers in their individual risk assessment and the definition of their testing strategies and contribute to guarantee the quality and safety of the marketed products. Conclusion Annual data evaluations demonstrate that a remarkable decrease of the pyrrolizidine alkaloid content burden in herbal drugs and extracts used for the production of herbal medicinal products has been achieved over the past few years. However, it has also become clear that this issue cannot be completely solved in the near future.

Applicants for marketing authorisation for human medicinal products in the European Union must submit an environmental risk assessment which is assessed by assessors from the national competent authorities. The EMA guideline on the environmental risk assessment of medicinal products for human use came into effect on 1 December 2006. After 12 years’ experience with the guideline, the EMA has released for public consultation a draft revision of the guideline. The revision proposes significant substantive and structural changes to the guideline. The major changes proposed in the revision are outlined together with the rationale for the changes and the expected impact on stakeholders.

In the contemporary world, scarcity of clean drinking water has become a matter of grave concern, as more than one billion people lack access to it globally. Per day, millions of tons of wastewater from industries are being released into the water bodies, making the water unhealthy for aquatic life as well as for human use. Thus, there is an urgent need for the development of highly efficient technologies that can generate of safe drinking water by recycling industrial wastewater. Recent scientific advancements have proved that nanotechnology can be highly instrumental in providing effective solutions for this imminent issue of water crisis. Based on the unique and superior properties of the nanostructured materials, highly efficient water treatment technologies have been developed. This chapter casts light upon different nanotechnology-based approaches for the wastewater treatment and their underlying scientific principles. A structured discussion on carbon/ polymer/metal/zeolite based adsorbants and membrane based nanofilteration techniques has been presented. Besides, a detailed review of the role of nanomaterials in antimicrobial control and extensive usage of heterogeneous photocatalysts in wastewater treatment is also discussed. In the end, the sensing and monitoring of pathogens and trace contaminants in wastewater followed by emerging challenges, future of nanotechnology and the potential hazards of using nanomaterials are thoroughly discussed.

Bilingual terminologies are important resources for natural language processing as well as for human use. The automatic acquisition of bilingual terminologies is mostly based on bilingual corpora. However, monolingual corpora could also be a good source for extracting bilingual terms. In fact, as English is used for international publications, we often find English words together with their translation in monolingual documents written in other languages. In this paper, we propose a rule-based approach for automatically extracting English-Vietnamese bilingual terminology from Vietnamese monolingual documents. Experiments on a medical corpus and on Wikipedia documents show that the extracted bilingual term candidates are of high quality.

This paper takes the relationship between humans and the ocean as the object of analysis, from the perspective of human use of the ocean, four era theories on the relationship between humans and the ocean are proposed, i.e., in the first era, the ocean is a geographic barrier for mankind; in the second era, the ocean is a road for human transportation; in the third era, the ocean is a granary for mankind; in the fourth era, the ocean is a treasure house of mankind’s natural resources. Viewing from the last three eras, we can know that the ocean plays an important role in promoting the creation, production, and accumulation of human wealth. This paper argues the four-era theory of the relationship between humans and the ocean, also get the following conclusion: every era has the most significant feature of this era. This most significant feature function is the most important, largest, latest, and trendy contribution of the oceans to humans in this era; the four-era theory of the relationship between humans and the ocean also shows the continuous improvement process of human influence and utilization of the oceans; the continuous improvement of human influence and utilization of the ocean is realized by improvement of science and technology; the ability of humans to influence and utilize the oceans in the second era surpassed the first era is due to advances in shipbuilding technology and navigation technology; humans’ ability to influence and utilize the ocean in the third era surpassed the second era due to advances in biotechnology; and the ability of humans to influence and utilize the ocean in the fourth era surpassed the third era due to the advancement and application of all-round science and technology; Historically, once a country has maritime hegemony, this country would become wealthy, powerful, and the leaders of maritime civilization.

Introduction Hormonal contraception with depot medroxyprogesterone acetate (DMPA) may increase HIV acquisition risk, but observational human studies are inconclusive, and animal models can help investigate this risk. In this study, we test the impact of a low DMPA dose, designed to resemble human contraceptive use, on Simian-Human Immunodeficiency Virus (SHIV) acquisition risk in pigtail macaques (Macaca nemestrina). Methods Macaques metabolize DMPA faster than humans. We previously identified a per-weight DMPA dose and administration frequency that achieves long-lasting suppression of ovulation in macaques. Eight macaques were given 1.5-mg/kg DMPA monthly, whereas 11 were untreated controls. For comparison, women receive 150 mg (approximately 2 mg/kg) every 3 months. We exposed monkeys to 20 suboptimal SHIV challenges, designed to slowly infect half of controls and allow increased infection in the DMPA group. Results It took a median 5.5 viral challenges to infect DMPA-treated macaques and 9 challenges for controls (P = 0.27; exact conditional logistic regression). The exact odds ratio was 2.2 (CI: 0.6 to 8.3). Ovulation was suppressed, and the vaginal epithelium was thinned after DMPA treatment in all animals (mean, 30 and 219 mm in DMPA-treated and control macaques, respectively, P = 0.03, t test using the Satterthwaite degrees-of-freedom approximation). Conclusions SHIV infections in DMPA-treated macaques were 2.2 times those of controls, but this was not statistically significant. The result is remarkably similar to studies of human DMPA use, which have shown HIV risk increases of a similar magnitude and of variable significance. Taken together with previous studies of higher DMPA doses in macaques, the results suggest a dose-dependent effect of DMPA on Simian Immunodeficiency Virus (SIV) or SHIV acquisition.

Parenteral naloxone has been approved to treat opiate overdose for over 4 decades. Intranasal naloxone, administered "off label" using improvised devices, has been widely used by both first responders and the lay public to treat overdose. However, these improvised devices require training for effective use, and the recommended volumes (2 to 4 mL) exceed those considered optimum for intranasal administration. The present study compared the pharmacokinetic properties of intranasal naloxone (2 to 8 mg) delivered in low volumes (0.1 to 0.2 mL) using an Aptar Unit-Dose device to an approved (0.4 mg) intramuscular dose. A parallel study assessed the ease of use of this device in a simulated overdose situation. All doses of intranasal naloxone resulted in plasma concentrations and areas under the curve greater than those observed following the intramuscular dose; the time to reach maximum plasma concentrations was not different following intranasal and intramuscular administration. Plasma concentrations of naloxone were dose proportional between 2 and 8 mg and independent of whether drug was administered to 1 or both nostrils. In a study using individuals representative of the general population, >90% were able to perform both critical tasks (inserting nozzle into a nostril and pressing plunger) needed to deliver a simulated dose of naloxone without prior training. Based on both pharmacokinetic and human use studies, a 4-mg dose delivered in a single device (0.1 mL) was selected as the final product. This product can be used by first responders and the lay public, providing an important and potentially life-saving intervention for victims of an opioid overdose.