As human pharmaceuticals are physiologically active substances, it is essential to assess their potential risk to ecosystems after being released into the environment. In Japan, the "Guidance on the Environmental Risk Assessment in New Pharmaceutical Development" (hereafter referred to as "the guidance") was issued in 2016. The guidance includes the environmental risk assessment (ERA) workflow, in which novel pharmaceuticals subjected to ecotoxicity testing are selected based on n-octanol/water partition coefficient (log Kow), action limit (0.01 µg/L), and predicted environmental concentration (PEC). However, for the ERA workflow, neither the action limit has been completely validated nor a method to calculate PEC has been sufficiently established. The objective of this study was to demonstrate the effectiveness and issues of the ERA workflow in the guidance. Using data accumulated from ecotoxicity studies and measured environmental concentration (MEC) data of human pharmaceuticals, we evaluated the validity of the action limit and PEC values. The action limit was found to be sufficiently on the safe side, and the PEC values (to median or 95th percentile MEC values) were generally on the safe side for the evaluated pharmaceuticals. Conversely, issues were also identified, which included a need to establish exemption rules for some specific pharmaceuticals with toxicological concerns at a concentration below the action limit and to refine the PEC calculation method based on the consideration of drug metabolism and environmental fate. The endeavor to address these issues will increase the reliability and effectiveness of the workflow.
Deep eutectic solvents (DESs) are liquids formed by mixing two or more solid components, typically hydrogen bond donors and acceptors, resulting in a large decrease in melting point. Since DESs were first reported in 2003, they have attracted growing attention owing to their low cost, tunable physicochemical properties, and potential environmental compatibility. In pharmaceutical sciences, DESs are increasingly being explored as alternative solvents and functional media for active pharmaceutical ingredient (API) development. This review outlines recent advances in the use of DESs in pharmaceutical research, focusing on the solubilization of poorly water-soluble APIs and the formation of multicomponent crystals. DESs can increase API solubility greatly compared with water, in some cases by several orders of magnitude. In addition, DESs can also be used as crystallization media and coformer sources, enabling the preparation of salts and cocrystals without conventional organic solvents. The effects of DES composition, viscosity, and water content on solubility, crystallization behavior, and processability are also discussed. Although challenges, such as high viscosity and separation of products, remain several mitigation strategies including dilution, additive use and solvent recycling have been proposed. Overall, DESs are a promising platform for innovative, sustainable API development.
There are approximately 60000 pharmacies in Japan. Effective utilization of this resource is a critical national public health issue. With the advent of work style reforms for physicians, pharmacists have a substantial scope to undertake initiatives to improve health literacy. However, if this is simply an extension of the current operations of pharmacies, significant added value cannot be expected. Instead, it is important to envision a future in which pharmacies function as community health stations, contributing to the health literacy of large numbers of people. To ensure that pharmacists have the necessary interpersonal resources, the government has announced policies aimed at streamlining dispensing operations, including outsourcing some of the preparation work involved in dispensing operations, introducing dispensing equipment, dispensing prescription-packaged medicines, and having non-pharmacists assist and support dispensing operations under pharmacist supervision. Considering the near-future vision of pharmacies and pharmacists from a backcasting perspective rather than a forecasting perspective is likely to lead to better outcomes in future.
The introduction of rheology-based indices into pharmaceutical formulation design and evaluation is expected to enable the establishment of a theoretical framework based on physical principles, offering an alternative to conventional optimization strategies that have relied on empirical techniques and rules. Properties such as structural attributes, disintegration behavior, and process responsiveness involve complex mechanical responses-including time-dependent deformation and structural relaxation-that cannot be sufficiently characterized by viscosity measurements under steady shear conditions. Evaluating not only viscosity but also dynamic viscoelasticity enables quantitative assessment of the functional roles of drugs and excipients within the formulation. This review outlines studies that have evaluated the physicochemical properties and functional performance of pharmaceutical formulations based on rheological measurements. It first summarizes research investigating how the viscoelastic properties of pharmaceutical excipients affect formulation characteristics, and then describes approaches for developing rheology-based indices that reflect the functional behavior of thixotropic spray formulations and disintegrants. Through the establishment of a framework based on physicochemical principles, the rheological approach has the potential to support the development of a new paradigm in formulation design-one that enables mechanism-based optimization and enhances reproducibility across various pharmaceutical dosage forms.
The author retired from Iwate Medical University in March 2025 upon reaching mandatory retirement age. On this milestone occasion, I was given the opportunity to write a review article for Yakugaku Zasshi. This review primarily outlines research conducted under Professor Hiroshi Okamoto (now Professor Emeritus, Tohoku University) at the Department of Biochemistry, Graduate School of Medicine, Tohoku University, where I was affiliated before joining the Faculty of Pharmaceutical Sciences at Iwate Medical University. CD38 synthesizes cyclic adenosine diphosphate (ADP)-ribose using nicotinamide adenine dinucleotide (NAD) as a substrate, inducing insulin secretion from pancreatic β-cells via an increase in cytoplasmic calcium ion (Ca2+) concentration. Conversely, DNA damage to pancreatic β-cells activates poly (ADP-ribose) polymerase (PARP), promoting poly (ADP-ribosyl) ation. This depletes intracellular NAD, leading to pancreatic β-cell necrosis. Here, inhibiting PARP activity allows PARP to function as a transcription factor, enhancing the expression of the regeneration/proliferation factor RegI, leading to pancreatic β-cell regeneration and proliferation. Thus research findings from the Okamoto Laboratory suggest that in pancreatic β-cells, cell death, function, and regeneration/proliferation are closely interlinked, with NAD at the center. While NAD's role as a coenzyme is well-established, its physiological significance as a substrate for proteins such as sirtuins, CD38, and PARP, and its link to aging, have also been proposed. The Okamoto Laboratory's research on pancreatic β-cell function, death, and regeneration/proliferation centered on NAD represents pioneering work demonstrating NAD's critical importance in the living organism.
Long-acting injectable antiretroviral therapy (LAI-ART) is an emerging HIV treatment whose social implications extend beyond its biomedical effects. To explore how LAI-ART is imagined in contexts where it is not yet available, we conducted 66 semi-structured interviews with gay and bisexual men living with HIV in Colombia. Guided by the concept of the social plasticity of pharmaceuticals - the capacity of medicines to acquire shifting social meanings beyond their pharmacological action - we explored how participants anticipated LAI-ART might reshape HIV-related stigma. First, LAI-ART was imagined as affording freedom from daily pill-taking and the burden of constant HIV management, offering relief from a persistent reminder of living with HIV. Second, oral pill bottles were described as "stigma objects," while injectables were imagined as invisible treatments enabling concealment and reducing social exposure to stigma. Third, participants linked LAI-ART to greater secrecy within social relationships, and framed injectables as symbols of scientific progress that could help dissociate HIV from illness. Finally, some participants emphasized the limits of pharmaceutical solutions, arguing that stigma is rooted not only in treatment practices but in broader contexts of misinformation and moral judgment about HIV. Our findings suggest that while pharmacologically equivalent, oral pills and injectable ART can be socially distinct, with LAI-ART expected to serve as a partial buffer, though not a remedy, for HIV-related stigma. As LAI-ART is not yet available in Colombia, participants' accounts primarily reflect internalized and anticipated stigma; future research is needed to examine its effects on enacted stigma once implementation occurs.
Extreme cold weather environments are challenging for medication storage and delivery, particularly for injectable analgesics vulnerable to freezing and device failure. These risks may compromise pain management in austere or operational settings where temperature control cannot be maintained. Sufentanil sublingual microtablets (sold in the UK as Dzuveo) provide an oral analgesic option with manufacturer-reported sub-zero stability. Evidence describing the effects of sustained extreme cold exposure and repeated freeze-thaw cycling on chemical stability and delivery system function is limited. We conducted a laboratory study assessing the effect of sustained freezing and repeated freeze-thaw exposure on sufentanil sublingual microtablets (30 µg active pharmaceutical ingredient). Tablets from two production batches (expiry August 2025 and July 2026) were allocated to room temperature control, static freezing at -20°C or -80°C, or repeated freeze-thaw cycling at both temperatures. Freeze-thaw cycling was designed to simulate intermittent carriage in extreme cold environments. Laboratory operators were blinded to sample allocation. The primary outcome was sufentanil mass and concentration measured using liquid chromatography-high resolution accurate mass spectrometry. Secondary outcomes included visual assessment of microtablet integrity and applicator function. 60 tablets were analysed, with one weight outlier excluded from concentration-based analyses. There were no statistically significant differences in sufentanil mass or concentration between control samples and those exposed to freezing or repeated freeze-thaw cycling at -20°C or -80°C. Visual inspection identified no evidence of microtablet degradation, and all applicators functioned normally across exposure conditions. Sufentanil sublingual microtablets and their delivery system maintained chemical stability and functional integrity following exposure to extreme cold temperatures and repeated freeze-thaw cycles. This laboratory study provides reassurance regarding formulation resilience in cold environments but does not assess clinical effectiveness. Further research is required to determine the impact on patient outcomes in operational or military settings.
Namaste Care, a non-pharmaceutical daily multicomponent palliative care intervention, offers care for people with dementia, aiming to improve quality of life of those living with dementia as well as their family and caregivers. This systematic review explores the Namaste Care intervention and its clinical and economic effects in multiple care settings. The aim of this review is to consolidate existing evidence on Namaste Care's clinical and economic outcomes and examine the tools used for data collection. A systematic literature search was conducted (PubMed, Scopus and Web of Science) to identify peer-reviewed studies on Namaste Care's impact on quality of life, costs, health, economic outcomes and benefits up to 22 February 2026. Methodological quality was assessed using the Mixed Methods Appraisal Tool, while the completeness of reporting of economic evaluation studies was evaluated according to the Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS). 31 studies reported the clinical and/or economic outcomes of Namaste Care. The results for quality of life and quality of dying were mixed, while 5 of 11 studies evaluating quality of life reported significant improvements. The various quality-of-life instruments used include the Quality of Life in Late-Stage Dementia (QUALID), EQ-5D-3L and EQ-5D-5L instruments, ICEpop CAPability Measure for Older People (ICECAP-O), ICECAP Supportive Care Measure (ICECAP-SCM), Quality of Life for People with Dementia (QUALIDEM) and Carers-DEMentia Quality of Life (C-DEMQOL). The clinical outcomes considered included pain, behavioural symptoms and quality of end-of-life care. The Medication Quantification Scale and Minimum Data Set indicated reductions in antidepressant and antianxiety medication use. Seven studies reported significant improvements in well-being, and two studies reported reduced stress among family members following Namaste Care sessions. A subset of five studies reported a range of economic outcomes. The findings suggest that Namaste Care improves well-being, reduces caregiver stress and lowers the use of antidepressant and antianxiety medications at a moderate cost. The current literature is characterised by small, non-random, heterogeneous studies. Randomised controlled trials, which include economic evaluations, help to improve evidence-based research to support funding and implementation decisions on Namaste Care. CRD42024560056.
Clearance (CL) is a primary pharmacokinetic (PK) parameter crucial to determine how quickly a drug is eliminated from the body, which guides the appropriate dosing interval to maintain a consistent concentration in blood. Given the importance of CL, this study aimed to use machine learning (ML) techniques to predict CL values by identifying patterns and relationships within an extracted dataset of PK variables from published articles. Variables evaluated in the extracted dataset included drug, dose, animal species, and route of administration. Nine distinct ML models were then applied to analyze the CL data, incorporating both imbalanced and balanced data generated through resampling methods. Since the CL data used in this study is a collection of all CL values (true CL and CL/F) extracted from scientific articles, the collected CL variable for both IV and non-IV administration routes are referred to as hybrid ML CL. To analyze the effect of ML models in predicting the CL values, we used the hybrid ML CL dataset for six different subsets of data including one solely from the intravenous route of administration. Linear regression, multi-layer perceptron, and random forest models consistently had the highest efficiency in predicting CL values, with an R2 score > 0.87. However, R2 increased to > 0.95 when analyzing only ungulates or small ruminants, and > 0.92 for the companion animal group. This study has the potential to help researchers employ computational, mathematical, and ML models to predict and estimate CL values and changes in CL values based on variables. This study focuses on evaluating the feasibility of predicting drug CL in situations where direct CL data are not available. Rather than addressing drug development processes, the research examines whether study design variables can serve as input parameters for a proposed cross-species extrapolation tool aimed specifically at predicting existing drug CL values.
Blood biomarkers are rapidly becoming established for Alzheimer's Disease (AD) diagnosis. However, there is a need for more scalable tools to reach the 99% of individuals with early cognitive impairment who are not seen in specialist healthcare services. A recent study validated a capillary blood sampling technique to detect the p-tau217 and GFAP biomarkers. Here we used our PROTECT research study to show that these biomarkers, when collected using self-administered fingerprick tests, correlate well with venous blood biomarkers and with cognition and function in 174 people who were cognitively normal or who had mild cognitive impairment or AD. They can be used in combination with computerised cognitive testing to identify people with the highest risk of AD. The GFAP biomarker appears to be associated with vascular risk, unlike p-tau217. Patient feedback indicates high acceptability and usability of the capillary test method, giving confidence in the feasibility of this technology. The work suggests that capillary blood biomarkers could be used to enable triage of people with varying levels of risk of AD in clinical practice and for clinical trials, and could be used outside of clinical settings.
Sleep and physical activity play a crucial role in brain and mental health. While traditional self-reported methods and research-grade accelerometers have several limitations, consumer-grade wearable devices, such as Fitbit, allow continuous, objective, and real-life data collection. The purpose of this article is to report the study protocol and participant characteristics of a wearable device survey that primarily aims to examine the relationship between brain health and long-term patterns of daily physical activity and sleep.Nearly 2,000 participants were recruited between September 2022 and December 2023, as part of the Tohoku Medical Megabank Brain Magnetic Resonance Imaging Study, to wear Fitbit Charge 5 devices for 1 year, continuously tracking physical activity and sleep. Additionally, home blood pressure measurements and questionnaire data on housing conditions, psychological distress, and medication were collected every 4 months for a total of four assessments.The mean age of the participants was 58.5 years and 37.4% were men. For the first 30 days after the recruitment, mean step count was 8,910 steps/day, and a mean total sleep time was 370.4 min/night (approximately 6.2 h). The mean morning systolic blood pressure and diastolic blood pressure were 126.2 and 75.5 mmHg, respectively.This study provides a unique opportunity to integrate longitudinal consumer-grade wearable data, brain MRI, multiomics data, and comprehensive health records from existing cohorts to advance precision medicine and help prevent mental and neurodegenerative diseases, such as dementia. Limitations include potential selection bias, and a relatively smaller sample size than larger global studies.
Mesenchymal stem cells (MSCs) have emerged as a leading cell source in regenerative medicine due to their multipotency and immunomodulatory capabilities. In recent years, extracellular vesicles (EVs) derived from MSCs have attracted increasing attention as a novel, cell-free therapeutic modality, exhibiting many of the biological effects similar to their parent cells. This review outlines the current status and future prospects of MSC-derived EVs, focusing on their therapeutic mechanisms, standardization efforts, and regulatory trends in Japan and overseas. We further discuss the challenges in the development of EV-based products, including scalable manufacturing, quality control strategies, viral safety, and impurity profiling. The application of Quality by Design (QbD) and single-particle analytics is also highlighted as a means to enhance product consistency and clinical reliability. MSC-EVs have the potential to revolutionize treatment paradigms for various refractory diseases, but their successful implementation will require harmonization of scientific, technical, and regulatory frameworks. This review provides a comprehensive overview of the translational pathway from basic research to clinical and commercial application of MSC-EV therapeutics.
Plants are indispensable to life on Earth and provide diverse natural products supporting nutritional, medicinal, industrial, and cultural needs. Phytometabolomics enables comprehensive profiling of plant metabolites, a capability greatly enhanced by advances in mass spectrometry techniques. However, challenges in sample preparation and solvent selection limit extraction efficiency and metabolite stability. In this context, green chemistry has introduced DES/NADES as sustainable alternatives to conventional solvents. NADES offer tunable composition, enhanced extraction efficiency, and improved stabilization of labile compounds along with low toxicity and biodegradability. This review highlights the application of NADES in the extraction of bioactives, presents a critical comparison with conventional solvents, and evaluates their compatibility with emerging extraction techniques. It also addresses key limitations, including high viscosity, challenges in standardization, and concerns related to scalability and safety. Collectively, NADES offer a promising and eco-friendly strategy for advancing phytometabolomics with broad implications for pharmaceutical, food, and natural product research.
Pediatric drug development has seen significant progress through the implementation of extrapolation strategies incorporating modeling and simulation (M&S) techniques. The ICH E11A guideline provides a systematic framework for pediatric extrapolation, advocating for comprehensive assessments of disease characteristics, pharmacology, and therapeutic outcomes to determine the appropriateness of such methodologies. At the 2025 Pharmaceuticals and Medical Devices Agency (PMDA) workshop, stakeholders emphasized the importance of adopting such strategies to address drug lag and loss observed in Japan, as well as the necessity of establishing flexible consultation mechanisms early in the development process. Here, to illustrate M&S capabilities, physiologically-based pharmacokinetic (PBPK) modeling was employed using physiological data from Japanese pediatric populations to simulate PKs, with validation across 14 drugs indicating predictive accuracy within a 0.5-2.0-fold range of observed PK parameters. These results provide a basis for further validation of this population. Ultimately this approach intends to support dosage and administration in preparation for pediatric clinical trials in Japan, as well as to reinforce the scientific justification. Moreover, PBPK modeling enhances theoretical insights into predicting PKs for special pediatric populations with unique disease conditions and assessing drug-drug interaction risks, which are not amenable to prospective clinical trials. Achieving further progress in this field necessitates multidisciplinary collaboration among industry, regulatory agencies, academia, and healthcare institutions, with each party fulfilling its respective responsibilities to collectively advance pediatric drug development.
The objective of the present research investigation is to assess the anti-glioblastoma potential of Ribociclib (Ribo) and Ribociclib-loaded folic acid conjugated chitosan-polycaprolactone nanoparticles (RFCPNPs). Folic acid was conjugated to glycol chitosan by carbodiimide chemistry, and the formation of the conjugation was confirmed by FT-IR and 1H NMR. RFCPNPs were fabricated by the single emulsification method, and particle size, PDI, surface charge, %EE, and % DL were 127.8 ± 4.37 nm, 0.197 ± 0.012, 5.05 ± 0.1 mV, 70.82 ± 4.25%, and 3.37 ± 0.20%, respectively. The presence of pH-sensitive biological macromolecule, i.e., chitosan, in the carrier system provides pH-sensitivity to RFCPNPs and displays diffusion-controlled release of the Ribo up to 48 h. RFCPNPs exhibited a bi-phasic release pattern, releasing approximately 22.9 ± 3.8%, 23.2 ± 5.8%, and 7.3 ± 1.2% of Ribo within 1 h, and 98.3 ± 1.6%, 86.6 ± 1.5%, and 75.8 ± 5.1% of Ribo were released from RFCPNPs in 48 h in pH 5.5, 6.8, and 7.4 dissolution media, respectively. The half-maximal inhibitory concentration (IC50) of RFCPNPs was found to be 2.7 ± 0.3 and 3.2 ± 0.10 μM in U87 MG and U138 MG cells, which is 8-10-fold-, and 2-3-fold less than the pure Ribo and unconjugated nanoparticles, respectively. The receptor blocking assay demonstrated the significant role of folic acid in the anti-glioblastoma efficacy of the RFCPNPs. RFCPNPs exhibited enhanced ROS generation, apoptosis, and reduced mitochondrial membrane potential of U87 MG cells compared to the pure Ribo. RFCPNPs exhibited approximately 40% apoptotic cells, more than 1.6 times greater than those of the plain drug counterpart. The Ribo and RFCPNPs exhibited 27.1 ± 2.2%, 66.2 ± 1.3% cellular migration inhibition, and 380 ± 46 and 10 ± 4 colonies, respectively. U87 MG spheroids treated with Ribo and RFCPNPs demonstrated 64.3 ± 5.2% and 34.7 ± 11.0% viable cells, respectively. These outcomes suggest that the optimized nanocarrier represents a promising approach for treating glioblastoma.
Tofacitinib (Tofa), a Biopharmaceutics Classification System Class III drug, exhibits pH-dependent solubility and a strong tendency to agglomerate, potentially affecting tablet uniformity, in vitro dissolution behavior, and in vivo performance. In this study, a Tofa free base tablet (WT2) prepared by wet granulation was evaluated in Beagle dogs and compared with a marketed reference tablet (RT). In vitro dissolution studies showed comparable drug release between WT2 and RT at pH 1.2 and 4.0, whereas WT2 exhibited slower, though still complete, dissolution at pH 6.8. Despite these differences, pharmacokinetic studies demonstrated comparable systemic exposure under both fasted and fed conditions. The geometric mean ratios and 90% confidence intervals for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUClast) met conventional bioequivalence criteria. Food intake slightly delayed absorption but had no significant effect on the extent of exposure. This research shows that differences in dissolution arising from pH-dependent solubility did not meaningfully affect systemic exposure of Tofa free base under the studied conditions.
Most cells have the ability to secrete extracellular vesicles (EVs), which are nanoscale membrane-bound vesicles. EVs carry a diverse array of biomolecule, that play key roles in immunological modulation, intercellular communication, and the regulation of pathological and physiological processes. For EV-based diagnosis of ocular diseases, eye-derived biofluids serve as important sources. EVs found in these biofluids have emerged as promising biomarkers for the early detection of ocular diseases, as their molecular cargo can reflect the biology of their parent cells. Furthermore, due to their high biocompatibility and low immunogenicity, EVs have been explored as therapeutic agents and targeted drug delivery nanocarriers in various ocular diseases. In this review, we summarize the advancements in EV-based research focused on the detection and treatment of ocular diseases. We provide an overview of the origin of EV applications in ophthalmology, review techniques for isolating EVs from ocular biofluids, highlight EV bioengineering strategies for drug delivery, and present recent developments in EV-based diagnostics and therapeutics. Finally, we discuss ongoing clinical trials and conclude with an overview of the current challenges and future considerations for the clinical translation of EV-based approaches in ocular disease.
A major scientific drive is to characterize the protein-coding genome, which is a primary basis for studying human health. But the fundamental question remains of what has been missed in previous analyses. Over the past decade, the translation of non-canonical open reading frames (ncORFs) has been observed across human cell types and disease states1-3, with major implications for biomedical science. However, a key gap in knowledge has been which ncORFs produce small microproteins or alternative protein molecules that contribute to the human proteome. Here we report the collaborative efforts of the TransCODE Consortium4 to produce a consensus landscape of protein-level evidence for ncORFs. We show that about 25% of a set of 7,264 ncORFs gives rise to detectable peptides in a large-scale analysis of 95,520 proteomics experiments. We develop an annotation framework for ncORF-encoded microproteins as human proteins and codify the new conceptual model of 'peptideins' as microproteins that have indeterminate potential as functional proteins. To probe the biological implications of peptideins, we create an evolutionary analysis approach, termed ORF relative branch length (ORBL), and determine that evolutionary constraint is common and associates with observation of ncORF-derived peptides. We then characterize a pan-essential cellular phenotype for one peptidein from the OLMALINC long non-coding RNA. Overall, we generate public research tools supported by GENCODE and PeptideAtlas and advance biomedical discovery for understudied components of the human proteome.
Primary cilia are cellular antennae protruding from the surface of nearly all cell types during the G0 phase. They control the organization and maturation of systemic tissues and organs by receiving selective signals. Ciliopathies are heritable disorders that cause dysplasia of various tissues and organs, as well as the progression of obesity. In contrast, recent studies using cultured cells have revealed that cilia were resorbed upon receiving selective proliferative stimuli, thereby reentering the cell cycle into the G1/S phase. However, the physiological significance and molecular mechanisms of ciliary resorption were unclear, as no diseases caused by abnormal ciliary resorption had been identified in humans or experimental animals. To address this problem, we focused on the role of the cytoplasmic dynein light chain Tctex-1. We found that activating the insulin-like growth factor-1 receptor at cilia results in the phosphorylation of threonine 94 in Tctex-1 and subsequent endocytosis of the ciliary pocket membrane surrounding the ciliary basal region. This mechanism is responsible for ciliary resorption and reentry into the G1/S phases of the cell cycle. Additionally, we found that phospho-(T94)Tctex-1 localizes to the ciliary transition zone of neural progenitor cells in the fetal cerebral cortex, where it regulates cell cycle reentry and neurogenesis. Recent reports indicate that mice with abnormal ciliary resorption develop microcephaly-like symptoms. Our study and these reports shed light on the physiological significance of ciliary resorption. Finally, this review discusses new directions in ciliary resorption research and its potential therapeutic applications.
The emergence of disease-modifying therapies targeting amyloid pathology represents a major paradigm shift in the management of Alzheimer disease (AD). However, their implementation poses substantial organizational, infrastructural, and clinical challenges for health systems. To identify the key challenges and establish priority recommendations for the effective incorporation of amyloid-targeting therapies into the Spanish National Health System. This multiphase consensus study was conducted within the Spanish National Health System between September 2024 and July 2025. The study comprised a narrative literature review, qualitative research, regional workshops, and a modified RAND/UCLA Delphi process. A total of 56 experts participated, including a scientific committee of 6 Alzheimer disease specialists and an expert panel of 50 multidisciplinary professionals involved in AD care. Identification of key challenges across the AD care pathway; development, evaluation, and prioritization of consensus-based recommendations; and estimation of patient demand, including projected increases in day hospital activity and magnetic resonance imaging utilization. Ten key challenge areas were identified, encompassing early detection and referral, diagnostic confirmation, assessment of patient eligibility, treatment administration in day hospitals, monitoring of amyloid-related imaging abnormalities, evaluation of treatment effectiveness, infrastructure and capacity, professional training, patient information and support, and health care planning. Of the 43 recommendations assessed, 38 were rated as appropriate and necessary, with 14 prioritized for immediate implementation. Demand estimation models indicated that 11 to 26 patients per 100,000 inhabitants could be treated under current care patterns, increasing to 17 to 115 per 100,000 inhabitants under alternative eligibility scenarios. This consensus defines the clinical, organizational, and infrastructural requirements necessary to integrate amyloid-targeting therapies into routine care within the Spanish National Health System. The prioritized recommendations define immediate actions to address the challenges identified and may serve as a reference for other health systems facing similar implementation processes.