Pharmaceutical Industry Research Articles

Leveraging AI and Machine Learning in Six-Sigma Documentation for Pharmaceutical Quality Assurance.

The pharmaceutical industry must maintain stringent quality assurance standards to ensure product safety and regulatory compliance. A key component of the well-known Six Sigma methodology for process improvement and quality control is precise and comprehensive documentation. However, there are a number of significant issues with traditional documentation procedures, including as slowness, human error, and difficulties with regulatory standards. This review research looks at innovative ways to employ machine learning (ML) and artificial intelligence (AI) to enhance Six Sigma documentation processes in the pharmaceutical sector. AI and ML provide cutting-edge technologies that have the potential to drastically alter documentation processes by automating data entry, collection, and analysis. Natural language processing (NLP) and computer vision technologies have the potential to significantly reduce human error rates and increase the efficacy of documentation processes. By applying machine learning algorithms to support real-time data analysis, predictive analytics, and proactive quality management, pharmaceutical organizations may be able to identify potential quality issues early on and take proactive efforts to address them. Combining AI and ML improves documentation accuracy and reliability while also strengthening compliance with stringent regulatory criteria. The primary barriers and limitations to the current state of Six Sigma documentation in the pharmaceutical industry are identified in this study. It examines the fundamentals of AI and ML with an emphasis on their specific applications in quality assurance and potential benefits for Six Sigma processes. The report includes extensive case studies that highlight notable developments and explain how AI/ML enhanced documentation is used in the real world.

Relevance and Potential Applications of C2-Carboxylated 1,3-Azoles.

Carbon dioxide (CO2) is an economically viable and abundant carbon source that can be incorporated into compounds such as 1,3-azoles relevant to the pharmaceutical, cosmetics, and pesticide industries. Of the 2.4 million commercially available C2-unsubstituted 1,3-azole compounds, less than 1 % are currently purchasable as their C2-carboxylated derivatives, highlighting the substantial gap in compound availability. This availability gap leaves ample opportunities for exploring the synthetic accessibility and use of carboxylated azoles in bioactive compounds. In this study, we analyze and quantify the relevance of C2-carboxylated 1,3-azoles in small-molecule research. An analysis of molecular databases such as ZINC, ChEMBL, COSMOS, and DrugBank identified relevant C2-carboxylated 1,3-azoles as anticoagulant and aroma-giving compounds. Moreover, a pharmacophore analysis highlights promising pharmaceutical potential associated with C2-carboxylated 1,3-azoles, revealing the ATP-sensitive inward rectifier potassium channel 1 (KATP) and Kinesin-like protein KIF18A as targets that can potentially be addressed with C2-carboxylated 1,3-azoles. Moreover, we identified several bioisosteres of C2-carboxylated 1,3-azoles. In conclusion, further exploration of the chemical space of C2-carboxylated 1,3-azoles is encouraged to harness their full potential in drug discovery and related fields.

Cultivation of a naturally resilient Chlorella sp.: A bioenergetic strategy for valorization of cheese whey for high nutritional biomass production

This study investigated Chlorella's capacity to treat cheese whey (CW) effluent and produce a high-nutritional value biomass, by using a systematic sequential experimental design. Physicochemical analysis of CW revealed its high pollution load, characterized by elevated levels of lactose, phosphorus, and nitrogen, as well as high turbidity due to the presence of whey solids. Screening experiments demonstrated that trace mineral addition and continuous air supply are essential factors for Chlorella biomass production in CW (>800 mg·mL−1). Furthermore, whey solids did not hinder Chlorella growth, with notable biomass production observed even in undiluted CW, demonstrating this microalga's ability to adapt metabolically to the complex environment. Laboratory-scale photobioreactor experiments confirmed Chlorella's ability to produce biomass in CW, outperforming controls (>800 mg·mL−1). Bioremediation potential assessment exhibited significant reductions in organic pollutants (>14 g·L−1 COD), nitrogen (>400 mg·L−1), phosphorus (>140 mg·L−1) and sodium (>650 mg·L−1). CW solids were also removed with Chlorella harvesting (>99 %). Harvested algal biomass was enriched with proteins (>40 g·100 g−1), polyunsaturated fatty acids (>9 % TFA) and pigments, offering potential applications in nutraceutical and pharmaceutical industries. Overall, this study highlights Chlorella's efficacy in CW treatment and biomass valorization, offering a sustainable solution for dairy wastewater management while producing valuable resources.

Head-to-head studies on connective tissue diseases and vasculitides

Head-to-head (H2H) studies enable the direct comparison of several alternative therapeutic approaches and thus provide the evidence-based foundation for the relative position of one treatment as compared to others for a specific indication. These trials constitute an important addition to placebo-controlled clinical trials. Among the controlled clinical trials not performed by the pharmaceutical industry, there are arelevant number of H2H trials for connective tissue diseases (CTDs) and vasculitides, particularly for systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This article encompasses a review of the H2H trials for CTDs and vasculitides and discusses their relevance for current treatment algorithms. For SLE the H2H trials were predominantly performed for the treatment of lupus nephritis, demonstrating the impact of low-dose cyclophosphamide and mycophenolate as well as azathioprine for maintenance therapy. In recent H2H trials rituximab could be established as induction and maintenance therapy for AAV, which has now been incorporated into current treatment guidelines. Further comparative trials will be necessary in order to select the most effective and safest treatment for every patient, in the sense of personalized medicine.

Do artificial intelligence system adoptions foster production management supply chain performance in pharmaceutical manufacturing firms? An empirical exploring study from the MENA region

PurposeThe goal of this study is to better understand the driving force behind the use of artificial intelligence (AI) in pharmaceutical manufacturing firms (PMFs) that are recognized as developing countries in the Middle East and North Africa (MENA) region that are listed by the Chambers of the Industries of Jordan, the Kingdom of Saudi Arabia, Morocco, and Algeria. Furthermore, the effect of adopting and using AI in managing raw materials (RMs), products, parts, and components for PMFs through supply chains (SCs).Design/methodology/approachA self-administrated questionnaire survey was used to gather data from 95 out of 511 participating managers (e.g. manufacturing, supplying, IT, operational, and logistical managers) utilizing a quantitative technique with a random sample size. In fact, 18.8% of the 89 different manufacturing firms (MFs) in the MENA area responded, with five to six managers from each company. The raw data was analyzed using partial least squares structural equation modeling (PLS-SEM).FindingsThe study’s findings show that the readiness to embrace artificial intelligence (AI) in the production management supply chain performance (PMSCP) of pharmaceutical manufacturing firms in the Middle East and North Africa (MENA) is positively and significantly influenced directly and indirectly by sustainable strategic supplier reliability (SSSR), shipping process dependability (SPD), technological factors (TFs), and infrastructure transformational development capability (ITDC).Originality/valueAs the studied countries are growing economies, such study findings might offer insightful consequences for stakeholders and policymakers regarding the significance of using artificial intelligence system adoptions in pharmaceutical manufacturing enterprises in the MENA region. The managers may also concentrate on the strong positive direct and indirect links between SSSR, SPD, TFs, and ITDC preparedness to accept AI adoption and its applications and systems in supply chain and production management departments and the consequences of informational and product delivery.

A Comparative Metagenomic Analysis of Specified Microorganisms in Groundwater for Non-Sterilized Pharmaceutical Products

In pharmaceutical manufacturing, ensuring product safety involves the detection and identification of microorganisms with human pathogenic potential, including Burkholderia cepacia complex (BCC), Escherichia coli, Pseudomonas aeruginosa, Salmonella enterica, Staphylococcus aureus, Clostridium sporogenes, Candida albicans, and Mycoplasma spp., some of which may be missed or not identified by traditional culture-dependent methods. In this study, we employed a metagenomic approach to detect these taxa, avoiding the limitations of conventional cultivation methods. We assessed the groundwater microbiome’s taxonomic and functional features from samples collected at two locations in the spring and summer. All datasets comprised 436–557 genera with Proteobacteria, Bacteroidota, Firmicutes, Actinobacteria, and Cyanobacteria accounting for > 95% of microbial DNA sequences. The aforementioned species constituted less than 18.3% of relative abundance. Escherichia and Salmonella were mainly detected in Hot Springs, relative to Jefferson, while Clostridium and Pseudomonas were mainly found in Jefferson relative to Hot Springs. Multidrug resistance efflux pumps and BlaR1 family regulatory sensor-transducer disambiguation dominated in Hot Springs and in Jefferson. These initial results provide insight into the detection of specified microorganisms and could constitute a framework for the establishment of comprehensive metagenomic analysis for the microbiological evaluation of pharmaceutical-grade water and other non-sterile pharmaceutical products, ensuring public safety.

A roadmap for affordable genetic medicines.

Nineteen genetic therapies have been approved by the U.S. Food and Drug Administration (FDA) to date, a number that now includes the first CRISPR genome editing therapy for sickle cell disease, CASGEVY (exagamglogene autotemcel). This extraordinary milestone is widely celebrated because of the promise for future genome editing treatments of previously intractable genetic disorders and cancers. At the same time, such genetic therapies are the most expensive drugs on the market, with list prices exceeding $4 million per patient. Although all approved cell and gene therapies trace their origins to academic or government research institutions, reliance on for-profit pharmaceutical companies for subsequent development and commercialization results in prices that prioritize recouping investments, paying for candidate product failures, and meeting investor and shareholder expectations. To increase affordability and access, sustainable discovery-to-market alternatives are needed that address system-wide deficiencies. Here, we present recommendations of a multi-disciplinary task force assembled to chart such a path. We describe a pricing structure that, once implemented, could reduce per-patient cost tenfold and propose a business model that distributes responsibilities while leveraging diverse funding sources. We also outline how academic licensing provisions, manufacturing innovation and supportive regulations can reduce cost and enable broader patient treatment.

Mapping medication selling practices at nonpharmacy outlets during the COVID-19 pandemic: an example of Indonesia.

Nonpharmacy outlets are common medication suppliers in Indonesia, yet little is known regarding their practices. This study aimed to evaluate the medication selling practices occurring in kiosks and minimarkets during the coronavirus disease 2019 pandemic. A cross-sectional study included all minimarkets (N = 101) and a convenience sample of kiosks (a minimum sample size, N = 67) in District X, Indonesia. A validated tool was used to collect data on the characteristics of kiosks/minimarkets and their medication selling practices (i.e. drug management and drug information). A sample of 67 kiosks and 52 minimarkets (response rate 51.5%) consented to participate in this study. Kiosks and minimarkets generally stocked nonprescription drugs, particularly cough and/or common cold products or analgesic-antipyretics; while >90% of kiosks and 15.4% of minimarkets provided prescription medicines. Medications in kiosks and minimarkets were mainly obtained from pharmacies (94.0% vs. 17.0%, respectively) or pharmaceutical wholesale representatives (68.7% vs. 96.0%, respectively). Most minimarkets or kiosks satisfied drug storage standards (100.0% vs. 88.1%, respectively). During the previous week, >80% of kiosks and minimarkets reported purchases of nonprescription drugs, and approximately 5% reported sales of prescription drugs. No drug information was provided by kiosk or minimarket staff. Minimarkets and kiosks may improve access to basic medications, but no information is provided regarding their use. These outlets should be licensed and policed to ensure the range and quality of drugs, and information provided to the Indonesian community is appropriate.

Tactics and Strategies for the Synthesis of Cereblon Ligands

AbstractTargeted protein degradation (TPD) has emerged as an important strategy to target disease-relevant proteins that were previously considered difficult to drug or even undruggable. Cereblon (CRBN) plays an outsized role in TPD as a preferred degradation-inducing effector protein for several reasons, including its anticipated broad protein substrate scope and its ligandability with drug-like small molecules. Notably, CRBN-based molecular glue degraders (MGDs) and proteolysis targeting chimeras (PROTACs) have shown success in clinical trials and, in some cases, as approved drugs. Thus, the interest in CRBN ligands within the pharmaceutical industry and academia has increased dramatically in recent years, highlighting the need for robust synthetic approaches towards them. This short review summarizes tactics and strategies to synthesize CRBN ligands, including the most recent developments in the field. Particular emphasis is put on the construction and direct functionalization of key CRBN binding motifs such as glutarimides and dihydrouracils.1 Introduction2 Cereblon Ligands with Glutarimide Binding Motif3 Cereblon Ligands with Dihydrouracil Binding Motif4 Cereblon Ligands with Other Binding Motifs5 Conclusions and Outlook

Effects of different carbon and nitrogen sources on liamocin production kinetics of Aureobasidium pullulans NBRC 100716 strain.

Liamocins are molecules with a polyol lipid structure produced by rare strains of Aureobasidium pullulans. In recent years, liamocins have attracted attention due to their antibacterial, anticancer and surface-active properties, and promising potential applications have been identified in the food, agriculture, medical and pharmaceutical industries. This study is the first to investigate the effects of different carbon and nitrogen sources on the growth and liamocin production kinetics of A. pullulans NBRC 100716 strain. This strain was selected among six different A. pullulans strains whose liamocin productions were tested by us for the first time. In fermentations carried out in shaking water baths, the carbon source that most supported the liamocin production of this strain was fructose, and the nitrogen source was peptone-yeast extract combination. In the medium containing fructose and the peptone-yeast extract mixture, A. pullulans NBRC 100716 produced 4.26g liamocin L-1. The specific liamocin production rate (qp) of the strain in this medium was 0.0090g liamocin/g mo.h. This study is also the first to produce liamocin with a fructophilic A. pullulans strain. Present findings in this research also demonstrated the excellent biosurfactant capacity of the liamocin produced by this strain. The obtained liamocin reduced the water surface tension to a degree that can compete with synthetic surfactants. Furthermore, this is the first report to reveal that the fatty acid profile of liamocin obtained from A. pullulans NBRC 100716 contains an appreciable amount of unsaturated fatty acids and is similar to the composition of vegetable oil.

A Unified Adsorption Kinetic Model Inspired by Epidemiological Model: Based on Adsorbates "Infect" Adsorbents.

Adsorption is a unit operation used in various fields, including the environmental, chemical, and pharmaceutical industries. Understanding the adsorption kinetics is crucial to designing efficient adsorption systems. However, existing empirical adsorption models are limited in providing insights into the mass transfer mechanisms. Additionally, the absence of a unified adsorption kinetic model hampers the effective comparison of different adsorption systems. Here, we viewed the adsorption as an "infectious process of adsorbates by adsorbents" akin to epidemiology. In epidemiology, individuals can be divided into susceptible, infected, and recovered compartments, ignoring the complexities of movement among individuals. Analogously, we have categorized the adsorbates as adsorbable, adsorbed, and removed compartments. Thus, we proposed a unified adsorption kinetic model (the monolayer-multilayer-adsorbable-adsorbed-removed model) that accommodates monolayer/multilayer adsorption. The model was designed to encompass diverse adsorption setups, including continuous and batch processes with fixed/dispersed adsorbents. The versatility and applicability of the model were demonstrated through validation using a diverse set of experimental data. This validation underscored its effectiveness in water/wastewater treatment, salt reduction, metal recovery, and drug purification. A MATLAB-based program for solving this model was made available to researchers for their utilization and further investigations. Overall, this study developed a versatile adsorption kinetic model that offers a comprehensive and unified understanding of adsorption kinetics across various applications.

Chemical characterization and antibacterial activities of Brazilian propolis extracts from Apis mellifera bees and stingless bees (Meliponini).

The aim of this study was to evaluate the physicochemical composition and antibacterial activity of Brazilian propolis extracts from different types, concentrations, and extraction solvents and from different regions in Brazil. A total of 21 samples were analyzed, comprising 14 samples from Apis mellifera (12 green, 1 brown, and 1 red) and 7 samples from stingless bees (3 mandaçaia, 2 jataí, 1 hebora, and 1 tubuna). The analyses performed were dry extract, total phenolic content (TPC) and antioxidant activity (DPPH and ABTS). The antibacterial activity was performed by Determination of Minimal Inhibitory Concentration (MIC) and Minimal Bactericidal Concentration (MBC). The results showed that very low levels of phenolic compounds and antioxidant activity decreased the antimicrobial activity of the propolis extracts from tubuna and jataí. However, there was no correlation between the increase in propolis concentration in the extract, and the increase in antimicrobial activity. The highest TPC and antioxidant activity was obtained for green propolis extract made with 70% raw propolis that presented similar antibacterial activity to the samples formulated with 30% or less raw propolis. The aqueous propolis extract showed lower antimicrobial activity compared to the alcoholic extracts, indicating that ethanol is a better solvent for extracting the active compounds from propolis. It was observed that the MIC (0.06 to 0.2 mg/mL) and MBC (0.2 to 0.5 mg/mL) values for Gram-negative bacteria were higher compared to Gram-positive bacteria (MIC 0.001-0.2 mg/mL, and the MBC 0.02-0.5 mg/mL). The propolis extracts that exhibited the highest antimicrobial activities were from stingless bees hebora from the Distrito Federal (DF) and mandaçaia from Santa Catarina, showing comparable efficacy to samples 5, 6, and 7, which were the green propolis from the DF. Hence, these products can be considered an excellent source of bioactive compounds with the potential for utilization in both the pharmaceutical and food industries.

Exploiting Nitroreductases for the Tailored Photoenzymatic Synthesis of Structurally Diverse Heterocyclic Compounds.

N-heterocyclic compounds have a broad range of applications and their selective synthesis is very appealing for the pharmaceutical and agrochemical industries. Herein we report the usage of the flavin-dependent nitroreductase BaNTR1 for the photoenzymatic synthesis of various anthranils and quinolines from retro-synthetically designed o-nitrophenyl-substituted carbonyl substrates, achieving high conversions (up to >99%) and good product yields (up to 96%). Whereas the effective production of anthranils required the inclusion of H2O2 in the reaction mixtures to accumulate the needed hydroxylamine intermediates, the formation of quinolines required the use of anaerobic or reducing conditions to efficiently generate the essential amine intermediates. Critical to our success was the high chemoselectivity of BaNTR1, performing selective reduction of the nitro group without reduction of the carbonyl moiety or the activated carbon-carbon double bond. The results highlight the usefulness of an innocuous chlorophyll- and nitroreductase-based photoenzymatic system for the tailored synthesis of diverse N-heterocycles from simple nitro compounds.

Experimental investigation on enhancement in pure axial deformation of soft pneumatic actuator (SPA) with cap ring reinforcement

Bio-inspired soft-robots are nowadays found their place in many applications due to its flexibility, compliance and adaptivity to unstructured environment. The main intricate part of such bio-inspired soft robots are soft pneumatic actuators (SPA) which replicate or mimic the limbs and muscles. The soft actuators are pneumatically actuated and provide bending motion in most cases. However, many engineering and medical applications need axially expanding soft pneumatic actuators to deal with delicate objects. Various studies have put forward designs for SPA with axial deformation, but the majority of them have limited axial deformation, constraining motion and less overall efficacy which limit the scope of utilization. The common practice to enhance the axial deformation of SPA is by incorporating directionally customized reinforcement using fibres or by other means like yarns, fabrics, etc These types of reinforcements are generally embedded to SPA during fabrication and may not have capability for any correction or modification later on hence lack the customization. This paper presents a novel method of radial reinforcement for the enhancement of axial deformation of SPAs with provision of customization. The present study aims to enhance and/or customize the axial deformation of SPA by incorporating external and detachable reinforcement in the form of annulus shaped cap ring. The investigation encompasses the design and attachment of four distinct cap ring geometries to SPA at different locations. Experimental results affirm that cap ring reinforcement bolster the radial stiffness, curbing lateral deformation while permitting axial deformation of soft pneumatic actuators. Out of 64 distinct configurations, the one with full reinforcement, featuring four cap rings of maximum size, yields a remarkable 169% increase in pure axial deformation compared to unreinforced cases. It is also observed that by varying the number and placement locations of cap rings the pure axial deformation can be customized. This novel insight not only propels soft pneumatic actuation technology but also heralds prospects for highly agile and versatile robotic systems which can be used in medical, prosthetics, pharmaceutical and other industries.

Comparative Analysis of Investment Potential of Leading Pharmaceutical Companies

This research paper aims to address the research question of identifying the most promising investment target among four leading pharmaceutical companies: Merck (MRK), Pfizer (PFE), Johnson & Johnson (JNJ), and Novartis AG (NVS). The study seeks to provide investors with valuable insights into the financial performance and investment potential of these industry giants, guiding them towards informed decision-making. In the academic field, this research contributes to the understanding of how financial metrics can be utilized to evaluate investment opportunities in the pharmaceutical sector, offering practical implications for investors and researchers alike. The methods employed in this study involved a comprehensive analysis of key financial indicators, including earnings per share (EPS), price-to-earnings (P/E) ratio, and profitability ratios such as gross profit margin and gross profit-to-assets (GP/A) ratio. By examining these metrics, the research aimed to assess the relative strengths and weaknesses of each company and determine the most attractive investment option among the four pharmaceutical giants. The results of the analysis revealed Pfizer (PFE) as the recommended investment target based on its lower P/E ratio, favorable PEG ratio, strong EPS growth rate, and improving net profit margin. This finding suggests that Pfizer presents a compelling investment opportunity in the pharmaceutical sector, offering potential for growth and financial stability. The implications of this research extend to investors seeking to navigate the complexities of the pharmaceutical industry, providing them with actionable insights to make informed investment decision.

Assessment of innovativeness, and price and reimbursement negotiation of medicines: recommendations of an expert panel

This paper illustrates the recommendations of a Working Group (WG) on the assessment of drugs innovativeness and the negotiation of price and reimbursement. The WG included researchers, institutions, clinicians, patient representatives and pharmaceutical companies. The first part of the contribution summarizes the literature on drug pricing models, which was considered in the WG, and, in particular, the pricing criteria, the evaluation and negotiation processes, the management of the uncertainty of the evidence, the use of cross-reference pricing and price negotiation for new indications of existing drugs. The second part illustrates the results of the WG with a focus on innovativeness assessment, value framework and price negotiation. The main recommendations of the WG are: to define more specific criteria for the identification of comparators and endpoints for macro therapeutic areas/settings; to produce guidelines on the use of indirect comparisons and studies supporting this evidence; to consider the drug value as the main driver of price and reimbursement negotiation; to maintain flexibility in the negotiation process, but, at the same time, to give greater structure and predictability in the assessment of value for money, with a more qualified role of cost-effectiveness and a range of threshold values for the incremental cost-effectiveness ratio; to selectively reintroduce Managed Entry Agreements and the Indication-based pricing model; to implement an early dialogue between the Italian Medicine Agency and the pharmaceutical companies in order to optimize the negotiation process, and a structured involvement of scientific societies and patient representatives.

“Emerging Occupational Risks in a Pharmaceutical Company Under Industry 4.0: An Assessment Using TICHNER and HIRAC Tools”

Abstract: The integration of Industry 4.0 technologies within the pharmaceutical manufacturing sector aligns with broader industrial objectives, aiming to enhance productivity and adaptability while meeting challenging standards for product quality and diversity while maximizing efficiency. However, this shift is not risk-free. This particularly concerns the well-being of workers which is one of the top concerns shared by manufacturers. As the industry navigates this transition, it is imperative to prioritize the safety of personnel. The rapid pace of technological innovation within pharmaceutical manufacturing carries significant implications, introducing new and emerging risks. Consequently, proactive identification and assessment of these potential threats are essential to effectively mitigate their impact and ensure preparedness for forthcoming changes. To address this gap, this study provides an approach for identifying potential sources and significant factors contributing to its increasing risks in implementing Industry 4.0 in manufacturing industries. This set of sources and factors was evaluated in a medium-sized pharmaceutical manufacturing company aided by TICHNER and HIRAC Tools through a mixed-method approach. The combination of these tools facilitates the identification, characterization, and analysis of new and emerging risks associated with Industry 4.0 implementation. The findings of the study showed that Psychosocial Hazards and Work Experience/ Knowledge are the most common potential sources of Psychological Risks, Unemployment, and Need for Qualified Workers. The approach will allow manufacturers to proactively manage the new and emerging challenges brought by Industry 4.0 and safeguard the well-being of the workforce.

Production of Steroid Hormones in Galena Opava

The drug product Antigest of the company Spofa was launched as soon as in 1965 and Czechoslovakia thus became forth country in the world where oral anticonception was introduced. The gestagen component of Antigest was methenmanidon acetate (superlutin), an original substance developed in the Research Institute of Natural Drugs. Superlutin and some other steroid drugs were produced in the Galena Opava plant. In the article, all the syntheses utilized in the manufacture of steroid drugs in Galena are described and the reasons why the manufacture of steroid drugs was terminated at the beginning of eighties are explained.

Drug-drug interactions and synergy: from pharmacological models to clinical application.

This review explores the concept of synergy in pharmacology, emphasizing its importance in optimizing treatment outcomes through the combination of drugs with different mechanisms of action. Synergy, defined as an effect greater than the expected additive effect elicited by individual agents according to specific predictive models, offers a promising approach to enhance therapeutic efficacy while minimizing adverse events. The historical evolution of synergy research, from ancient civilizations to modern pharmacology, highlights the ongoing quest to understand and harness synergistic interactions. Key concepts such as concentration-response curves, additive effects, and predictive models are discussed in detail, emphasizing the need for accurate assessment methods throughout translational drug development. While various mathematical models exist for synergy analysis, selecting the appropriate model and software tools remains a challenge, necessitating careful consideration of experimental design and data interpretation. Furthermore, this review addresses practical considerations in synergy assessment, including preclinical and clinical approaches, mechanism of action, and statistical analysis. Optimizing synergy requires attention to concentration/dose ratios, target site localization, and timing of drug administration, ensuring that the benefits of combination therapy detected at bench-side are translatable into clinical practice. Overall, the review advocates for a systematic approach to synergy assessment, incorporating robust statistical analysis, effective and simplified predictive models, and collaborative efforts across pivotal sectors such as academic institutions, pharmaceutical companies, and regulatory agencies. By overcoming critical challenges and maximizing therapeutic potential, effective synergy assessment in drug development holds promise for advancing patient care. Significance Statement Combining drugs with different mechanisms of action for synergistic interactions optimizes treatment efficacy and safety. Accurate interpretation of synergy requires the identification of the expected additive effect. Despite innovative models to predict the additive effect, consensus in drug interaction research is lacking, hindering the bench-to-bedside development of combination therapies. Collaboration among science, industry, and regulation is crucial for advancing combination therapy development, ensuring rigorous application of predictive models in clinical settings.

Regio- and Stereoselective Transfer Hydrogenation of Aryloxy Group-Substituted Unsymmetrical 1,2-Diketones: Synthetic Applications and Mechanistic Studies.

Developing a general method that leads to the formation of different classes of chiral bioactive compounds and their stereoisomers is an attractive but challenging research topic in organic synthesis. Furthermore, despite the great value of asymmetric transfer hydrogenation (ATH) in both organic synthesis and the pharmaceutical industry, the monohydrogenation of unsymmetrical 1,2-diketones remains underdeveloped. Here, we report the aryloxy group-assisted highly regio-, diastereo-, and enantioselective ATH of racemic 1,2-diketones. The work produces a myriad of enantioenriched dihydroxy ketones, and further transformations furnish all eight stereoisomers of diaryl triols, polyphenol, emblirol, and glycerol-type natural products. Mechanistic studies and calculations reveal two working modes of the aryloxy group in switching the regioselectivity from a more reactive carbonyl to a less reactive one, and the potential of ATH on 1,2-diketones in solving challenging synthetic issues has been clearly demonstrated.