Successful Drug Research Articles

Treatment of Carbapenem-Resistant Acinetobacter baumannii in Real Life (T-ACI): A Prospective Single-Center Observational Study

Background: Carbapenem-resistant Acinetobacter baumannii (CRAB) poses significant challenges in healthcare due to its multidrug resistance and high mortality rates among critically ill patients. Results: We enrolled 45 patients. Cefiderocol was administered to 40% of patients, often (38.8%) in combination with other antibiotics. Colistin was administered to 60% of patients and always in combination, mostly with ampicillin–sulbactam. The overall ECS and OCS rates were 77.8% and 66.7%, respectively. Patients treated with an initial cefiderocol-based regimen showed a higher rate of ECS compared with patients initially treated with colistin-based regimens (100% vs. 63%, p < 0.05). Patients treated with cefiderocol alone showed a higher rate of ECS compared with patients treated with cefiderocol-based regimens (100% vs. 70.6%, p < 0.05). No differences in OCS rates were recorded depending on the treatment received. Additionally, cefiderocol regimens were associated with fewer ADRs compared to colistin-based treatment. Methods: This prospective observational study enrolled patients with CRAB infections from January 2022 to August 2023. Patients were treated with cefiderocol-based or colistin-based regimens and were monitored for 28 days to assess early clinical success (ECS), overall clinical success (OCS) and adverse drug reactions (ADRs). Conclusions: This study highlights the potential advantages of cefiderocol, even used as a monotherapy, in treating CRAB, especially when early clinical and laboratory response was assessed. This research contributes to the ongoing discussion on the most effective and safe treatments for combating CRAB infections, supporting the use of cefiderocol in clinical practice.

A compound-target pairs dataset: differences between drugs, clinical candidates and other bioactive compounds

Providing a better understanding of what makes a compound a successful drug candidate is crucial for reducing the high attrition rates in drug discovery. Analyses of the differences between active compounds, clinical candidates and drugs require high-quality datasets. However, most datasets of drug discovery programs are not openly available. This work introduces a dataset of compound-target pairs extracted from the open-source bioactivity database ChEMBL (release 32). Compound-target pairs in the dataset either have at least one measured activity or are part of the manually curated set of known interactions in ChEMBL. Known interactions between drugs or clinical candidates and targets are specifically annotated to facilitate analyses of differences between drugs, clinical candidates, and other active compounds. In total, the dataset comprises 614,594 compound-target pairs, 5,109 (3,932) of which are known interactions between drugs (clinical candidates) and targets. The extraction is performed in an automated manner and fully reproducible. We are providing not only the datasets but also the code to rerun the analyses with other ChEMBL releases.

Berberine-Loaded Bovine Serum Albumin Nanoparticles: Fabrication, Characterization, and Drug Release Evaluation

Abstract Introduction/Objective Introduction: Numerous studies have highlighted the diverse biochemical and pharmacological properties of berberine (BER), including its anti-inflammatory, antioxidant, anticancer, and hypolipidemic effects. Nanoparticles play a crucial role in enhancing drug delivery by providing a larger surface area, facilitating quicker dissolution in the bloodstream. Methods/Case Report Methods: Blank bovine serum albumin nanoparticles (BSA NPs) were prepared using a desolvation process, followed by the fabrication of berberine-loaded BSA nanoparticles (BER-NP). Physicochemical characterization, including particle size and zeta potential, was conducted using a Malvern Zetasizer. The mean particle size and distribution were determined using photon correlation spectroscopy (PCS), and transmission electron microscope (TEM) images were obtained for visualization. Fourier transform infrared (FTIR) spectra and differential scanning calorimetry (DSC) thermograms were recorded to assess drug encapsulation efficiency (EE). Berberine release from BER-NPs was evaluated using dialysis membranes. Results (if a Case Study enter NA) Results: FTIR spectra and DSC thermograms confirmed successful drug loading into the nanoparticles. Encapsulation efficiency was determined by UV absorption spectroscopy, revealing high efficiency in the encapsulation process. Dialysis membranes demonstrated controlled release kinetics of berberine from BER-NPs, indicating their potential for targeted drug delivery. Conclusion Conclusion: Berberine-loaded bovine serum albumin nanoparticles exhibit favorable characteristics for drug delivery applications, including enhanced permeation across biological barriers. These nanoparticles hold promise for targeted therapy and combination drug regimens, offering potential benefits for various medical interventions.

Reassessing ayahuasca regulation in Brazil: strategic framing and cumulative gains

Background In the early twentieth century, ayahuasca gained popularity in northern Brazil, causing political tension due to moral hostility. However, over the course of the century, despite the proscription of DMT and the intensification of the ‘War on Drugs’, three phases of cumulative political gains eventually led to the full regulation of ayahuasca, in 2010. How was this achieved? Methods This paper provides a comprehensive reassessment of the existing literature on ayahuasca in Brazil, utilizing social movement theory. Emphasis is placed on framing methods, or how movements strategically present their aims to particular audiences, in order to effect political change. Results First, ayahuasca churches constructed a religious frame that emphasized their Christian pedigree. Second, when harassment intensified, ayahuasca was reframed as a charitable endeavour. Finally, in the transition to democracy, the religions added a scientific frame, collaborating with the state to review scientific evidence and establish policy parameters for regulation. Conclusion Framing ayahuasca as Christian and focusing on charity and science were neither straightforward nor unproblematic, but did allow ayahuasca groups to successfully avoid persecution, establish relationships with powerful actors, and eventually achieve full regulation. This case study provides unique insights into the role of social movements in successful drug policy reform, especially how movements can strategically adapt to and influence prevailing moral codes, resulting in concrete political victories.

Leveraging pleiotropy for the improved treatment of psychiatric disorders.

Over 90% of drug candidates fail in clinical trials, while it takes 10-15 years and one billion US dollars to develop a single successful drug. Drug development is more challenging for psychiatric disorders, where disease comorbidity and complex symptom profiles obscure the identification of causal mechanisms for therapeutic intervention. One promising approach for determining more suitable drug candidates in clinical trials is integrating human genetic data into the selection process. Genome-wide association studies have identified thousands of replicable risk loci for psychiatric disorders, and sophisticated statistical tools are increasingly effective at using these data to pinpoint likely causal genes. These studies have also uncovered shared or pleiotropic genetic risk factors underlying comorbid psychiatric disorders. In this article, we argue that leveraging pleiotropic effects will provide opportunities to discover novel drug targets and identify more effective treatments for psychiatric disorders by targeting a common mechanism rather than treating each disease separately.

Formulation of Felodipine lipid nanoparticle-loaded oral fast-dissolving films

Abstract Felodipine, a calcium channel blocker used to treat hypertension, is a BCS Class II drug characterized by low solubility, high permeability and significant hepatic metabolism, which limits its bioavailability to 15 %. This study focuses on improving the bioavailability of Felodipine by developing oral fast-dissolving films (OFDFs) incorporating lipid nanoparticles. Felodipine loaded lipid nanoparticles were prepared using glyceryl monooleate (GMO) as lipid and Poloxamer 407 as the surfactant, and then incorporated into OFDFs using the solvent casting technique. A Box-Behnken design with Design Expert Stat-Ease® 360 was used to evaluate the impact of GMO, Poloxamer 407 concentration, and sonication time on particle size and entrapment efficiency. The resulting nanoparticle dispersions had particle sizes ranging from 74.92 nm to 112.1 nm and entrapment efficiencies between 80.43 % and 95.23 %. Differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD) confirmed successful drug encapsulation. The OFDF showed optimal mechanical properties, disintegration within (41.33 ± 3.51) s, and an in-vitro drug release of (89.82 ± 2.75) % in 6 min. Scanning electron microscopy (SEM) revealed a smooth, uniform, porous surface and the films remained stable for three months. The study concludes that Felodipine loaded lipid nanoparticles in fast-dissolving OFDFs improve permeability, dissolution, and onset of action, making them a promising approach for antihypertensive therapy.

Preparation and characterization of niosomes for the delivery of a lipophilic model drug: comparative stability study with liposomes against phospholipase-A2

Vesicular nanocarriers like niosomes and liposomes are widely researched for controlled drug delivery systems, with niosomes emerging as promising alternatives due to their higher stability and ease of manufacturing. This study aimed to develop and characterize a niosomal formulation for the encapsulation and sustained release of temozolomide (TMZ), a model lipophilic drug, and to compare the stability of niosomes and liposomes, with a particular focus on the behavior of their lipid bilayers. Niosomes were prepared using the thin-film hydration method, composed of Span 60 (Sorbitan monostearate), cholesterol, and soy lecithin in varying molar ratios. The study investigated critical properties such as drug loading capacity, release kinetics, and resistance to enzymatic degradation. The optimized formulation was analyzed for drug entrapment efficiency and stability against phospholipase A2 (PLA2) degradation. The optimized niosomal formulation, with a 4:2:1 molar ratio of Span 60: cholesterol, achieved a high TMZ entrapment efficiency of 73.23 ± 1.02% and demonstrated sustained drug release over 24 hours. In comparison, liposomes released their TMZ payload within 4 hours upon exposure to PLA2, while the niosomes maintained their release profile, indicating superior stability. Spectroscopic and thermal analysis confirmed successful drug encapsulation with no component incompatibilities.

Clinical research vehicles as a modality for medical research education and conduct of decentralized trials, supporting justice, equity, and diversity in research.

Current clinical research lacks diversity in those that participate. This lack of diversity is concerning given its importance for successful drug development. The frequency and severity of many diseases, along with the pharmacological properties of therapies, can display significant differences based on patient diversity. A clinical trial population that is more reflective of these differences will help researchers better understand the therapeutic profile of the treatment and provide generalizable knowledge to the medical community. The advent of decentralized clinical trial designs is meant to help address this lack of diversity by using portable digital health technologies and virtual interactions to enhance clinical trial access and broaden participation. By leveraging these technologies, trial conduct can occur at locations other than traditional research sites. This shift in trial location may help address some of the logistical, educational, engagement, and trust barriers that have historically prevented enrollment of diverse populations. However, these types of trials still have limitations. Ethical concerns around justice, equity, and diversity will still exist with decentralized clinical trials, which could be mediated using clinical research vehicles. When utilized, this modality may enhance the scientific design and conduct of clinical trials and better follow these ethical principles. These enhancements and improved ethical direction could be accomplished through increasing community involvement, improving health literacy, supporting more diverse trial sites, creating community-based research footholds, fostering connections with researchers, limiting technical challenges, and preventing data security issues.

Illicit drug use in Limerick City: A stakeholder and policy analysis using multiple streams model.

The changing drug situation in Ireland has led to the development of various drug policies. This paper aims to use Limerick City as a case study to examine approaches to policy development. The study is qualitative and uses a hybrid technique that combines document, content, and stakeholder analysis. Kingdon's multiple streams model underpins this study. In addition, guidelines for the systematic search for grey literature were adopted as the search strategy. Problem Stream: Illicit drug use and its related problems have changed. The increasing availability of drugs, increasing usage and changes in the types of drugs being used have led to increased drug-related crimes, adverse health outcomes and elevated demand for treatment services. Local drug policies and initiatives emerge by recognising drug-related problems in the region. Policy Stream: The current national drug strategy 2017-2025 which informs action plans in Limerick is the first to focus on a unified health approach. Some national policies have evolved to ensure that guidelines meet current service needs. However, these changes have occurred in some cases with no clear actions. Political Stream: Statutory, voluntary and community stakeholders provide drug addiction and drug addiction-related services, which have evolved rapidly since their first introduction. The Mid-West Regional Drug Task Force was identified as essential in coordinating stakeholders locally. One area for improvement is limited evidence of the voices of persons who take drugs included in service/policy development. This regional analysis also suggests that local implementation of policies concerning dual diagnosis and supervised injection facilities can be further expanded. Despite the challenges experienced by stakeholders in Limerick, a hands-on approach has been adopted in the creation of strategies to tackle the drug problem. The approaches to drug policy development have delivered continuous development of services. However, services remain underdeveloped in areas removed from the capital city of Dublin. Navigating the complex drug landscape reveals that inclusivity, adaptation, and ongoing research are critical components of successful and long-lasting drug policies.

Nanomedicine in Management of Cerebral Infarction and Brain Cancer: Role of Inflammation.

Cerebral infarction, the blockage of blood vessels in the brain, is generally an age-related illness. Factors such as unhealthy diets, stressful behaviours and decreased environmental consistency with physiological barriers also contribute to increased casualties. Long-term brain function reconstruction and successful drug therapy are needed. The most frequent malignant brain tumour, glioblastoma, has been linked to variations in mitochondrial ROS, chaperone-mediated autophagy, and the interaction between lncRNA (BC200) and miRNA. Glioblastoma stem cells express high levels of ATP/P2X7 receptors, promoting survival by activating M2 muscarinic receptors. This expert opinion provides an overview of the latest experimental drug therapies aimed at protecting against and restoring cerebral stroke. Nanomedicine overcomes the challenges associated with traditional therapy and physiological obstacles in the treatment of cerebral infarction by improving stroke management, including diagnosis, imaging, and treatment, addressing a diverse range of associated factors.

Approved medicines for paediatric solid tumours in Europe: Lessons from the life cycle of a paediatric investigation plan

BackgroundDespite the positive changes brought by the Paediatric Regulation in the European Union (EU) in 2007, drug development in children remains challenging. MethodsTo better understand the issues encountered to reach an authorisation for paediatric patients, we reviewed the pathway of the 11 Paediatric Investigational Plans (PIPs) with indications targeting paediatric solid tumours granted by the Committee for Medicinal Products for Human Use (CHMP) between 2007 and 2022. ResultsOn average 5,5 years were necessary to reach approval after a PIP was agreed. All the PIPs underwent at least one modification (median 3 modifications per PIP). The use of single arm trials, in the context of refractory/relapsed disease in absence of standard of care treatment, was supportive for granting a paediatric indication in the majority of the cases. In 6 out of 11 approved products, extrapolation from adults was used. For 2/11 the approval focused on an older population first compared to the initial age group agreed in the PIP due to the development of a suitable formulation for younger children still ongoing at the time of first approval. Scientific advice sought on paediatric development use of extrapolation from adults, major objections raised by CHMP and post-marketing requirements were examined. ConclusionAnalysing the process necessary to reach an authorisation for paediatric patients, we highlight the major challenges faced in the paediatric approval process and the positive examples of successful drug development that reached final approval. Our analysis is expected to provide useful insights to drug developers, investigators and regulators.

A best practices framework for spatial biology studies in drug discovery and development: enabling successful cohort studies using digital spatial profiling

ABSTRACT The discovery of biomarkers, essential for successful drug development, is often hindered by the limited availability of tissue samples, typically obtained through core needle biopsies. Standard ‘omics platforms can consume significant amounts of tissue, forcing scientist to trade off spatial context for high-plex assays, such as genome-wide assays. While bulk gene expression approaches and standard single-cell transcriptomics have been valuable in defining various molecular and cellular mechanisms, they do not retain spatial context. As such, they have limited power in resolving tissue heterogeneity and cell–cell interactions. Current spatial transcriptomics platforms offer limited transcriptome coverage and have low throughput, restricting the number of samples that can be analyzed daily or even weekly. While the Digital Spatial Profiling (DSP) method does not provide single-cell resolution, it presents a significant advancement by enabling scalable whole transcriptome and ultrahigh-plex protein analysis from distinct tissue compartments and structures using a single tissue slide. These capabilities overcome significant constraints in biomarker analysis in solid tissue specimens. These advancements in tissue profiling play a crucial role in deepening our understanding of disease biology and in identifying potential therapeutic targets and biomarkers. To enhance the use of spatial biology tools in drug discovery and development, the DSP Scientific Consortium has created best practices guidelines. These guidelines, built on digital spatial profiling data and expertise, offer a practical framework for designing spatial studies and using current and future spatial biology platforms. The aim is to improve tissue analysis in all research areas supporting drug discovery and development.

Endogenous cell membrane interactome mapping for the GLP-1 receptor in different cell types.

The GLP-1 receptor, one of the most successful drug targets for the treatment of type 2 diabetes and obesity, is known to engage multiple intracellular signaling proteins. However, it remains less explored how the receptor interacts with proteins on the cell membrane. Here, we present a ligand-based proximity labeling approach to interrogate the native cell membrane interactome for the GLP-1 receptor after agonist simulation. Our study identified several unreported putative cell membrane interactors for the endogenous receptor in either a pancreatic β cell line or a neuronal cell line. We further uncovered new regulators of GLP-1 receptor-mediated signaling and insulinotropic responses in β cells. Additionally, we obtained a time-resolved cell membrane interactome map for the receptor in β cells. Therefore, our study provides a new approach that is generalizable to map endogenous cell membrane interactomes for G-protein-coupled receptors to decipher the molecular basis of their cell-type-specific functional regulation.

Formulation, Design, Optimization, and Characterization of Novel Long-acting Injectable Dosage Form of Anti-psychotic Drug

Background: The current research aimed to create and analyze a new long-acting Brexpiprazole (BRX) injectable for successful anti-psychotic drug therapy in order to decrease dosage frequency and increase patient compliance. Systems for drug transport to particular body sites or regulating release rates with accuracy are known as drug delivery systems (DDS). By affixing the drug to a carrier particle like liposomes, nanoparticles, microspheres, etc., which modifies the drug's absorption and release properties, using carrier technology, drugs may be delivered in an intelligent manner. Methods: Utilizing Resomer RG 502 H and RESOMER® RG 752 H extended-release Polymer, Using a quasi-emulsion solvent diffusion, microspheres were made, and emulsification and solvent evaporation process. Results: The produced microspheres were assessed for stability tests, in vitro drug release, flow characteristics, and drug entrapment efficiency. FTIR experiments were used to establish how well the drug excipients worked together. The acarbose microspheres that were created had an 89.9 to 96.1 percent drug entrapment efficiency. The impact of factors like polymer content on medication release was studied. The Stability study of the formulation was carried out under different conditions, and data were established. Comparative pharmacokinetic studies between marketed oral formulation and Brexpirazole microsphere test formulations in Wistar/SD Rats were carried out and concluded. Conclusion: Brexpiprazole (BRX) novel long-acting injectable formulation, could be used effectively for the treatment of mentally challenged anti-psychotic patients worldwide.

Fiber Optics Analysis of Floating Hollow Microspheres for a Poorly Water-Soluble Drug

This study investigates the development and evaluation of floating hollow microspheres for the delivery of omeprazole, a poorly water-soluble drug. The research aims to enhance omeprazole's bioavailability by addressing its low solubility and susceptibility to degradation in an acidic gastric environment. Hollow ethyl cellulose microspheres encapsulating omeprazole were prepared using the solvent evaporation technique. The microspheres displayed 91.3% buoyancy and 82.41% drug entrapment efficiency, with sustained drug release in simulated gastric fluid over 12 hours. Characterization techniques such as X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM) were used. XRD analysis indicated that the encapsulated drug was in an amorphous state, improving dissolution rates and bioavailability. FTIR confirmed successful drug encapsulation, and SEM revealed the morphology and porous structure of the microspheres. The results highlighting the potential of floating hollow microspheres to enhance the oral bioavailability of poorly water-soluble drugs. Recommendations include refining the formulation process and exploring microfluidic technology for generating uniform microspheres with high drug loading. The study provides valuable insights for the development of advanced drug delivery systems.

Application of human-derived samples in preclinical research

Drug discovery research takes many years and tons of effort, and the success rate is extremely low. In order to overcome this situation, pharmaceutical companies struggle to improve the probability of success drug research and development with multiple approaches. Recently, it is important to predict the clinical effects of the candidates as early as possible in drug discovery stage, to stratify patients with diseases, and to provide appropriate readouts for evaluation of pharmacological efficacy for increasing the success rate. In this environment, the importance of non-clinical research that actively utilizes human-derived samples including patient-derived samples is increasing. In this article, author describes the use of human-derived samples in non-clinical research, especially focusing on the utilization of induced pluripotent stem cells. Human-derived samples are valuable experimental materials that have, at least in part, human-specific characteristics that experimental animals do not possess. In particular, patient-derived samples are thought to have the genetic predisposition and at least some disease characteristics that cause the disease, and are useful from the perspective of elucidating the pathogenesis, disease modeling, and predictability of clinical effects. This is also valuable for drug discovery research in diseases that are difficult to reproduce in experimental animals such as mice. Whereas, human-derived samples have some limitations, and we need ethical procedures and consideration when researchers use them. Author will provide an overview of the use of human-derived samples in non-clinical research based on the perspectives as described above and introduce our research group cases, and future research prospects using them.

Investigating FSGS-like injury in zebrafish larvae by nifurpirinol: efficacy and molecular insight.

Identifying effective drugs for focal segmental glomerulosclerosis (FSGS) treatment holds significant importance. Our high-content drug screening on zebrafish larvae relies on nitroreductase/metronidazole (NTR/MTZ)-induced podocyte ablation to generate FSGS-like injury. A crucial factor for successful drug screenings is minimizing variability in injury induction. For this, we introduce nifurpirinol (NFP) as a more reliable prodrug for targeted podocyte depletion. NFP showed a 2.3-fold increase in efficiency at concentrations 1,600-fold lower compared with MTZ-mediated injury induction. Integration into the screening workflow validated its suitability for the high-content drug screening. The presence of crucial FSGS hallmarks, such as podocyte foot process effacement, proteinuria, and activation of parietal epithelial cells, was observed. After the isolation of the glomeruli from the larvae, we identified essential pathways by proteomic analysis. This study shows that NFP serves as a highly effective prodrug to induce the FSGS-like disease in zebrafish larvae and is well-suited for a high-content drug screening to identify new candidates for the treatment of FSGS.NEW & NOTEWORTHY This research investigated the use of nifurpirinol in nanomolar amounts as a prodrug to reliably induce focal segmental glomerulosclerosis (FSGS)-like damage in transgenic zebrafish larvae. Through proteomic analysis of isolated zebrafish glomeruli, we were further able to identify proteins that are significantly regulated after the manifestation of FSGS. These results are expected to expand our knowledge of the pathomechanism of FSGS.

Computer Simulations of Responsive Nanogels at Lipid Membrane.

The swelling and collapse of responsive nanogels on a planar lipid bilayer are studied by means of mesoscopic computer simulations. The effects of molecular weight, cross-linking density, and adhesion strength are examined. The conditions for collapse-mediated engulfing by the bilayer are found. In particular, the results show that at low hydrophobicity level the increase in the nanogel softness decreases the engulfing rate. On the contrary, for stronger hydrophobicity level the trend changes to the opposite one. At the same time, when the cross-linking density is too low or the adhesion strength is too high the nanogel deformation at the membrane suppresses the engulfing regardless of the network swelling ratio. Finally, for comparative reasons, the behavior of the nanogels is also studied at the solid surface. These results may be useful in the design of soft particles capable of tuning of their elasticity and porosity for successful intracellular drug delivery.

It's good to know what to BACE the specificity of your inhibitors on.

Production, aggregation, and clearance of the amyloid β peptide (Aβ) are important processes governing the initial pathogenesis of Alzheimer's disease (AD). Inhibition of β-site amyloid precursor protein (APP) cleaving enzyme (BACE1) (one of two key proteases responsible for Aβ production) as an AD-therapeutic approach so far has failed to yield a successful drug. BACE1 and its homologue BACE2 are frequently inhibited by the same inhibitors. Several genetic and cerebral organoid modeling studies suggest that BACE2 has dose-dependent AD-suppressing activity, which makes its unwanted inhibition potentially counterproductive for AD treatment. The in vivo effects of an unwanted cross inhibition of BACE2 have so far been impossible to monitor because of the lack of an easily accessible pharmacodynamic marker specific for BACE2 cleavage. In this issue of the JCI, work led by Stefan F. Lichtenthaler identifies soluble VEGFR3 (sVEGFR3) as a pharmacodynamic plasma marker for BACE2 activity not shared with BACE1.

ATP-binding cassette transporter inhibitor potency and substrate drug affinity are critical determinants of successful drug delivery enhancement to the brain

BackgroundPharmacotherapy for brain diseases is severely compromised by the blood-brain barrier (BBB). ABCB1 and ABCG2 are drug transporters that restrict drug entry into the brain and their inhibition can be used as a strategy to boost drug delivery and pharmacotherapy for brain diseases.MethodsWe employed elacridar and tariquidar in mice to explore the conditions for effective inhibition at the BBB. Abcg2;Abcb1a/b knockout (KO), Abcb1a/b KO, Abcg2 KO and wild-type (WT) mice received a 3 h i.p. infusion of a cocktail of 8 typical substrate drugs in combination with elacridar or tariquidar at a range of doses. Abcg2;Abcb1a/b KO mice were used as the reference for complete inhibition, while single KO mice were used to assess the potency to inhibit the remaining transporter. Brain and plasma drug levels were measured by LC-MS/MS.ResultsComplete inhibition of ABCB1 at the BBB is achieved when the elacridar plasma level reaches 1200 nM, whereas tariquidar requires at least 4000 nM. Inhibition of ABCG2 is more difficult. Elacridar inhibits ABCG2-mediated efflux of weak but not strong ABCG2 substrates. Strikingly, tariquidar does not enhance the brain uptake of any ABCG2-subtrate drug. Similarly, elacridar, but not tariquidar, was able to inhibit its own brain efflux in ABCG2-proficient mice. The plasma protein binding of elacridar and tariquidar was very high but similar in mouse and human plasma, facilitating the translation of mouse data to humans.ConclusionsThis work shows that elacridar is an effective pharmacokinetic-enhancer for the brain delivery of ABCB1 and weaker ABCG2 substrate drugs when a plasma concentration of 1200 nM is exceeded.