Successful Drug Research Articles

Abstract 7497: Advancing multi-biomarker CTC assay and CDx development through the automated GenoCTC system

Abstract Introduction: The successful outcomes observed in clinical trials emphasize the effectiveness of therapeutic approaches relying on biomarker tests, particularly in the development of cancer drugs. The parallel development of a drug and its associated predictive biomarker is considered an ideal strategy for achieving rapid and successful drug development in precision medicine. In this context, we employ an automated circulating tumor cell (CTC) isolation platform, known as GenoCTC, to facilitate the development of biomarker-driven CTC assays, with the ultimate goal of developing companion diagnostic (CDx) tests. Method: This study employed the 5th generation GenoCTC device, a fully automated system designed for marker-based CTC enrichment using immune magnetophoresis. We confirmed the isolation of CTCs through spiking tests, utilizing cancer biomarkers such as cMET, Mesothelin (MSLN), and Claudin 3 (CLDN3). cMET is a biomarker extensively studied in various cancers, particularly non-small cell lung cancer. We previously showed the prognostic significance of cMET expressing CTCs in HR+ and HER2- metastatic breast cancer patients. MSLN and CLDN3 are tumor-associated proteins showing overexpression across diverse cancer types, with a potential for the development of antibody-based cytotoxic drugs. The GenoCTC device allows efficient separation of CTCs expressing these biomarkers, ensuring high accuracy, precision, specificity, and sensitivity. Simultaneously, therapeutic drugs directed at these markers are progressing through phase trials or preclinical studies. Conclusion: Our results show that cMET, MSLN, and CLDN3 are potential markers for the development of biomarker tests, that can improve the patient selection process for personalized therapy targeting these biomarkers. Citation Format: Chaithanya Chelakkot, Jieun Park, Chae Rin Kim, Yeonu Lee, Yu Rim Lee, Saehyung Lee, Jun Young Choi, Young Ho Moon, Yoon-La Choi, Young Kee Shin, Hun Seok Lee. Advancing multi-biomarker CTC assay and CDx development through the automated GenoCTC system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7497.

Abstract 492: Investigating solute carrier SLC46A3 to enhance nanotherapeutic delivery for cancer

Abstract BACKGROUND: Nanoparticle therapeutics have multifaceted potential to improve efficacy and decrease toxicity of cancer treatments. Nanotherapeutics can encapsulate a range of cargos and have tunable surface chemistry that can enhance drug delivery to tumors. Cellular features also play a role in successful drug delivery, and predictive biomarkers may improve patient selection for clinical trials. In previous work, we identified SLC46A3, a poorly characterized lysosomal solute carrier, as a strong negative regulator of lipid-based nanoparticle uptake across many cancer models. We hypothesize that the expression of SLC46A3 will act as a predictive biomarker for therapeutic nanoparticles. METHODS: To test this hypothesis, we used two engineered model systems to probe the relationship between SLC46A3 expression and therapeutic response: lentiviral overexpression in a natively low-expressing melanoma model and genetic deactivation in a natively high-expressing breast cancer model. A library of FDA-approved and experimental therapeutic nanoparticles were screened in both models under a range of conditions. Liposomal formulations of chemotherapeutics were included with high and low surface functionalization of polyethylene glycol to investigate the impact of this ubiquitous ‘stealth’ polymer on our biomarker of interest. Solid lipid nanoparticles with nucleic acid cargo were also included. Orthogonal methods were used to probe these interactions and the therapeutic efficacy of nanotherapeutics, including pulsed dosing viability assays and label-free live-cell imaging. RESULTS: We found that SLC46A3 expression is a class-specific biomarker of lipid-based nanoparticle uptake and is predictive of distinctive patterns of response to therapy-loaded nanoparticles in both formulation and time-dependent manners. Additionally, we present a new technology for long-term, live cell imaging of nanoparticle uptake and trafficking that can discriminate mechanisms of cytotoxicity, accelerating the study of nano-bio interactions. These findings highlight a promising approach for the functional validation of nanoparticle-specific biomarkers using clinically relevant formulations that have the potential for rapid repurposing. Citation Format: Julianna Kenny-Serrano, Elizabeth B. Nelson, Gil Covarrubias, Namita Nabar, Joelle Straehla, Aanchal Gupta, Natalie Boehnke, Paula Hammond. Investigating solute carrier SLC46A3 to enhance nanotherapeutic delivery for cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 492.

An Overview on Stimuli Sensitive Drug Delivery System

Stimuli-sensitive systems are a state of reactivity to sensory stimulation or excitability. These systems respond to changes in the body’s physiology due to environmental factors such as temperature, enzymes, glucose, magnetic fields, redox reactions, ions, and more. They are particularly useful for the controlled and sustained delivery of drugs in the body. Controlled drug delivery has become a standard criterion in modern pharmaceutical product design, with ongoing intensive research aimed at achieving a superior drug product characterized by effectiveness, reliability, and safety. These stimuli-sensitive systems are employed in various forms for different purposes, including parenteral, ocular, peroral, rectal, vaginal, nasal, dermal, and transdermal drug delivery. This study focuses on the latest advancements in stimuli-sensitive drug delivery systems, aiming to address the limitations of traditional therapeutic methods. The goal is to achieve targeted drug release in specific areas using various endogenous and exogenous stimuli. This allows for personalized and patient-centric treatment strategies. The development of stimuli-sensitive drug delivery systems remains a significant human endeavor for successful drug delivery, given the various shortcomings of existing conventional systems. To overcome these limitations, various stimuli-sensitive drug delivery systems (DDSs) have been developed in recent years

Small Molecule-Drug Conjugates: Opportunities for the Development of Targeted Anticancer Drugs.

Conventional chemotherapy is insufficient for precise cancer treatment due to its lack of selectivity and inevitable side effects. Targeted drugs have emerged as a promising solution for precise cancer treatment. A common strategy is to conjugate therapeutic agents with ligands that can specifically bind to tumor cells, providing targeted therapy. Similar to the more successful antibody drug conjugates (ADCs), small molecule drug conjugates (SMDCs) are another promising class of targeted drugs, consisting of three parts: targeting ligand, cleavable linker and payload. Compared to ADCs, SMDCs have the advantages of smaller size, better permeability, simpler preparation process and non-immunogenicity, making them a promising alternative to ADCs. This review describes the characteristics of the targeting ligand, linker and payload of SMDCs and the criteria for selecting a suitable one. We also discuss recently reported SMDCs and list some successful SMDCs that have entered clinical trials.

Challenges for the Discovery of Non-Covalent WRN Helicase Inhibitors.

The Werner Syndrome RecQ helicase (WRN) is a synthetic lethal target of interest for the treatment of cancers with microsatellite instability (MSI). Different hit finding approaches were initially tested. The identification of WRN inhibitors proved challenging due to a high propensity for artefacts via protein interference, i. e., hits inhibiting WRN enzymatic activities through multiple, unspecific mechanisms. Previously published WRN Helicase inhibitors (ML216, NSC19630 or NSC617145) were characterized in an extensive set of biochemical and biophysical assays and could be ruled out as specific WRN helicase probes. More innovative screening strategies need to be developed for successful drug discovery of non-covalent WRN helicase inhibitors.

Peripheral and central neurobiological effects of botulinum toxin A (BoNT/A) in neuropathic pain: a systematic review.

Botulinum toxin (BoNT), a presynaptic inhibitor of acetylcholine (Ach) release at the neuromuscular junction (NMJ), is a successful and safe drug for the treatment of several neurological disorders. However, a wide and recent literature review has demonstrated that BoNT exerts its effects not only at the "periphery" but also within the central nervous system (CNS). Studies from animal models, in fact, have shown a retrograde transport to the CNS, thus modulating synaptic function. The increasing number of articles reporting efficacy of BoNT on chronic neuropathic pain (CNP), a complex disease of the CNS, demonstrates that the central mechanisms of BoNT are far from being completely elucidated. In this new light, BoNT might interfere with the activity of spinal, brain stem, and cortical circuitry, modulating excitability and the functional organization of CNS in healthy conditions. Botulinum toxins efficacy on CNP is the result of a wide and complex action on many and diverse mechanisms at the basis of the maladaptive plasticity, the core of the pathogenesis of CNP. This systematic review aims to discuss in detail the BoNT's mechanisms and effects on peripheral and central neuroplasticity, at the basis for the clinical efficacy in CNP syndromes.

Cell-Penetrating Peptides: Promising Therapeutics and Drug-Delivery Systems for Neurodegenerative Diseases.

Currently, one of the most significant and rapidly growing unmet medical challenges is the treatment of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). This challenge encompasses the imperative development of efficacious therapeutic agents and overcoming the intricacies of the blood-brain barrier for successful drug delivery. Here we focus on the delivery aspect with particular emphasis on cell-penetrating peptides (CPPs), widely used in basic and translational research as they enhance drug delivery to challenging targets such as tissue and cellular compartments and thus increase therapeutic efficacy. The combination of CPPs with nanomaterials such as nanoparticles (NPs) improves the performance, accuracy, and stability of drug delivery and enables higher drug loads. Our review presents and discusses research that utilizes CPPs, either alone or in conjugation with NPs, to mitigate the pathogenic effects of neurodegenerative diseases with particular reference to AD and PD.

Doxorubicin loaded octacalcium phosphate particles as controlled release drug delivery systems: Physico-chemical characterization, in vitro drug release and evaluation of cell death pathway

Mastering new and efficient ways to obtain successful drug delivery systems (DDS) with controlled release became a paramount quest in the scientific community. Increase of malignant bone tumors and the necessity to optimize an approach of localized drug delivery require research to be even more intensified. Octacalcium phosphate (OCP), with a number of advantages over current counterparts is extensively used in bone engineering. The aim of the present research was to synthesize bioactive and biocompatible doxorubicin (DOX) containing OCP particles. DOX-OCP was successfully obtained in situ in an exhaustive range of added drug (1–20 wt%, theoretical loading). Based on XRD, above 10 wt% of DOX, OCP formation was inhibited and the obtained product was low crystalline α-TCP. In-vitro drug release was performed in pH 7.4 and 6.0. In both pH environments DOX had a continuous release over six weeks. However, the initial drug burst for pH 7.4, in the first 24 h, ranged from 15.9 ± 1.3 % to 33.5 ± 12 % and for pH 6.0 23.7 ± 1.5 % to 36.2 ± 12 %.The DOX-OCP exhibited an inhibitory effect on viability of osteosarcoma cell lines MG63, U2OS and HOS. In contrast, MC3T3-E1 cells (IC50 > 0.062 µM) displayed increased viability and proliferation from 3rd to 7th day. Testing of the DDS on ferroptotic markers (CHAC1, ACSL4 and PTGS2) showed that OCP-DOX does not induce ferroptotic cell death. Moreover, the evaluation of protein levels of cleaved PARP, by western blotting analysis, corroborated that apoptosis is the main pathway of programmed cell death in osteosarcoma cells induced by DOX-OCP.

Generative artificial intelligence in drug discovery: basic framework, recent advances, challenges, and opportunities.

There are two main ways to discover or design small drug molecules. The first involves fine-tuning existing molecules or commercially successful drugs through quantitative structure-activity relationships and virtual screening. The second approach involves generating new molecules through de novo drug design or inverse quantitative structure-activity relationship. Both methods aim to get a drug molecule with the best pharmacokinetic and pharmacodynamic profiles. However, bringing a new drug to market is an expensive and time-consuming endeavor, with the average cost being estimated at around $2.5 billion. One of the biggest challenges is screening the vast number of potential drug candidates to find one that is both safe and effective. The development of artificial intelligence in recent years has been phenomenal, ushering in a revolution in many fields. The field of pharmaceutical sciences has also significantly benefited from multiple applications of artificial intelligence, especially drug discovery projects. Artificial intelligence models are finding use in molecular property prediction, molecule generation, virtual screening, synthesis planning, repurposing, among others. Lately, generative artificial intelligence has gained popularity across domains for its ability to generate entirely new data, such as images, sentences, audios, videos, novel chemical molecules, etc. Generative artificial intelligence has also delivered promising results in drug discovery and development. This review article delves into the fundamentals and framework of various generative artificial intelligence models in the context of drug discovery via de novo drug design approach. Various basic and advanced models have been discussed, along with their recent applications. The review also explores recent examples and advances in the generative artificial intelligence approach, as well as the challenges and ongoing efforts to fully harness the potential of generative artificial intelligence in generating novel drug molecules in a faster and more affordable manner. Some clinical-level assets generated form generative artificial intelligence have also been discussed in this review to show the ever-increasing application of artificial intelligence in drug discovery through commercial partnerships.

COATI: Multimodal Contrastive Pretraining for Representing and Traversing Chemical Space.

Creating a successful small molecule drug is a challenging multiparameter optimization problem in an effectively infinite space of possible molecules. Generative models have emerged as powerful tools for traversing data manifolds composed of images, sounds, and text and offer an opportunity to dramatically improve the drug discovery and design process. To create generative optimization methods that are more useful than brute-force molecular generation and filtering via virtual screening, we propose that four integrated features are necessary: large, quantitative data sets of molecular structure and activity, an invertible vector representation of realistic accessible molecules, smooth and differentiable regressors that quantify uncertainty, and algorithms to simultaneously optimize properties of interest. Over the course of 12 months, Terray Therapeutics has collected a data set of 2 billion quantitative binding measurements of small molecules to therapeutic targets, which directly motivates multiparameter generative optimization of molecules conditioned on these data. To this end, we present contrastive optimization for accelerated therapeutic inference (COATI), a pretrained, multimodal encoder-decoder model of druglike chemical space. COATI is constructed without any human biasing of features, using contrastive learning from text and 3D representations of molecules to allow for downstream use with structural models. We demonstrate that COATI possesses many of the desired properties of universal molecular embedding: fixed-dimension, invertibility, autoencoding, accurate regression, and low computation cost. Finally, we present a novel metadynamics algorithm for generative optimization using a small subset of our proprietary data collected for a model protein, carbonic anhydrase, designing molecules that satisfy the multiparameter optimization task of potency, solubility, and drug likeness. This work sets the stage for fully integrated generative molecular design and optimization for small molecules.

Predicting the intrinsic membrane permeability of Caco-2/MDCK cells by the solubility-diffusion model

Membrane permeability is one of the main determinants for the absorption, distribution, metabolism and excretion of compounds and is therefore of crucial importance for successful drug development. Experiments with artificial phospholipid membranes have shown that the intrinsic membrane permeability (P0) of compounds is well-predicted by the solubility-diffusion model (SDM). However, using the solubility-diffusion model to predict the P0 of biological Caco-2 and MDCK cell membranes has proven unreliable so far. Recent publications revealed that many published P0 extracted from Caco-2 and MDCK experiments are incorrect. In this work, we therefore used a small self-generated set as well as a large revised set of experimental Caco-2 and MDCK data from literature to compare experimental and predicted P0. The P0 extracted from Caco-2 and MDCK experiments were systematically lower than the P0 predicted by the solubility-diffusion model. However, using the following correlation: log P0,Caco-2/MDCK = 0.84 log P0,SDM – 1.85, P0 of biological Caco-2 and MDCK cell membranes was well-predicted by the solubility-diffusion model.

Investigating the efficacy of mirtazapine-embedded invasomal gel nanocarriers via I-optimal design for management of atopic dermatitis

The objective of the present study was to optimize a novel invasomal gel (inva-gel) formulation enriched with terpene for upgrading the therapeutic action of anti-depressant mirtazapine on atopic dermatitis as an off-label use. Various factors were studied by I-optimal design to propose an optimized invasome with desirable characteristics. Its incorporation into different hydrogel bases was targeted to suggest a desirable inva-gel formulation, inspect its ex-vivo performance, and conduct in-vivo pre- and post-sacrifice assessments on atopic dermatitis-induced rats. Results revealed positive ethanol action on increasing entrapment efficiency (up to 77.88%) and decreasing size of invasomal vesicles (from 390.30 nm to 190.60 nm). Increased terpene amounts provided more space for mirtazapine incorporation with enhanced solubility and encapsulation inside invasomes. Terpene's molecular weight and lipophilicity significantly affected physicochemical characteristics of invasomes. More cross-linkages would occur by raising gel:liquid invasome ratio (from 0.5:1 to 2.5:1) and using carbopol other than hydroxylpropyl methyl cellulose (HPMC), therefore increasing rheological properties of inva-gels. Synergistic effects of phospholipid, ethanol, limonene, and carbopol to enhance mirtazapine permeation through skin were observed. Throughout the pre-sacrifice assessments, optimized inva-gel demonstrated a significant decrease in dermatitis severity score (from 8.33 to 3.00) and scratching behavior (from 184.32 s to 37.42 s) in disease-induced rats, hence showing favorable skin profile. Concerning the post-sacrifice assessments, optimized inva-gel significantly alleviated inflammation and pruritus symptoms by minimizing epidermal thickening (from 92.32 μm to 50.17 μm), down-regulating various inflammatory mediators, and decreasing infiltration of inflammatory mast cells. Besides, the ear swelling and spleen index values were markedly decreased (from 77.37 mg to 22.76 mg and from 0.56% to 0.35%, respectively). In conclusion, novel anti-depressant mirtazapine-embedded inva-gel displayed successful transdermal drug permeation offering valuable merits in atopic dermatitis management.

Flexible Coatings Facilitate pH-Targeted Drug Release via Self-Unfolding Foils: Applications for Oral Drug Delivery.

Ingestible self-configurable proximity-enabling devices have been developed as a non-invasive platform to improve the bioavailability of drug compounds via swellable or self-unfolding devices. Self-unfolding foils support unidirectional drug release in close proximity to the intestinal epithelium, the main drug absorption site following oral administration. The foils are loaded with a solid-state formulation containing the active pharmaceutical ingredient and then coated and rolled into enteric capsules. The coated lid must remain intact to ensure drug protection in the rolled state until targeted release in the small intestine after capsule disintegration. Despite promising results in previous studies, the deposition of an enteric top coating that remains intact after rolling is still challenging. In this study, we compare different mixtures of enteric polymers and a plasticizer, PEG 6000, as potential coating materials. We evaluate mechanical properties as well as drug protection and targeted release in gastric and intestinal media, respectively. Commercially available Eudragit® FL30D-55 appears to be the most suitable material due to its high strain at failure and integrity after capsule fitting. In vitro studies of coated foils in gastric and intestinal media confirm successful pH-triggered drug release. This indicates the potential advantage of the selected material in the development of self-unfolding foils for oral drug delivery.

Competence of pediatric residents and nurses in metered-dose inhaler techniques for asthma patients at Tikur Anbessa Specialized Hospital

Introduction: A Metered Dose Inhaler (MDI) is a device containing dissolved or suspended drugs to deliver drugs for pulmonary diseases efficiently. However, studies in Ethiopia show low competency among health professionals. Thus, we assessed the competency of residents and nurses working in a tertiary hospital. 
 Methods: From June to September 2022, 181 pediatrics and child health department residents and nurses participated in a pretested questionnaire and MDI technique practice. The knowledge score for residents and nurses was determined based on correct answers to questions from 0 to 6 for residents and 0 to 5 for nurses. Good knowledge was defined as a score of 80–100%, moderate knowledge from 60–79%, and poor knowledge from <60% of the total score. The good practice was ≥7 from 11 and all essential steps, while the poor practice was <7 of the total score and skipped essential steps. The chi-square or Fisher exact test was employed to compare groups as appropriate. The 95% confidence interval and a p-value of 0.05 were used to determine statistical significance. . 
 Results: Of the 181 study participants, 103 (56.9%) were residents. The participants' mean age was 32. MDI technique knowledge was poor for more than half of the residents (52.4%) and 46.4% of the nurses. Twenty-six (14.4%) of participants practiced the MDI technique steps, scoring 7 out of 11 steps. However, only 3.3% practiced the technique correctly. Whereas only 5.8% of residents and 0% of nurses practiced the essential steps of the MDI technique. When using a new inhaler drug, nearly half of the participants (47%) did not assess the patients' practice. 
 Conclusion: Healthcare professionals' competency in performing the MDI technique is low. Appropriate training programs are needed to enhance their ability to use inhaled devices and ensure successful drug delivery.

African Medical School Academic Success and Social Drug use among Undergraduate Students

Background: It has long been known that using drugs like alcohol, khat, and tobacco is one of the main causes of human suffering. It is now regarded as one of the most significant socioeconomic and public health concerns in the world. Although it has an impact on many facets of society, juvenile substance abuse is alarmingly on the rise. Objective: This study’s goal is to evaluate how social drug usage affects students’ academic performance, specifically among those who will undergraduate from Africa medical college in 2023. Methodology: A cross-sectional study that was done on an institutional level among Africa medical college undergraduates. For the current study, a sample of 173 students was selected using a straightforward random selecting procedure from nine departments. Result: This survey included a total of 173 graduating students from various departments. Overall, 97.4 women, or 64.2%, and 174.5 women, or 35.8%, were present. Social drugs were taken by 33.6% of people at some point in their life. The most often used social drugs, according to this study, were beer, khat, and cigarettes (41.8%, 40.7%, and 12.1%, respectively). The most frequent effects of social drug use on students’ academic performances were higher absenteeism from class (31.9%) and a decline in cumulative grade point (27.5%), followed by a lack of interest in routine activities (25.3%) and worsening academic performance (15.2%), according to respondents. Peer pressure and socialization (17.8%) were the two most frequent reasons given by respondents, whereas academic unhappiness (13.3%), the desire to improve academic performance (11.1%), and loss of family control (8.9%) were the least frequent. Age, Religion, Ever Social Drug Use, Current Social Drug Use, Started Using Social Drug Use, and Impact of Social Drug Use show statistically significant associations with CGPA, according to statistical analysis and p-value. Conclusion and Recommendation: The studies revealed that social drug use had a negative impact on kids’ academic performance. The most prevalent outcomes were an increase in absences from school, a drop in cumulative grade point, and a decrease of interest in everyday chores. Khat, alcohol, and cigarettes were the most popular social drugs. This finding calls for further in-depth investigation into the various challenges connected to social drug use as well as instruction by responsible organizations about the detrimental effects that social drug use has on students’ academic performance, particularly when they first enrol in college.

Green Synthesis of a Novel Phytoalexin Derivative: In Silico Profiling, Apoptotic Induction, and Antiproliferative Activity against MCF-7 cells - From Vineyards to Potent Anticancer Drug Molecule.

Resveratrol's structural similarity to commercialized anti-breast cancer medications such as Tamoxifen underlines its potential as a promising option for developing successful anti-breast cancer drugs. However, the pharmacokinetic issues associated with resveratrol, such as its low bioavailability, have piqued the attention of researchers in developing novel derivatives. A novel phytoalexin derivative, RsvD1, was successfully synthesized using resveratrol extracted from green grape peels as a precursor to investigate its anti-breast cancer efficacy on Estrogen receptor (ER) positive and negative breast cancer cells. The comparative analysis revealed that RsvD1 exhibited remarkable radical scavenging ability (IC50 = 2.21 μg/mL), surpassing the control, Trolox (IC50 = 6.3 μg/mL). Furthermore, RsvD1 demonstrated enhanced and selective antiproliferative activity against ER-positive MCF-7 cells (IC50 = 20.09 μg/mL) compared to resveratrol, the parent molecule (IC50 = 30.90 μg/mL). Further investigations unveiled that RsvD1 induced apoptosis and DNA damage in MCF-7 cells, leading to cell cycle arrest at the G0/G1 phase after 24 hours of incubation. RTqPCR gene expression analysis indicated that RsvD1 down-regulated the CAXII (ER-dependent) genes. In silico predictions demonstrated that RsvD1 possesses promising potential as a drug candidate due to its drug-like characteristics and favourable ADMET profile. Moreover, molecular docking studies provided insights into the theoretical binding mode between RsvD1 and ERα protein. The study highlights the therapeutic potential of the synthesized resveratrol derivative, RsvD1, positioning it as a promising scaffold for developing novel analogues with improved therapeutic properties and selectivity, specifically targeting ER+ breast cancer cells. Moreover, the compound's non-cytotoxic yet antiproliferative properties, coupled with its capability to induce programmed cell death and cell cycle arrest, enhance its potential as a highly effective drug candidate. As a result, this paves a promising path for the development of innovative and selective inhibitors targeting ER+ breast cancer with enhanced efficacy.

Opposed to Pain: Antikamnia Chemical Company.

The Antikamnia (AK) Chemical Company founded in 1890, which eventually was renamed The Antikamnia Remedy Company in 1819, was an important medicine company that thrived prior to passage of the 1906 Food and Drug act using smart worldwide marketing. As dangerous as the AK products were, success continued after 1906 by pursuing methods to flout regulations and stick to the marketing methods and legal maneuvering that kept AK sales strong. This article describes the tumultuous history of one of the most successful drug companies between 1890 and well into the 1920s.

Comparative understanding of peroxide quantitation assays: a case study with peptide drug product degradation.

Peroxide-mediated oxidation of drug molecules is a known challenge faced throughout the pharmaceutical development pathway-from early-stage stability studies to manufacturing processes. During the initial development stage, the major source of peroxide is the formulation excipients, whether they are pre-loaded or generated in situ due to slow degradation, and in the late phase, peroxides can be introduced during sanitization processes or generated via cavitation. In essence, a control strategy for peroxide mitigation often becomes a critical quality attribute for successful drug development. To this end, quantitation of peroxide is essential to monitor the peroxide level to ensure product quality and proposed shelf-life. However, methods for reliable and robust quantitation to detect trace levels of peroxide in a complex drug product matrix become increasingly challenging. This article discusses three high-throughput assays based on absorbance, fluorescence and chemiluminescence measurements to detect peroxide at a low level and compares the methods through validation studies in water. Selected methods have also been tested to understand the forced degradation of model peptide drug products with spiked hydrogen peroxide. Peptide degradation profiles and residual peroxide levels are presented to provide an understanding of the suitability of the quantitation methods and their performance.

Reaching Outer Space and Enabling the mRNA Revolution: A Critical Role of Partnerships for Successful Drug and Vaccine Development.

mRNA and targeted delivery of mRNA carry the promise to enable targeted treatment of undruggable diseases with high unmet medical needs. The transient nature of mRNA opens options for safe influencing of protein biology, immune responses, and complex ailments without impacting DNA heritage. Technical challenges such as mRNA stability and targeted delivery require next generation solutions, which attracted substantial funding and research interests. To build an integrated mRNA value chain and enable the development of novel therapeutics, Merck KGaA Darmstadt, Germany has initiated an internally incubated program, "Targeted mRNA Delivery" (TMD). This collaborative approach brings together scientists, researchers, engineers, and commercial experts from diverse backgrounds to overcome the multidimensional challenges associated with mRNA technology. In this chapter, the multiple opportunities and challenges for the development of mRNA formulations and therapeutics are described comprehensively. Specifically, the TMD program is presented as a use case to show how intrapreneurs were gathered to establish internal mRNA capabilities and foster collaborations for technology development. In the realm of targeted mRNA delivery, partnerships, encompassing internal partnership and external private, public, and hybrid collaborations, play a crucial role in driving innovation and addressing these hurdles. Within multinational pharmaceutical companies, the establishment of "internal startups" is an effective solution to drive innovation to the next level with support from different business sectors, where existing capabilities and positioning are seamlessly blended with the agility and speed of a startup.

Benzenesulfonamide decorated dihydropyrimidin(thi)ones: carbonic anhydrase profiling and antiproliferative activity.

In the last decades, carbonic anhydrases (CAs) have become the top investigated innovative pharmacological targets and, in particular, isoforms IX and XII have been widely studied due to the evidence of their overexpression in hypoxic tumors. The frantic race to find new anticancer agents places the quick preparation of large libraries of putative bioactive compounds as the basis of a successful drug discovery and development programme. In this context, multi-component and, in general, one-step reactions are becoming very popular and, among them, Biginelli's reaction gave clean and easy-to-isolate products. Thus, we synthesized a series of Biginelli's products (10-17a-b) and similar derivatives (20-21) bearing the benzenesulfonamide moiety, which is known to inhibit CA enzymes. Through the stopped-flow technique, we were able to assess their ability to inhibit the targeted CAs IX and XII in the nanomolar range with promising selectivity over the physiologically relevant isoforms I and II. Crystallography studies and docking simulations helped us to gain insight into the interaction patterns established in the enzyme-inhibitor complex. From a chemical similarity-based screening of in-house libraries of compounds, a diphenylpyrimidine (23) emerged. The surprisingly potent inhibitory activity of 23 for CAs IX and XII along with its strong antiproliferative effect on two (triple-negative breast cancer MDA-MB-231 and glioblastoma U87MG) cell lines laid the foundation for further investigation, again confirming the key role of CAs in cancer.