Recent developments and applications of ambient mass spectrometry imaging in pharmaceutical research: an overview.

The application of ambient mass spectrometry imaging "MSI" is expanding in the areas of fundamental research on drug delivery and multiple phases of the process of identifying and developing drugs. Precise monitoring of a drug's pharmacological workflows, such as intake, distribution, metabolism, and discharge, is made easier by MSI's ability to determine the concentrations of the initiating drug and its metabolites across dosed samples without losing spatial data. Lipids, glycans, and proteins are just a few of the many phenotypes that MSI may be used to concurrently examine. Each of these substances has a particular distribution pattern and biological function throughout the body. MSI offers the perfect analytical tool for examining a drug's pharmacological features, especially in vitro and in vivo effectiveness, security, probable toxic effects, and putative molecular pathways, because of its high responsiveness in chemical and physical environments. The utilization of MSI in the field of pharmacy has further extended from the traditional tissue examination to the early stages of drug discovery and development, including examining the structure-function connection, high-throughput capabilities in vitro examination, and ex vivo research on individual cells or tumor spheroids. Additionally, an enormous array of endogenous substances that may function as tissue diagnostics can be scanned simultaneously, giving the specimen a highly thorough characterization. Ambient MSI techniques are soft enough to allow for easy examination of the native sample to gather data on exterior chemical compositions. This paper provides a scientific and methodological overview of ambient MSI utilization in research on pharmaceuticals.

Current Pharmaceutical Research on the Significant Pharmacophore Mannich bases in Drug Design.

A multitude of distinct Mannich bases have been synthesized and evaluated as potential therapeutics for a wide variety of diseases and medical conditions, either in the form of prodrugs or as molecules that trigger a biological response from specific targets. The Mannich reaction has been utilized to enhance the biological activity of numerous compounds, resulting in notable progress in various areas such as anticonvulsant, antimalarial, anticancer, anti-inflammatory, antiproliferative, antibacterial, antimicrobial, antitubercular, antiprotozoal, topoisomerases I and II inhibition, α-glucosidase inhibition, carbonic anhydrase inhibition, as well as research related to anti-Alzheimer's disease and anti-Parkinson's disease. Bioactive semisynthetic Mannich bases derived from natural compounds such as chalcone, curcumin, and thymol have also been identified. Pharmaceutical compounds characterized by low solubility may encounter challenges related to their oral bioavailability, half-life, distribution within tissues, rapid metabolism, toxicity, and various other relevant variables. Mannich bases have the ability to undergo protonation under physiological circumstances, facilitating interactions between ligands and receptors, and enhancing their solubility in water. The experimental findings indicate that the solubility of Mannich base prodrugs is higher compared to that of the parent compound. The use of the multicomponent Mannich reaction has been established as a valuable synthetic methodology for the construction of multifunctional compounds through the application of diverse synthetic strategies under varying reaction conditions. The continuous investigation of synthetic techniques for Mannich reactions involves several approaches, such as employing protocols in aquatic environments, utilizing catalysts that are both biodegradable and reusable, exploring the use of ionic liquids, investigating solvent-free and/or catalyst-free media, and exploring reaction conditions involving microwave and ultrasound irradiation. Consequently, the Mannich reaction has emerged as a powerful technique in the field of medicinal chemistry. It is utilized for the creation of new chemical compounds that possess diverse and attractive biologic features. Additionally, this reaction is employed to alter the physicochemical properties of a potential drug candidate, thereby influencing its bioavailability, efficacy, and pharmacological activity. Due to their favorable bioactivities and synthesis techniques, Mannich bases remain a subject of ongoing attention in the field of medicinal/pharmaceutical chemistry.

Surgical management of peritoneal metastasis: Opportunities for pharmaceutical research.

Cytoreductive surgery (CRS) has emerged as a survival-extending treatment of peritoneal metastasis (PM); recent advances include using intraperitoneal chemotherapy (IPC) at normothermic or hyperthermic temperatures, or under pressure (CRS + IPC). Clinical CRS + IPC research has established its highly variable efficacy and suggested tumor size, tumor locations and presence of ascites as potential determinants. On the other hand, there is limited knowledge on the effects of pharmaceutical properties on treatment outcomes. The present study investigated the inter-subject variability of paclitaxel binding to proteins in patient ascites because some PM patients show accumulation of ascites and because activity and transport of highly protein-bound drugs such as paclitaxel are affected by protein binding. Ascites samples were collected from 26 patients and investigated for their protein contents using LC/MS/MS proteomics analysis and for the concentrations of total proteins and two major paclitaxel-binding proteins (human serum albumin or HSA and α-1-acid glycoprotein or AAG). The association constants of paclitaxel to HSA and AAG and the extent of protein binding of paclitaxel in patient ascites were studied using equilibrium dialysis. Proteomic analysis of four randomly selected samples revealed 288 proteins, >90% of which are also present in human plasma. Between 72% - 94% of paclitaxel was bound to proteins in patient ascites. The concentrations of HSA and AAG in ascites showed substantial inter-subject variations, ranging from 14.7 - 46.3 mg/mL and 0.13-2.56 mg/mL, respectively. The respective paclitaxel association constants to commercially available HSA and AAG were âˆ¼ 3.5 and âˆ¼ 120 mM. Calculation using these constants and the HSA and AAG concentrations in individual patient ascites indicated that these two proteins accounted for >85% of the total protein-binding of paclitaxel in ascites. The extensive drug binding to ascites proteins, by reducing the pharmacologically active free fraction, may lead to the diminished CRS efficacy in PM patients with ascites. Clinical advances in CRS + IPC have outpaced current knowledge of pharmaceutical properties in this setting. IPC, as a locally acting therapy, is subjected to processes different from those governing systemic treatments. This study, to our knowledge, is the first to illustrate the implications of drug properties in the CRS + IPC efficacy against PM. While drugs are now an integral part of PM patient management, there is limited pharmaceutical research in this treatment setting (e.g., effects of hyperthermia or pressure on drug transport or release from delivery systems, pharmacokinetics, pharmacodynamics). Hence, CRS + IPC of PM represents an area where additional pharmaceutical research can assist further development and optimization.

Mapping community pharmacy services in Brazil: a scoping review

Abstract The delivery of clinical pharmacy services has been growing in Brazilian community pharmacies, and it is necessary to have a comprehensive understanding of the topic. This scoping review aimed to provide an overview of Brazilian studies about clinical pharmacy services in community pharmacies. Original research articles, with no restriction of time, study design, or patient's health condition, were included. Searches were conducted in PubMed, Scopus, Web of Science, Scielo, and Lilacs. Two reviewers conducted the screening, full-text reading, and data extraction independently. ROB and ROBINS-I were used for the assessment of quality. Charts and tables were built to summarise the data. Seventy-two articles were included. A diversity of study designs, number of participants, terms used, and outcomes was found. São Paulo and Sergipe States had the highest number of studies (n=10). Pharmacists' interventions were not fully reported in 65% of studies, and most studies presented an unclear risk of bias. Studies were very diverse, impairing the comparisons between the results and hindering their reproducibility. This review suggests using guidelines and checklists for better structuration of pharmacists' interventions as well as reporting results and measuring fidelity in future research.

Research and Education Needs for Complex Generics.

Complex generics are generic versions of drug products that generally have complex active ingredients, complex formulations, complex routes of delivery, complex dosage forms, are complex drug-device combination products, or have other characteristics that can make it complex to demonstrate bioequivalence or to develop as generics. These complex products (i.e. complex generics) are an important element of the United States (U.S.) Food and Drug Administration's (FDA's) Generic Drug User Fee Amendments (GDUFA) II Commitment Letter. The Center for Research on Complex Generics (CRCG) was formed by a grant from the FDA to address challenges associated with the development of complex generics. To understand these challenges, the CRCG conducted a "Survey of Scientific Challenges in the Development of Complex Generics". The three main areas of questioning were directed toward which (types of) complex products, which methods of analysis to support a demonstration of bioequivalence, and which educational topics the CRCG should prioritize. The survey was open to the public on a website maintained by the CRCG. Regarding complex products, the top three selections were complex injectables, formulations, and nanomaterials; drug-device combination products; and inhalation and nasal products. Regarding methods of analysis, the top three selections were locally-acting physiologically-based pharmacokinetic modeling; oral absorption models and bioequivalence; and data analytics and machine learning. Regarding educational topics, the top three selections were complex injectables, formulations, and nanomaterials; drug-device combination products; and data analytics, including quantitative methods and modeling & simulation. These survey results will help prioritize the CRCG's initial research and educational initiatives.

France's competitiveness in global pharmaceutical research: The situation is improving.

AIMS: The French pharmaceutical companies' association (LEEM) biennially carries out a study on the attractiveness of France in pharmaceutical clinical research. This study aims to measure France's global competitiveness for international clinical trials (CT) and assess its strengths and areas of excellence. METHODS: A descriptive and comparative analysis was conducted using the data from both the ClinicalTrials.gov registry for the 2015-2019 period and those reported in a national web-based database (OSCAR) involving the major pharmaceutical companies operating in France in 2018-2019. OSCAR allows to describe the administrative authorization and starting process for all drug trials conducted in France. RESULTS: Among 8607 worldwide drug trials initiated in 2019, 34.3% (n=2.954) were funded exclusively by pharmaceutical companies (52.1% in France). On average, France was involved in 10.5% of all global industrial CTs launched over 2018-2019, still ranking in the 4th position among European countries. Early-phase trials represented 17.3% of trials conducted by the drug companies in France, versus 25% in Germany and 29% in United Kingdom. Oncology remains an area of excellence in France with 18.7% of all worldwide CTs conducted in this therapeutic area over the study period involving at least some French centres, ranking France 2nd among European countries. The median of total deadline before the first patient inclusion of 204 days in 2018-2019 with no marked improvement as compared to 2016-2017 period. However, the delay getting initial trial authorization was slightly reduced and an overall deadline of 167 days was observed for CTs entered the pilot phase initiated recently by the European regulation. CONCLUSION: After ten difficult years, areas of excellence, such as oncology and rare diseases and more recently, the outstanding mobilization for the COVID-19 research, have enabled France to maintain its pharmaceutical research. Furthermore, a set of additional decisions would strengthen this position in the next years.

Oral biopharmaceutics tools: recent progress from partnership through the Pharmaceutical Education and Research with Regulatory Links collaboration.

OBJECTIVES: To summarise key contributions of the Pharmaceutical Education and Research with Regulatory Links (PEARRL) project (2016-2020) to the optimisation of existing and the development of new biopharmaceutics tools for evaluating the in vivo performance of oral drug products during the development of new drugs and at the regulatory level. KEY FINDINGS: Optimised biopharmaceutics tools: Based on new clinical data, the composition of biorelevant media for simulating the fed state conditions in the stomach was simplified. Strategies on how to incorporate biorelevant in vitro data of bio-enabling drug products into physiologically based pharmacokinetic (PBPK) modelling were proposed. Novel in vitro biopharmaceutics tools: Small-scale two-stage biphasic dissolution and dissolution-permeation setups were developed to facilitate understanding of the supersaturation effects and precipitation risks of orally administered drugs. A porcine fasted state simulated intestinal fluid was developed to improve predictions and interpretation of preclinical results using in vitro dissolution studies. Based on new clinical data, recommendations on the design of in vitro methodologies for evaluating the GI drug transfer process in the fed state were suggested. The optimized design of in vivo studies for investigating food effects: A food effect study protocol in the pig model was established which successfully predicted the food-dependent bioavailability of two model compounds. The effect of simulated infant fed state conditions in healthy adults on the oral absorption of model drugs was evaluated versus the fasted state and the fed state conditions, as defined by regulatory agencies for adults. Using PBPK modelling, the extrapolated fasted and infant fed conditions data appeared to be more useful to describe early drug exposure in infants, while extrapolation of data collected under fed state conditions, as defined by regulators for adults, failed to capture in vivo infant drug absorption. SUMMARY: Substantial progress has been made in developing an advanced suite of biopharmaceutics tools for streamlining drug formulation screening and supporting regulatory applications. These advances in biopharmaceutics were achieved through networking opportunities and research collaborations provided under the H2020 funded PEARRL project.

Estudo da eficácia de encapsulação da Cinarizina em cubossomos não-iônicos: caracterização estrutural e citotóxica / Study of the encapsulation efficacy of Cinnarizine in non-ionic cubosomes: structural and cytotoxic characterization

Os cubossomos são partículas nanoestruturadas em forma de bicamada lipídica, bicontínuas e altamente curvadas, as quais devem ser estabilizadas por um polímero não-iônico, neste caso o Pluronic® F-127. Podem ser compostos por alguns tipos de lipídios específicos que possuem a capacidade de se auto associar em estruturas cúbicas quando estão em excesso de água, como o fitantriol (PHY) e a monoleína (GMO). Devido a sua estrutura única, cubossomos possuem um grande potencial para serem considerados como sistemas drug delivery. Os sistemas drug delivery são amplamente utilizados na pesquisa farmacêutica e em contextos clínicos para aumentar a eficácia de compostos utilizados para diagnóstico e de fármacos. No caso da cinarizina (CNZ), fármaco já aprovado para o tratamento de náuseas, vômitos e vertigens causadas pela doença de Ménière, existem inúmeros efeitos colaterais associados a sua baixa solubilidade. Desta forma, a encapsulação em cubossomos se torna uma abordagem promissora para resolver os problemas de atividade farmacológica relacionados ao fármaco. Neste trabalho, realizamos uma caracterização biofísica da interação da CNZ em cubossomos (contendo PHY ou myverol, MYV, sendo este composto por 80% de GMO). As técnicas biofísicas utilizadas foram: espalhamento de raios-X em baixos ângulos (SAXS), espalhamento dinâmico de luz (DLS), microscopia eletrônica de transmissão (TEM), crio microscopia eletrônica de transmissão (Crio-TEM), análise de rastreamento de nanopartículas (NTA) e potencial zeta. A cromatografia líquida de alta eficiência (HPLC) foi realizada para verificar a porcentagem de eficiência de encapsulação (%EE) da CNZ nos cubossomos, enquanto que a citotoxicidade foi avaliada em eritrócitos através da análise da atividade hemolítica. Inicialmente, a influência de diferentes solventes (acetona, clorofórmio, etanol e octano) nas propriedades estruturais de cubossomos de PHY foi investigada, a fim de se minimizar os efeitos do solvente utilizados para a encapsulação da CNZ. Para amostras com acetona, descobriu-se que apenas altas concentrações tiveram influência na estrutura cristalográfica das nanopartículas, sendo o resultado foi totalmente reversível após 24h. O etanol fez com que o parâmetro de rede aumentasse de 10-15%. O clorofórmio e o octano tiveram efeitos diferentes sobre cubossomos de PHY em comparação com a acetona e o etanol; ambos induziram uma transição cúbico-hexagonal-micelar. Posteriormente, constatamos que as nanopartículas de PHY e MYV apresentaram diferentes estruturas cristalográficas, sendo elas Pn3m e Im3m, respectivamente. Devido a problemas com a baixa solubilidade de CNZ em PHY os estudos para esse lipídio foram suspensos. Nos testes para cubossomos de MYV ao incorporar a CNZ foi observado uma alteração da estrutura cúbica de Im3m para Pn3m e os valores dos parâmetros de rede se alteraram de acordo com a estrutura cristalina encontrada, porém os valores não apresentaram diferenças significativas de tamanho quando se trata da mesma estrutura, sugerindo que a CNZ não interferiu no parâmetro de rede. Os tamanhos das nanopartículas apresentaram uma população monodispersa com ~200 nm. DLS mostrou uma interferência da CNZ no tamanho dos cubossomos, variando de forma diretamente proporcional a concentração de CNZ na amostra, enquanto as técnicas de NTA e microscopia apresentaram nanopartículas de tamanhos bastante variados, mas independente da interferência da CNZ. A encapsulação de CNZ também foi dosada por HLPC em cubossomos de MYV, obtendo um limite superior de 0,6 mg/mL. A atividade citotóxica dos cubossomos foi testada em eritrócitos, revelando uma taxa de hemólise bastante inferior em cubossomos com CNZ em relação a cubossomos puros. Acreditamos que os cubossomos podem sim ser utilizados como sistemas carreadores de CNZ

Cubosomes are nanostructured particles in the form of a lipid bilayer, bicontinuous and highly curved, which must be stabilized by a non-ionic polymer, in this case Pluronic® F-127. They can be composed of some types of specific lipids that have the ability to self-associate in cubic structures when they are in excess of water, such as phytantriol (PHY) and monolein (GMO). Due to their unique structure, cubosomes have a great potential to be considered as drug delivery systems. Drug delivery systems are widely used in pharmaceutical research and clinical settings to increase the efficacy of compounds used for diagnostics and drugs. In the case of cinnarizine (CNZ), a drug already approved for the treatment of nausea, vomiting and vertigo caused by Ménière's disease, there are numerous side effects associated with its low solubility. Thus, cubosomal encapsulation becomes a promising approach to solve drug-related problems of pharmacological activity. In this work, we performed a biophysical characterization of the CNZ interaction in cubosomes (containing PHY or myverol, MYV, which is composed of 80% GMO). The biophysical techniques used were: low angle X-ray scattering (SAXS), dynamic light scattering (DLS), transmission electron microscopy (TEM), cryo transmission electron microscopy (Crio-TEM), nanoparticle tracking analysis (NTA) and zeta potential. High performance liquid chromatography (HPLC) was performed to verify the percentage of encapsulation efficiency (%EE) of CNZ in cubosomes, while cytotoxicity was evaluated in erythrocytes by analyzing the hemolytic activity. Initially, the influence of different solvents (acetone, chloroform, ethanol and octane) on the structural properties of PHY cubosomes was investigated in order to minimize the effects of the solvent used for the encapsulation of CNZ. For samples with acetone, it was found that only high concentrations had an influence on the crystallographic structure of the nanoparticles, with the result being fully reversible after 24h. Ethanol caused the network parameter to increase by 10-15%. Chloroform and octane had different effects on PHY cubosomes compared to acetone and ethanol; both induced a cubic-hexagonal-micellar transition. Later, we found that PHY and MYV nanoparticles presented different crystallographic structures, being Pn3m and Im3m, respectively. Due to problems with the low solubility of CNZ in PHY, studies for this lipid were suspended. In the tests for MYV cubosomes when incorporating CNZ, a change in the cubic structure from Im3m to Pn3m was observed and t he lattice parameters changed according to the crystal structure found, but the differences observed were not significant when it comes to the same structure, suggesting that the CNZ did not interfere with the network parameter. The nanoparticle sizes showed a monodisperse population with ~200 nm. DLS showed an interference of CNZ in the size of the cubosomes, varying directly proportionally to the concentration of CNZ in the sample, while NTA and microscopy techniques showed nanoparticles of widely varying sizes, but independent of CNZ interference. CNZ encapsulation was also dosed by HLPC in MYV cubosomes, obtaining an upper limit of 0.6 mg/ml. The cytotoxic activity of cubosomes was tested in erythrocytes, revealing a much lower rate of hemolysis in cubosomes with CNZ compared to pure cubosomes. We believe that cubosomes can indeed be used as CNZ carrier systems

Estimated Research and Development Investment Needed to Bring a New Medicine to Market, 2009-2018.

IMPORTANCE: The mean cost of developing a new drug has been the subject of debate, with recent estimates ranging from $314 million to $2.8 billion. OBJECTIVE: To estimate the research and development investment required to bring a new therapeutic agent to market, using publicly available data. DESIGN AND SETTING: Data were analyzed on new therapeutic agents approved by the US Food and Drug Administration (FDA) between 2009 and 2018 to estimate the research and development expenditure required to bring a new medicine to market. Data were accessed from the US Securities and Exchange Commission, Drugs@FDA database, and ClinicalTrials.gov, alongside published data on clinical trial success rates. EXPOSURES: Conduct of preclinical and clinical studies of new therapeutic agents. MAIN OUTCOMES AND MEASURES: Median and mean research and development spending on new therapeutic agents approved by the FDA, capitalized at a real cost of capital rate (the required rate of return for an investor) of 10.5% per year, with bootstrapped CIs. All amounts were reported in 2018 US dollars. RESULTS: The FDA approved 355 new drugs and biologics over the study period. Research and development expenditures were available for 63 (18%) products, developed by 47 different companies. After accounting for the costs of failed trials, the median capitalized research and development investment to bring a new drug to market was estimated at $985.3 million (95% CI, $683.6 million-$1228.9 million), and the mean investment was estimated at $1335.9 million (95% CI, $1042.5 million-$1637.5 million) in the base case analysis. Median estimates by therapeutic area (for areas with ≥5 drugs) ranged from $765.9 million (95% CI, $323.0 million-$1473.5 million) for nervous system agents to $2771.6 million (95% CI, $2051.8 million-$5366.2 million) for antineoplastic and immunomodulating agents. Data were mainly accessible for smaller firms, orphan drugs, products in certain therapeutic areas, first-in-class drugs, therapeutic agents that received accelerated approval, and products approved between 2014 and 2018. Results varied in sensitivity analyses using different estimates of clinical trial success rates, preclinical expenditures, and cost of capital. CONCLUSIONS AND RELEVANCE: This study provides an estimate of research and development costs for new therapeutic agents based on publicly available data. Differences from previous studies may reflect the spectrum of products analyzed, the restricted availability of data in the public domain, and differences in underlying assumptions in the cost calculations.

Metabolomics in pharmacology - a delve into the novel field of pharmacometabolomics.

Introduction: Pharmacometabolomics is an emerging science pursuing the application of precision medicine. Combining both genetic and environmental factors, the so-called pharmacometabolomic approach guides patient selection and stratification in clinical trials and optimizes personalized drug dosage, improving efficacy and safety.Areas covered: This review illustrates the progressive introduction of pharmacometabolomics as an innovative solution for enhancing the discovery of novel drugs and improving research and development (R&D) productivity of the pharmaceutical industry. An extended analysis on published pharmacometabolomics studies both in animal models and humans includes results obtained in several areas such as hepatology, gastroenterology, nephrology, neuropsychiatry, oncology, drug addiction, embryonic cells, neonatology, and microbiomics.Expert opinion: a tailored, individualized therapy based on the optimization of pharmacokinetics and pharmacodynamics, the improvement of drug efficacy, and the abolition of drug toxicity and adverse drug reactions is a key issue in precision medicine. Genetics alone has become insufficient for deciphring intra- and inter-individual variations in drug-response, since they originate both from genetic and environmental factors, including human microbiota composition. The association between pharmacogenomics and pharmacometabolomics may be considered the new strategy for an in-deep knowledge on changes and alterations in human and microbial metabolic pathways due to the action of a drug.

[Pharmaceutical Research on Liver Diseases Using iPS Cell and Genome Editing Technologies].

The liver is a major organ responsible for maintaining the body's homeostasis and xenobiotic metabolism. Liver transplantation is essential for the alleviation of many severe liver diseases. However, there are many patients who cannot receive liver transplants because of donor shortage. Therefore development of effective therapeutic drugs that can replace the need for liver transplantation is desired. To this end, model cells that faithfully reproduce hepatic functions are essential. It is expected that human induced pluripotent stem cell (iPS)-derived hepatocyte-like cells, which faithfully reproduce hepatic functions, would be a valuable tool for drug discovery. Hepatic differentiation from human iPS cells has been performed using growth factors, but the hepatic differentiation efficiency was quite low and liver functions of human iPS cell-derived hepatocyte-like cells were lower than those of primary human hepatocytes. Therefore we tried to improve the hepatic differentiation technology using gene transfer, genome editing, three-dimensional culture, and extracellular matrix technologies. As a result, the purity of human iPS cell-derived hepatocyte-like cells was improved into 90% or more, and the liver functions of human iPS cell-derived hepatocyte-like cells were improved to a level comparable to primary human hepatocytes. In this article, we introduce the research results we have acquired over the last decade.

Human organotypic bioconstructs from organ-on-chip devices for human-predictive biological insights on drug candidates.

INTRODUCTION: Historically, drug development and marketing failures have been experienced by pharma organizations largely from insufficient human-predictability of biological data. AREAS COVERED: Organs-on-chips (OOCs) are emerging, cutting edge microphysiology systems for in vitro production of microengineered three-dimensional, miniature organotypic constructs obtained by cultivating small amounts of human primary, or induced pluripotent stem, cells in native-like microhabitats. These preparations circumvent experimental limitations inherent to animal assays and two-dimensional monolayers, the mainstay core biological assays of traditional drug research. This report reviews the fundamental tenets, key components (chip plate, biomaterials, cell differentiation approaches, and monitoring sensors) and issues concerning OOC systems (engineered top-down and bottom-up strategies for tissue/organ assembly, public aids to OOC development, regulatory validation, advantages, limitations, prospective and perspective of OOCs, ethics). Examples of OOC platforms (cancer-, lung-, blood-brain barrier-, heart-, intestine-, kidney-, liver-, pharmacokinetics-, placenta and vessel-on-chip) and their importance for drug research and development are presented. EXPERT OPINION: OOC device-generated bioconstructs hold great promise as experimental human tissue and organ platforms for generating human-pertinent knowledge on drug candidates for clinical assessment and reducing reliance on animal models. MPS technologies currently enable ready-to-assemble tissue patches and, hopefully, in coming decades, full-size, patient-personalized organs for regenerative medical interventions.

The Emergence of Universal Chromatographic Methods in the Research and Development of New Drug Substances.

Manufacturing process development of new drug substances in the pharmaceutical industry combines numerous chemical challenges beyond the efficient synthesis of complex molecules. Optimization of a synthetic route involves the screening of multiple reaction variables with a desired outcome that not only depends on an increased product yield but is also highly influenced by the removal efficacy of residual chemicals and reaction byproducts during the subsequent synthetic route. Consequently, organic chemists must survey a wide array of synthetic variables to develop a highly productive, green, and cost-effective manufacturing process. The time constraints of developing robust quantitative methods prior to each processing step can easily lead to sample analysis becoming a bottleneck in synthetic route development. In this regard, conventional "on demand" analytical method development and optimization approaches, traditionally used for guiding synthetic chemistry efforts, become unsustainable. This Account introduces recent efforts to address the aforementioned challenges through the development and implementation of generic or more universal chromatographic methods that can cover a broad spectrum of targeted compound classes. Such generic methods require significant resolving power to enable baseline resolution of multicomponent mixtures in a single experimental run without additional method customization but must be simple enough to allow for routine use by chemists, chemical engineers and other researchers with little experience in chromatographic method development. These powerful analytical methodologies are often employed to minimize the time spent developing new analytical assays, while also facilitating method transfer to manufacturing facilities and application in regulatory settings. Diverse examples of universal and fit-for-purpose analytical procedures are presented herein, illustrating the power of modern readily available analytical technology for streamlining the development of new drug substances in organic chemistry laboratories across both academic and industrial sectors. With recent advances in analytical instrumentation and column technologies, universal chromatographic methods are quickly becoming a proactive and effective strategy to accelerate the discovery and implementation of new synthetic methodologies, especially but not limited to laboratories where the synthetic process route is undergoing rapid change and optimization. Targets of these generic methods include analysis of organic solvents, acid and basic additives, nucleotide species, palladium scavengers, impurity mapping, enantiopurity, synthetic intermediates, active pharmaceutical ingredients and their counterions, dehalogenation byproducts, and mixtures of organohalogenated pharmaceuticals, among other chemicals used or formed in process chemistry reactions.

[Clinical Pharmaceutical Research Based on New Proteome Analysis Based on Chromatographic Separation].

Comprehensive identification of antigens in immune complexes (IC-antigens) is beneficial to provide insights into pathophysiology and could form the basis for novel diagnostic and treatment strategies for many immune-related diseases. Immune complexome analysis is a method for comprehensively identifying and profiling IC-antigens in biological fluids (such as serum and cerebrospinal fluid). We applied this strategy to the analysis of circulating ICs in autoimmune diseases (rheumatoid arthritis, Sjögren's syndrome, systemic scleroderma, and systemic lupus erythematosus), infectious diseases, and cancers. Fluorogenic derivatization-liquid chromatography-tandem mass spectrometry (FD-LC-MS/MS) consists of fluorogenic derivatization of proteins, followed by HPLC of the derivatized proteins, isolation of the proteins differentially expressed in a certain group, enzymatic digestion of the isolated proteins followed by LC-tandem MS using a database-searching algorithm for protein identification. We have applied this method to understand the cardioprotective effect of pre-administration of docetaxel in adriamycin/docetaxel combination anti-cancer therapy, and the cellular processes that are affected by non-steroidal anti-inflammatory drugs (NSAIDs) in mouse stomach tissue during ulcer formation.

Pharmaceutical Research for Inherited Metabolic Disorders of the Liver Using Human Induced Pluripotent Stem Cell and Genome Editing Technologies.

Orthotopic liver transplantation, rather than drug therapy, is the major curative approach for various inherited metabolic disorders of the liver. However, the scarcity of donated livers is a serious problem. To resolve this, there is an urgent need for novel drugs to treat inherited metabolic disorders of the liver. This requirement, in turn, necessitates the establishment of suitable disease models for many inherited metabolic disorders of the liver that currently lack such models for drug development. Recent studies have shown that human induced pluripotent stem (iPS) cells generated from patients with inherited metabolic disorders of the liver are an ideal cell source for models that faithfully recapitulate the pathophysiology of inherited metabolic disorders of the liver. By using patient iPS cell-derived hepatocyte-like cells, drug efficacy evaluation and drug screening can be performed. In addition, genome editing technology has enabled us to generate functionally recovered patient iPS cell-derived hepatocyte-like cells in vitro. It is also possible to identify the genetic mutations responsible for undiagnosed liver diseases using iPS cell and genome editing technologies. Finally, a combination of exhaustive analysis, iPS cells, and genome editing technologies would be a powerful approach to accelerate the identification of novel genetic mutations responsible for undiagnosed liver diseases. In this review, we will discuss the usefulness of iPS cell and genome editing technologies in the field of inherited metabolic disorders of the liver, such as alpha-1 antitrypsin deficiency and familial hypercholesterolemia.

Navigating manuscript assessment: The new practitioner's guide to primary literature peer review.

For pharmacists, the first years after graduation are spent developing their knowledge base, advancing as a practitioner, and honing their abilities as healthcare providers and drug information experts. New practitioners encounter many challenges during this time, which for many include publishing original research or reviewing manuscripts for colleagues and medical journals. Inexperience navigating the publication process, from submission to receipt of (and response to) peer review commentary, is often cited as a major barrier to timely publication of resident and new practitioner research. Serving as a peer reviewer in turn provides the new practitioner with insight on this process and can be an enlightening experience used to garner confidence in subsequently submitting their own formal manuscripts. A number of publications describing steps for peer review are available, however, many of these articles address more experienced reviewers or critique the peer review process itself. No definitive resource exists for new pharmacy practitioners interested in developing their peer review skills. The information presented in this summative guide should be used in conjunction with practice opportunities to help new practitioners develop proficiency at peer review.

NAMS-gallup survey on women's knowledge, information sources, and attitudes to menopause and hormone replacement therapy.

The North American Menopause Society (NAMS) sponsored a Gallup Organization survey of 833 women aged 45-60 to determine attitudes and experience with menopause and various forms of hormone replacement therapy (HRT). The results of this survey are presented herein.