General Formulation Research Articles

Differences in fluidity and viscosity of brand-name and generic injectable ointment.

Generic medications contain the identical active ingredient in the same concentration as their branded counterparts and are administered in the same manner, aiming to deliver comparable efficacy, dosage, and clinical outcomes. Nevertheless, variations in additives and formulation processes, particularly noticeable in topical medications, can influence factors like ease of use and patient adherence. Therefore, in this study, we aimed to compare the rheological attributes of branded and generic injectable ointments, assessing disparities in formulation performance and their impact on patient care. Posterisan® Forte and Hemoporison® ointments were used as the branded and generic versions, respectively, and their viscosity, ductility, and viscoelastic properties were evaluated. Posterisan® Forte showcased enhanced spread ability, maintaining uniform flow characteristics across varying temperatures, whereas Hemoporison® displayed pronounced thixotropic properties and stiffness, suggesting potential benefits for applications necessitating reversible viscosity adjustments and heightened rigidity. Despite sharing identical additives, observable differences in physical characteristics highlight the necessity of understanding formulation traits, which could influence ointment behavior. Alterations in fluidity and viscosity may affect how patients perceive and apply the medication, potentially influencing treatment outcomes and the occurrence of adverse effects.

The Viability of Emerging Public and Private Generic Drug Infrastructure in India: An in-vitro Case Study Using Statins as Model Drug

The healthcare system has been fundamentally altered by the introduction of generic medications, and their market share continues to rise because these are genuine, dependable, secure, affordable, and accessible to all the needy and poor in society. In this regard, the generic drug industry, which strives for authenticity, affordability, and accessibility, plays a significant role. Using HMG CoA reductase inhibitors (Atorvastatin and Rosuvastatin) as model drugs, the study aimed to determine the viability of the emerging public and private generic drug infrastructure in India, which included Janaushadhi, Dava India, and other assorted companies. The organoleptic properties and official and non-official quality control tests were evaluated. According to the in-vitro dissolution profiles, the Mankind brand of atorvastatin has shown the highest dissolution profile (75.29%), and the Dava India brand of rosuvastatin has the maximum drug release (97.26%) in one hour release. The Peppas model best explained the drug release model, which inferred the release profile to be diffusion-specific. The compatibility analysis of the tablet formulation has been shown through FTIR studies. These results concluded that public generic drugs are as effective as private generic drugs, and patients can easily take the cost-effective brand of medication.

Predicting pharmaceutical supply chain disruptions before and during the COVID-19 pandemic.

Disruptions to the pharmaceutical supply chain (PSC) have negative implications for patients, motivating their prediction to improve risk mitigation. Although data analytics and machine learning methods have been proposed to support the characterization of probabilities to inform decisions and risk mitigation strategies, their application in the PSC has not been previously described. Further, it is unclear how well these models perform in the presence of emergent events representing deep uncertainty such as the COVID-19 pandemic. This article examines the use of data-driven models to predict PSC disruptions before and during the COVID-19 pandemic. Using data on generic drugs from the pharmacy supply chain division of a Fortune 500 pharmacy benefit management firm, we have developed predictive models based on the naïve Bayes algorithm, where the models predict whether a specific supplier or whether a specific product will experience a supply disruption in the next time period. We find statistically significant changes in the relationships of nearly all variables associated with product supply disruptions during the pandemic, despite pre-pandemic stability. We present results showing how the sensitivity, specificity, and false positive rate of predictive models changed with the onset of the COVID-19 pandemic and show the beneficial effects of regular model updating. The results show that maintaining model sensitivity is more challenging than maintaining specificity and false positive rates. The results provide unique insight into the pandemic's effect on risk prediction within the PSC and provide insight for risk analysts to better understand how surprise events and deep uncertainty affect predictive models.

Joint input-state estimation of structures subjected to complex loads via augmented Kalman Filter with physics informed latent force models

Joint input-state estimation algorithms such as the Augmented Kalman Filter (AKF) rely on the assumption that the distribution of the input loads follows simple spatial patterns, which are either spatially distributed or sparse. However, in many real situations the spatial distribution of the loads is complex and time-varying, which poses a significant challenge. To tackle this issue, this paper introduces a novel method named the Augmented Kalman Filter with Physics Informed Latent Force Models (AKF-PILFM), which incorporates knowledge about the physics underlying the dynamics of the input loads in the estimation based on training data. In the paper, the general formulation of the AKF-PILFM is described, followed by its tailored application to structures subjected to loads with a complex spatiotemporal behavior such as wave loads. The dominant characteristics of the wave loads are identified from training data via the Dynamic Mode Decomposition, enabling the development of a state space model of the loads that can be integrated with the AKF-PILFM. To demonstrate the effectiveness of the proposed methodology, a numerical example is provided consisting of a 3D steel jacket structure subjected to nonlinear irregular waves. The AKF-PILFM shows accurate estimation results and, in the example, outperforms an existing method based on the Gaussian Process Latent Force Models and equivalent modal loads, signifying that the load’s spatiotemporal behavior substantially influences the structural response.

Novel dissolution methods for drug release testing of Long-Acting injectables

Long-acting parenteral drug products are a popular choice for therapeutic areas requiring long term treatment. These products range from dispersed systems such as drug suspensions and polymeric microspheres to in situ forming polymeric implants. The lack of reliable drug release testing methods for these drug products not only impedes the development of new drug products but also affects generic drug development. Current release methods suffer from a range of problems such as high variability, poor reproducibility, poor discriminatory ability, lack of depot-like structure formation (that could mimic the in vivo situation). Moreover, shorter duration (less than a week) of release renders them unsuitable for in vitro-in vivo correlations (IVIVCs). To overcome these issues, novel adapters were developed for both USP-type-II & IV apparatus. These adapters were validated and assessed using the long-acting injectable (LAI) suspension drug product Depo Provera 150® as well as its Q1/Q2 equivalents. For USP-type-IV apparatus, two open adapter designs (conical and ellipsoidal shaped cavity with volume capacities of 50 µl and 1 ml, respectively) were developed. A closed conical adapter design with a volume capacity of 0.05 ml was developed for USP apparatus type-II. All three novel adapter designs effectively retained the suspensions, achieved release durations of 3–6 weeks with good reproducibility, minimal variability (RSD≤5%) and had good discriminatory ability. Based on this, the adapter-based dissolution methods were deemed suitable for IVIVC development of long-acting injectables. A successful Level A IVIVC was developed for Depo SubQ Provera 104® and its Q1Q2 equivalents using USP apparatus type IV with a conical adapter design. The closed adapter design for apparatus type-II was also investigated for suitability with risperidone in situ forming implants. The adapter was able to securely retain and maintain the shape of the in situ forming implants and resulted in release profiles of up to one month with good discriminatory ability and low standard error (RSD≤5%). These novel adapters hold promise of wide use for in vitro release testing of different long-acting parenteral drug products.

A study of India’s ‘People’s Medicine Scheme’: Policy recommendations and insights to promote and improve access to generic medicines based on pilot survey in Bengaluru Urban District, India

Access to affordable and quality medicines plays a vital role for achieving Universal Health Coverage and in reducing out-of-pocket expenditures (OOPE) for households especially in developing nations such as India. Pradhan Mantri Bhartiya Janaushadhi Pariyojana (PMBJP), a Government of India initiative, aims to make low-cost and quality generic drugs and surgical equipment accessible to all segments of the population through its dedicated store outlets known as Pradhan Mantri Bhartiya Janaushadhi Kendra (PMBJK). In this study, a pilot survey comprising 20 stores/PMBJKs and 150 citizens was undertaken in the Bengaluru Urban District, India to understand various aspects of the PMBJKs including availability of drugs, stock-outs, accessibility to stores, perception and awareness levels along with challenges faced by store owners and citizens/beneficiaries. Based on the survey results, we capture the availability of drugs for 35 medicines and consumables belonging to 12 therapeutic categories across 20 store outlets. We also provide valuable insights and interdisciplinary recommendations on several facets including adopting technology-based measures for day-to-day functioning of stores, need for in-depth supply chain analysis for ensuring availability of drugs, encouraging prescription of generic medicines, increasing awareness levels in addition to promoting grassroot-level research, surveys and feedback mechanisms. These suggestions are expected to find their utility in policy-making, strengthen the implementation of the PMBJP scheme across Bengaluru and India as well as contribute towards achieving related Sustainable Development Goals.

Nonlinear Economic State Equilibria via van der Waals Modeling.

The renowned van der Waals (VDW) state equation quantifies the equilibrium relationship between the pressure P, volume V, and temperature kBT of a real gas. We assign new variable interpretations adapted to the economic context: P→Y, representing price; V→X, representing demand; and kBT→κ, representing income, to describe an economic state equilibrium. With this reinterpretation, the price elasticity of demand (PED) and the income elasticity of demand (YED) are non-constant factors and may exhibit a singularity of the cusp-catastrophe type. Within this economic framework, the counterpart of VDW liquid-gas phase transition illustrates a substitution mechanism where one product or service is replaced by an alternative substitute. The conceptual relevance of this reinterpretation is discussed qualitatively and quantitatively via several illustrations ranging from transport (carpooling), medical context (generic versus original medication), and empirical data drawn from the electricity market in Germany.

Application of <i>in vitro</i> studies to predict the pharmacokinetics of rivaroxaban tablets

Introduction. The most important stage of pharmaceutical development of a generic drug is a clinical trial involving humans – a bioequivalence study. Considering the importance of finding rivaroxaban drugs in the list of vital and essential drugs, as part of ensuring technological sovereignty, the use of scientific robust and effective methods for determining the quality of the dosage form is required.Aim. Conduct a study of rivaroxaban tablets on a physiologically relevant tester to predict pharmacokinetic profiles.Materials and methods. The objects of the study are "Xarelto®, film-coated tablets, 10 mg" (series BXJS871, with an expiration date of October 31, 2024, Bayer AG, Germany), "Xarelto®, film-coated tablets, 20 mg" (series BXKDF32, with an expiration date of May 17, 2026, Bayer AG, Germany) and "Rivaroxaban, film-coated tablets, 10 mg" and "Rivaroxaban, film-coated tablets, 20 mg", domestically produced, with valid expiration dates. During the study, reagents were used to prepare dissolution media and perform quantitative determination. The physiologically relevant test was performed on the SC PRT-6 device (LLC "Scientific Compliance", Russia). The quantitative content of released rivaroxaban within the comparative dissolution kinetics test in a medium of 0.1 in a medium of 0.1 % sodium lauryl sulfate solution in a phosphate buffer solution pH 6.5 was carried out on a SF-2000 spectrophotometer (LLC "OKB Spektr", Russia). The quantitative content of released rivaroxaban within the comparative dissolution kinetics test in biorelevant dissolution media and physiological relevance test was assessed on a high-performance liquid chromatograph "Chromatec-Crystal HPLC 2014" (CJSC "Chromatec", Russia). Pharmacokinetic profiles were modeled in the PK-Sim® (Systems Biology Software Suite 11.2, Bayer Technology Services GmbH, Germany) program based on the data obtained within the physiologically relevant test. The clinical study of rivaroxaban tablets was a prospective, open-label, randomized, crossover, two-stage comparative study in two groups of volunteers with a single dose of drugs on the fast condition. The study randomized 30 healthy male volunteers aged 18–45 years.Results and discussion. A complex of in vitro tests was conducted, profiles were obtained that allow us to evaluate the dynamics and degree of release of the studied drugs in various parts of the human gastrointestinal tract. A comparison of the sequential and hybrid schemes for conducting the physiological relevance test was carried out. Within the framework of the set of tests, qualitative and quantitative correlation with the clinical trials data was observed only for the hybrid physiological relevance test scheme. Based on the results of physiological relevance test using different schemes, pharmacokinetic profiles for a pair of drugs were predicted and the prediction error was assessed.Conclusion. A set of scientific in vitro tests was conducted for the drugs "Xarelto®, film-coated tablets, 10 mg and 20 mg", "Rivaroxaban, film-coated tablets, 10 mg and 20 mg". Based on the physiological relevance test results, pharmacokinetic profiles for a pair of drugs were predicted with low error and high reliability. As part of the comparison of data obtained during clinical trial and modeling, the smallest prediction error was noted when performing physiological relevance test using a hybrid scheme.

Fuzzy clustering with capacity constraints: Algorithm, convergence analysis and numerical experiments

In this paper we study the fuzzy clustering problem with capacity constraints. Despite of the fact that the fuzzy clustering approach is widely encountered in the literature, the inclusion of capacity constraints is recent and has several practical applications. We propose a general formulation of the clustering problem, where each point has an associated weight and the sum of the weights of the points that compose each group is established a priori. We discuss existence of solutions of the involved problems, providing a mathematical foundation for the established formulas. Besides, we propose a practical algorithm for solving this problem and present its convergence analysis. This algorithm follows an alternate minimization scheme, wherein a given iteration addresses the problem first in terms of the probabilities of each point xj belonging to each cluster i, denoted as uij, finding subsequently the position of the centroids, ci,i=1,…,g,j=1,…,n. This procedure is K-means-like, with the distinction that, as a point does not exclusively belong to a group, the computation of uij requires optimization techniques. In our case, this involves solving a linear system derived from the Karush–Kuhn–Tucker (KKT) conditions. With the aim of validating our algorithm, we present numerical tests with synthetic and real-world data to demonstrate its performance for the given problems. Since the proposal successfully solved these numerical tests within a reasonable computational time, it can be considered a valuable resource for addressing real-world applications.

“New Creation:” Grace and Experiences of a Renewed Nature

In everyday life, one encounters many experiences of affliction that, for whatever reason, nature (ours or others’) cannot resolve. Yet, when nature’s finite resources are exhausted and hope seems in vain, humans often experience extra-ordinary moments of renewal and resolution—breakthroughs, remissions, insights, and conversions. We experience these moments in our natural existence; yet, we feel they cannot originate, cannot be attributed to nature alone. Rather, these experiences, called “graces” in Christianity, are attributed to a divine power acting in us. How do we come to describe these experiences in this way? Is it possible to formulate a general theory of these experiences as “graces”? Is there an “experience” of grace in general, a “state of grace”, which serves as ground and unifying experience for the “graces” we receive? Working from the Catholic theological point of view, this paper examines such experiences of affliction and renewal, as well as the basic Catholic framework schematizing them as found in the Bible and Catholic religious writings. In doing so, this paper highlights the theme of impossibility (absolutely or in context) underlying each experience, and broadly categorizes them as happening within three regions of human life: the external, ethical sphere, the interior self-relationship, and the vertical relationship to the Divine. In dialogue with theologians and phenomenological thinkers, general formulations of the experiences are placed within their respective spheres, and certain problems in the identification or interpretation of these experiences are identified. The paper then explores how the experience of a “New Creation” can serve not only as a label for the totality of these experiences, but also as a totalizing and overarching ground-experience of “grace” and an interpretive hermeneutic for graces in general. As a result, a graced moment of total personal “rebirth” or “recreation”, prevenient with respect to any personal co-operation or experiences of grace as grace, is identified as a potential ground for all other graces considered. Finally, this paper considers some potential implications of this account of grace for both Catholic thought and Phenomenology more generally.

Assessment of bioequivalence of veterinary drugs “Hollicalm” and “Serenia” in the form of tablets in the body of dogs

This paper describes the results of a study of the bioequivalence of the generic drug “Hollicalm” in comparison with the reference drug “Sereniya”. The experiment was carried out on 6 dogs. For this experiment, a sequential bioequivalence study design was used. The period between the administration of reference and generic drugs to animals was 72 hours. The drugs were administered to dogs once, individually, orally. The study drugs contained 60 mg of maropitant per tablet. The dose of the active substance that was administered to each animal was 8 mg of maropitant per 1 kg of animal weight. Blood samples were taken from dogs before drug administration, then at 14 time points within 48 hours to subsequently obtain blood serum. The content of maropitant was determined in the samples of blood serum using high-performance liquid chromatography coupled with mass-spectrometry detection. The obtained concentrations of the active substance served as the basis for calculating its pharmacokinetic parameters in dogs. The statistical analysis showed that two-sided confidence intervals for the Cmax and AUC0-t ratios were in the range of 80–125%. The results of the study allowed us to draw a conclusion about the bioequivalence of the drugs “Hollicalm” and “Sereniya”.

A General Formulation of the Resonance Spectrum Expansion Self-Shielding Method

The resonance spectrum expansion (RSE) self-shielding method was recently proposed by Nagoya and Osaka universities as a powerful alternative to existing approaches. First investigations of the RSE at Polytechnique Montreal show that it can effectively replace the actual subgroup method used for production calculations in DRAGON5. The Japanese implementation of the RSE method is limited to a solution of the Boltzmann transport equation (BTE) with the method of characteristics. We are proposing a new implementation of the RSE method compatible with various types of solutions for the BTE, including the collision probability and the interface current methods. We based our validation study on a subset made up of eight Rowlands pin cell benchmark cases. The absorption rates obtained after self-shielding are compared with exact values obtained using an elastic slowing-down calculation where each resonance is modeled individually in the resolved energy domain. Validation of Rowlands benchmark with effective multiplication factor calculations was also conducted with respect of the SERPENT2 Monte Carlo code. It is shown that the RSE method is compatible with both advanced and legacy energy meshes and performs slightly better than the production subgroup methods actually used.

Drug Pricing Stewardship from Mark Cuban's Cost Plus Generic Drug Program.

The exceedingly high US spending per capita on prescription medications is mediated, at least in part, by the inefficiencies of existing generic pharmaceutical distribution and reimbursement systems; yet, the extent of potential savings and areas for targeted interventions for generic drug prescribers remains underexplored. We aimed to analyze 2021 Medicare Part D spending on generic drugs in comparison with pricing of a low-cost generic drug program, the Mark Cuban Cost Plus Drug Company (MCCPDC), to gauge the extent of achievable potential savings. In this retrospective, observational study, we performed a systematic analysis of potential Medicare Part D savings when using MCCPDC generic pricing. The 2023 MCCPDC data, as of August 2023, were obtained from the provider's publicly available database. The 2021 Medicare Part D data and prescriber datasets were obtained from the US Centers for Medicare and Medicaid Services. Outcomes included total prescription volume, proportion of drugs with savings, total US dollar Medicare savings, and average weighted price reduction per unit drug. Results were stratified by medical and surgical subspecialties to identify areas for targeted interventions. Subspecialty-wise contribution to total savings versus contribution to total prescription volume was characterized. Total estimated Medicare Part D savings were $8.6 billion using 90-day MCCPDC pricing, with surgical drugs accounting for over $900 million. Nearly 80% of the examined drugs were more price effective through MCCPDC using 90-day supply. Commonly prescribed drugs in cardiology, psychiatry, neurology, transplant surgery, and urology demonstrated the highest estimated absolute savings. The most disproportionate savings relative to prescription volume were observed for drugs in oncology, gynecology, infectious disease, transplant surgery, and colorectal surgery. This study underscores the significant potential for Medicare Part D savings through strategies that address the systemic overpayment for generic medications. We identified key areas for reform as well as specific medical and surgical subspecialties where targeted interventions could yield substantial savings.

A Method for the Colorimetric Quantification of Sodium Lauryl Sulphate in Tablets: A Proof of Concept.

The deformulation stage of original drug products, which includes the quantification of critical excipients, is crucial for the successful development of generic drug products of solid dosage form. Sodium lauryl sulphate (SLS) belongs to the group of critical excipients due to its influence on the bioavailability of drugs, such as metformin. The purpose of this work is to carry out a feasibility study in order to develop a simple, economical, and robust analytical method for the quantification of SLS in metformin-containing tablets after their dissolution in water. Firstly, SLS is extracted with chloroform in acidic conditions, followed by the addition of methylene blue (MB) in order to form a SLS-MB ion pair, which is then measured photometrically at a wavelength of 651 nm. Additionally, interference from matrix components (excipients and APIs) was assessed, and it was found that metformin also forms a blue complex; therefore, this specific extraction method was developed. Other matrix components did not interfere with SLS determination. This method shows a well-estimated precision of 3.3% and accuracy of 5%, a calibration linearity of R2 = 0.99990, and a working range of 0.38 µg/mL to 10 µg/mL of SLS in water. The midpoint of the calibration graph corresponds to the concentration of SLS obtained by dissolving a single tablet in 1 L of water. This method seems appropriate for total SLS determination in tablets and can be applicable for deformulation.

المحاكاة العددية للتدفقات المضغوطة المكو نة من عنصرين مع المعادلة العامة للحالة

Numerical simulations of compressible two-component flows with a general equation of state (EOS), written in the form of the Mie-Gru¨neisen EOS, have been conducted using the diffuse interface method on a structured mesh. The unsteady and inviscid one-dimensional sixequation model of Kapila is employed to describe compressible two-component flows. The model is hyperbolic and non-conservative. The solution of the hyperbolic equations, including the non-conservative equation for the volume fraction evolution, is obtained using an extended Harten-Lax-Leer (HLL) approximate Riemann solver. A general formulation for various EOSs is proposed to enable simulations of a wide range of applications. In which the two constituents are either governed by the same EOS or different types of EOS. In this model, both fluids have the same velocity, but each fluid has its own pressure. Therefore, the pressure relaxation process is performed instantaneously to drive both constituents' pressures towards equilibrium. Several computational test problems were conducted in one and two dimensions to show the ability of the numerical method to simulate such problems. The computed results are presented without introducing spurious pressure oscillations in the method.

A comprehensive study on the identification and characterization of major degradation products of synthetic liraglutide using liquid chromatography-high resolution mass spectrometry.

Liraglutide (LGT) is a synthetic glucagon-like peptide-1 analogue mainly used for the treatment of type-2 diabetes or obesity. Comprehensive stability testing is essential in the development and routine quality control of synthetic therapeutic peptide pharmaceuticals. The GLP-1 peptide drugs are usually formulated in aqueous-base solution, which can generate stability issues during manufacturing, storage or shipment. The current study endeavors to observe the chemical stability behavior of LGT by exposing the drug substance to oxidative and hydrolytic stress conditions. A simple liquid chromatography (LC) method was developed where sufficient resolution between LGT and the generated degradation products was achieved. In total, 19 degradation products (DPs) were separated under acidic, basic and oxidative stress conditions. Using LC-HRMS, MS/MS studies, the generated degradation products were identified and characterized. The mechanistic fragmentation pathway for all generated DPs were established and the plausible chemical structure for the identified DPs was predicted based on MS/MS data. The results strongly suggest that LGT is highly susceptible to degrade under oxidative and hydrolytic conditions. Furthermore, this study provides insights into the hydrolytic and oxidative stability of LGT, which can be implied during generic and novel formulation drug development and discovery in synthesizing relatively stable GLP-1 analogues.

Analisis Pengelolaan Obat Di Instalasi Farmasi Puskesmas X Kabupaten Sukoharjo

The management of medicines in community health centers is a key element in healthcare services. This study aims to analyze the management of medicines at the Pharmacy Installation of X Community Health Center in Sukoharjo Regency. The aim of this research is to determine the suitability of indicators for the selection, planning, procurement, distribution, and use of drugs at this community health center, and to identify the strategic position of the pharmacy installation within the SWOT matrix. This research employs a descriptive analysis study design with a nonexperimental qualitative approach. Data were collected retrospectively through a review of documented records. Data collection techniques included document review, observation, and interviews at X Community Health Center in Sukoharjo Regency. The results showed that the indicators for compliance with the community health center's formulary were in accordance with standards, but the compliance of medicine items with the national formulary and the national essential medicines list was not up to standard. In the planning and procurement stages, all indicators met standards, such as the comparison between the number of medicine items planned and those actually used, the frequency of procurement of each medicine item annually, and planning deviations. In the distribution stage, the indicators for medicine matching with stock cards and the warehouse management system met standards. In the usage stage, the percentage of prescriptions with generic medicines met standards. The SWOT analysis results indicated a position in quadrant 1.

Pharmacokinetics and Safety of Linezolid Tablets of 2 Different Manufacturers in Healthy Chinese Subjects in Fasting and Fed States.

This study aimed to evaluate the pharmacokinetics (PKs) and safety of a generic drug, linezolid, compared to those of a reference drug in healthy Chinese subjects under both fasting and fed conditions. This was a randomized, open-label, 2-period, 2-sequence crossover study. The subjects received a single dose of the test or reference drug, linezolid (600mg), in each period. The PK parameters were calculated using a non-compartmental method and compared between the 2 drugs. Bioequivalence was analyzed using geometric mean ratios (GMRs) of the 2 formulations and their corresponding 90% confidence intervals (CIs). The safety of the 2 formulations was assessed under both fasting and fed conditions. Forty-eight subjects completed the study, 24 each in the fasting and feeding groups. The average plasma concentration-time patterns of linezolid were similar for both medications under both conditions. The GMR and 90% CIs of the maximum plasma concentration and the area under the plasma concentration-time curve of linezolid were ranged from 0.80 to 1.25. Both drugs were well tolerated with a similar incidence of adverse drug reactions. In conclusion, the PK and safety profiles of the 2 formulations were comparable. Food intake did not influence the PK profiles of linezolid. These results suggest that the test drug can be used as an alternative to reference drugs.

Targeted therapies and conventional care for the treatment of ankylosing spondylitis in China: a cost-effectiveness analysis based on the network-meta analysis

ObjectiveThis study aimed to evaluate the long-term cost-effectiveness of conventional care (CC) and seven first-line targeted therapies marketed in China for the treatment of patients with ankylosing spondylitis (AS)–namely secukinumab, ixekizumab, infliximab, etanercept, adalimumab and golimumab and tofacitinib–from the perspective of the Chinese health care system.MethodsThe York model was structured as a 12-week decision tree leading into two Markov models. This study set 1 year as a recurring cycle and a lifetime timeframe for the model. Primary model outcomes included the costs in Chinese yuan (CNY), health outcomes in quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER) under a willingness-to-pay threshold of ¥89,358 (equal to the per capita gross domestic product in China in 2023) per QALY. Parameters in the York model were captured from network meta-analyses and literature including treatment response, short-term disease progression, patient functioning and long-term structural disease progression. Utilities are dependent on indicators such as the BASDAI score, the BASFI score, gender and age. Drug prices were analysed using the median price of the Chinese market from YAOZH net in the basic analysis. Costs and outcomes were discounted at 5.0%. We performed deterministic and probabilistic sensitivity analyses to investigate the robustness of the results. The prices of original drugs and generic drugs were used in the scenario analysis.ResultsCompared with CC, the ICER of golimumab was ¥104,217.4/QALY, which is between 1 and 3 times the GDP per capita, while the ICERs of the other six targeted therapies were less than ¥89,358/QALY. The specific economic rank of the targeted therapy was as follows:secukinumab > ixekizumab > tofacitinib > infliximab > etanercept > adalimumab > golimumab. Treatment response rates such as the BASDAI50, changes in the BASDAI/BASFI scores and the discounting rate were key model drivers. According to the scenario analysis, IL-17 inhibitors were still the most economical intervention when original drugs and generic drugs were used.ConclusionTargeted therapies are cost-effective treatments for AS. Overall, IL-17 inhibitors were the dominant treatment. The choice of the brand-new prices or generic drug prices can greatly affect economics.

Implementation of variable cross-section curved beam in train-turnout dynamic interactions

The abundance of variable cross-section curved rails in railway turnouts emphasizes the necessity of intricately modeling them, which facilitates a more accurate evaluation of train-turnout interactions. This study presents a general formulation for analyzing both free and forced vibrations of a variable cross-section curved Timoshenko beam and its implementation in train-turnout dynamic interactions. First, the natural frequencies and mode shapes for in-plane and out-of-plane free vibrations of the beam are determined through eigenvalue analysis, taking into careful consideration the characteristics of variable cross-section and curvature. Then, the forced vibration solution is derived using modal superposition and orthogonality. Furthermore, comparative analyses using finite element method (FEM) validate the natural frequencies and dynamic responses of a beam under various boundary conditions, confirming the reliability and accuracy of the proposed method. Finally, the developed beam model is then applied to simulate the switch rail and point rail under train-turnout interactions, revealing the differences from existing methods that modeled these components as uniform cross-section straight beams. Numerical analyses provide new insights by comparing wheel-rail forces and rail acceleration. Considering curve and variable cross section characteristics could contribute to a more accurate evaluation of train-turnout dynamic interactions.