General Formulation Research Articles

Generalization of Biasing Particle Insertion and Deletion for Grand Canonical Monte Carlo Simulation.

A general formulation of biasing particle insertion/deletion for the grand canonical Monte Carlo (GCMC) simulation is presented. The proposed formulation unifies the concepts of the conventional cavity- and configurational-type biasing techniques and modifies a cavity biasing method to strictly satisfy the detailed balance condition. Numerical examples of this modified cavity bias method are presented for Lennard-Jones fluid and hydrogen adsorption on a platinum surface. The results obtained using this method are compared with those obtained using various GCMC methods. Furthermore, a rigorous on-the-fly on-lattice GCMC simulation for surface adsorption is formulated and performed for comparison. The numerical examples clearly demonstrate the efficiency and accuracy of the proposed formulation.

Competition in International Generic Drug Markets

This cross-sectional study compares the small molecule generic drug markets of a group of high-income countries with similar pharmaceutical regulatory environments.

Pathways for non-manufacturers to drive generic drug repurposing for cancer in the U.S.

Repurposing generic drugs as new treatments for life-threatening diseases such as cancer is an exciting yet largely overlooked opportunity due to a lack of market-driven incentives. Nonprofit organizations and other non-manufacturers have been ramping up efforts to repurpose widely available generic drugs and rapidly expand affordable treatment options for patients. However, these non-manufacturers find it difficult to obtain regulatory approval in the U.S. Without a straightforward path for approval and updating drug labeling, non-manufacturers have relied on off-label use of repurposed drugs. This limits the broad clinical adoption of these drugs and patient access. In this paper, we explore the regulatory landscape for repurposing of small molecule generic drugs within the U.S. We describe case studies of repurposed drugs that have been successfully incorporated into clinical treatment guidelines for cancer without regulatory approval. To encourage greater adoption of generic drugs in clinical practice-that is, to encourage the repurposing of these drugs-we examine existing Food and Drug Administration (FDA) pathways for approval of new uses or indications for generic drugs. We show how non-manufacturers, who are generally more active in generic drug repurposing than manufacturers, could utilize existing regulatory authorities and pathways, and we describe the challenges they face. We propose an extension of the existing 505(b)(2) new drug application (NDA) approval pathway, called a "labeling-only" 505(b)(2) NDA, that would enable non-manufacturers to seek approval of new indications for well-established small molecule drugs when multiple generic products are already available. It would not require new chemistry, manufacturing, and controls (CMC) data or introducing new drug products into the marketplace. This pathway would unlock innovation broadly and enable patients to benefit from the enormous potential of low-cost generic drugs.

An Adaptive Three-Arm Comparative Clinical Endpoint Bioequivalence Study Design With Unblinded Sample Size Re-Estimation and Optimized Allocation Ratio.

A three-arm comparative clinical endpoint bioequivalence (BE) study is often used to establish bioequivalence (BE) between a locally acting generic drug (T) and reference drug (R), where superiority needs to be established for T and R over Placebo (P) and equivalence needs to be established for T vs. R. Sometimes, when study design parameters are uncertain, a fixed design study may be under- or over-powered and result in study failure or unnecessary cost. In this paper, we propose a two-stage adaptive clinical endpoint BE study with unblinded sample size re-estimation, standard or maximum combination method, optimized allocation ratio, optional re-estimation of the effect size based on likelihood estimation, and optional re-estimation of the R and P treatment means at interim analysis, which have not been done previously. Our proposed method guarantees control of Type 1 error rate analytically. It helps to reduce the average sample size when the original fixed design is overpowered and increases the sample size and power when the original study and group sequential design are under-powered. Our proposed adaptive design can help generic drug sponsors cut cost and improve success rate, making clinical study endpoint BE studies more affordable and more generic drugs accessible to the public.

Relationship between Prices and Quality of Essential Medicines from Different Manufacturers Collected in Cameroon, the Democratic Republic of the Congo, and Nigeria.

Achieving universal access to affordable medicines and at the same time ensuring the quality of medicines presents a challenge, especially in low- and middle-income countries. Here, the relationship between medicine prices and medicine quality was investigated in three African countries. From different types of health facilities and medicine vendors, 711 samples of 18 different essential medicines were purchased and analyzed for quality (assay and dissolution) according to the United States Pharmacopeia. Without exception, all originator brand medicines and all SRA generics (generic medicines manufactured in countries with stringent regulatory authorities [SRAs]) complied with pharmacopeial specifications. In contrast, 21.1% of the non-SRA generics (manufactured in countries without SRAs) were substandard. The median prices of originator brands and SRA generics were three times and two times higher than those of non-SRA generics, respectively. Within the non-SRA generics, no positive correlation was observed between medicine quality and medicine price. Medicines manufactured in India, China, or African countries showed similar quality and similar prices. Only a single WHO-prequalified medicine sample was found among the 711 samples. Non-SRA generic medicines produced by manufacturers for which WHO had published Public Inspection Reports showed a significantly lower rate of substandard medicines (7.3%) and, at the same time, significantly lower prices (by 33%) than other non-SRA generics. Falsified medicines (total 2.0%) were found among all categories of medicines and had prices similar to those of non-SRA generics. Our findings indicate that adequate quality assurance does not necessarily imply an increase in medicine prices.

Evaluating quality reward and other interventions to mitigate US drug shortages

AbstractDrug shortages have been persistent in the United States for over a decade, posing serious threats to public health and the healthcare system. While previous research has investigated the causes and effects of drug shortages, there is a dearth of research exploring potential solutions to mitigate this problem. Using a system dynamics model of the US generic drug market, we evaluate the long‐term effectiveness of two existing policy interventions (expediting drug approvals and nudging manufacturers to ramp up their production) and the “quality reward” initiative that is being actively explored by the FDA and industry. Our results indicate that while the existing interventions can be helpful in addressing shortages, their long‐term effect seems limited. In contrast, quality reward can mitigate drug shortages in a sustainable way. However, a caveat of quality reward is the potential emergence of a monopolistic supply market with negative consequences. We suggest that a carefully designed quality disclosure mechanism can address this issue. To the best of our knowledge, this is the first study to quantitatively and comparatively evaluate the long‐term effectiveness of quality reward and other interventions on drug shortages and provide structural explanations for their performance.

Knowledge Editing for Large Language Models: A Survey

Large Language Models (LLMs) have recently transformed both the academic and industrial landscapes due to their remarkable capacity to understand, analyze, and generate texts based on their vast knowledge and reasoning ability. Nevertheless, one major drawback of LLMs is their substantial computational cost for pre-training due to their unprecedented amounts of parameters. The disadvantage is exacerbated when new knowledge frequently needs to be introduced into the pre-trained model. Therefore, it is imperative to develop effective and efficient techniques to update pre-trained LLMs. Traditional methods encode new knowledge in pre-trained LLMs through direct fine-tuning. However, naively re-training LLMs can be computationally intensive and risks degenerating valuable pre-trained knowledge irrelevant to the update in the model. Recently, Knowledge-based Model Editing (KME), also known as Knowledge Editing or Model Editing , has attracted increasing attention, which aims to precisely modify the LLMs to incorporate specific knowledge, without negatively influencing other irrelevant knowledge. In this survey, we aim to provide a comprehensive and in-depth overview of recent advances in the field of KME. We first introduce a general formulation of KME to encompass different KME strategies. Afterward, we provide an innovative taxonomy of KME techniques based on how the new knowledge is introduced into pre-trained LLMs, and investigate existing KME strategies while analyzing key insights, advantages, and limitations of methods from each category. Moreover, representative metrics, datasets, and applications of KME are introduced accordingly. Finally, we provide an in-depth analysis regarding the practicality and remaining challenges of KME and suggest promising research directions for further advancement in this field.

Bi-orthogonality relations: general formulation, conversion to the FE format, and application for analysis of homogeneous and periodic waveguides

Bi-orthogonality relations are a powerful tool to solve complicated wave propagation problems in a surprisingly simple way. For any symmetric waveguide, these relations identify so-called Class A and Class B boundary conditions, for which eigenfrequencies and eigenmodes of a slice of waveguide provide dispersion diagrams of propagating waves and (for periodic wave-guides) location of pass- and stop-bands. It is a straightforward matter to convert these 'class-consistent' boundary conditions to the FE format and use standard FE modal analysis software to study properties of waveguides of arbitrary complexity. However, an application of this methodology, especially for periodic waveguides, is challenged by the necessity to track mode shapes and pair Class A and B eigenfrequencies into their modal families. A novel algorithm to resolve this issue is proposed and tested on post-processing results of modal analysis in the AN-SYS environment. Underlying theory of bi-orthogonality, analytical solutions of benchmark problems, and FE case-studies are presented and explained.

A generic formulation of anisotropic thermo-elastoviscoplasticity at finite deformations for finite element codes

A generic formulation of anisotropic thermo-elastoviscoplasticity at finite deformations for finite element codes

Microscopic analysis of relaxation behavior in nonlinear optical conductivity of graphene

We produce a general formalism to study the interband dynamical optical conductivity in the nonlinear regime of graphene in the presence of a quantum bath comprising phonons and electrons. When a quantum solid of graphene is subjected to an intense electric field in the optical frequency range, the observation of a nonlinear response is facilitated by formulating a quantum master equation of the density operator associated with the Hamiltonian encapsulated in a spin-boson model of dissipative quantum statistical mechanics. Our results reveal the nonlinear steady-state regime’s population inversion and decoherence. The present method enables us to investigate further the nonlinear interband optical conductivity of pristine and gapped graphene characterized by a single dimensionless parameter at finite temperatures. Different bath spectra’ effects on phonons and electrons are examined in detail. The temperature dependence of conductivity reveals that changing temperature can enable us to make a transition from the linear to the nonlinear regime for fixed optical field parameters. Interestingly, a fascinating switching-like behavior is observed for the low-temperature optical conductivity of the gapped graphene while we vary the energy gap as well as the frequency of the externally applied field. Although our general formulation can address a variety of nonequilibrium responses of the two-band system, it also facilitates a connection with the phenomenological modeling of nonlinear optical conductivity.

An Analysis of Consumer Awareness Regarding Jan Aushadhi Kendras

India has made significant advancements in various health aspects, including an increase in the life expectancy of both men and women, low infant and maternal mortality rates, improved immunization coverage, and the elimination of diseases like polio and smallpox. According to the World Health Organization, around 5.8 million Indians succumb to diseases like diabetes, cancer, stroke, and heart and lung diseases. Non-communicable diseases (NCDs) pose a substantial health challenge in India, with one out of every four Indians dying before the age of 70 due to an NCD. The Indian healthcare system is grappling with rising healthcare costs, which disproportionately burden the poor, as well as the emergence of new diseases and non-communicable diseases. Approximately 100 million Indians fall into poverty each year due to high healthcare expenses, with out-of-pocket spending constituting over 50 percent of this burden. To reduce healthcare costs, the government has established Jan Aushadhi Kendras, which offer generic medicines with the same composition as branded ones at affordable prices. A recent study focused on identifying the key factors influencing the purchase of generic drugs from Jan Aushadhi medical stores, public awareness of these stores, and consumer satisfaction. The study found that 40 percent of the public is unaware of Jan Aushadhi, and consumers opt for generic medicines due to their affordability, even though the quality is lower than that of branded drugs. Jan Aushadhi Kendra is known for selling significant quantities of sanitary pads. While most consumers are satisfied with Jan Aushadhi products, some express dissatisfaction due to differences in quality and composition. Government agencies and health departments must enhance the quality of generic medicines and educate healthcare professionals and the general public about them.

Development and optimization of an in vitro release assay for evaluation of liposomal irinotecan formulation

Onivyde®, a pegylated irinotecan liposomal formulation, is approved by the USFDA for treating metastatic pancreatic adenocarcinoma. Despite the substantial interest in developing its generic versions, the unique structural and manufacturing complexities of liposomal formulations pose challenges. In this study, we address this gap by developing a robust in vitro release test (IVRT) using dialysis membrane techniques. The release of Onivyde® is influenced by several key factors, including the composition of the release medium, temperature, initial formulation concentration, the materials and molecular weight cut-offs of dialysis bags, and the pH of the release medium. Our optimized IVRT for Onivyde® incorporates a release medium containing 5 mM ammonium bicarbonate in a HEPES solution with a pH of 7.4. Additionally, the method includes an initial formulation concentration of 4.6 µg/mL and 50 kDa dialysis bags, while maintaining a temperature of 37 °C with continuous agitation at 80 rpm. This optimized IVR assay effectively differentiates between varying qualities of irinotecan liposomal formulations. Our findings contribute to optimizing IVRT for liposomal irinotecan formulations, enabling better quality control procedures. This assay serves as a reliable tool for evaluating generic irinotecan liposomal formulations, aiding in their development and ensuring in vitro comparability.

Design, synthesis, in vitro and in vivo trypanosomaticidal efficacy of novel 5-nitroindolylazines

Leishmaniasis and trypanosomiasis rank among lethal vector-borne parasitic diseases that are endemic in tropical and sub-tropical countries. There are currently no preventive vaccines against them, and once diagnosed, a handful of less effective drugs clinically accessible are the only therapeutic options offered to treat these ailments. And although curable, the eradication and elimination of these diseases are hampered by the emergence of multidrug-resistant strains of the causal pathogens. Hence, there is accrued necessity for the development of new, effective, and affordable drugs. In recent decades, several molecular scaffolds, including nitroaromatics, endoperoxides, etc., have been attempted as building blocks to generate new effective clinical antitrypanosomatid agents with low toxicity so far to no avail. In this regard, a series of nitroindolylazine derivatives was synthesised in a three-step process involving nucleophilic substitution (SN), hydrazination and Schiff base condensation reactions, and was evaluated against various Leishmania and Trypanosoma species and strains. Several promising hits portraying leishmanicidal and trypanocidal with in vitro submicromolar activities, and devoid of toxicity on mammalian cells were uncovered. Among these, nitrofurylazine 11 (Tc IC50: 0.08 ± 0.03 μM) and nitrothienylazine 13 (Tc IC50: 0.09 ± 0.01 μM) were evaluated in vivo against Trypanosoma congolense, the causative agent of nagana, which is livestock most virulent trypanosome species in mice-infected preliminary study. However, only partial efficacy was observed as all mice succumbed due to high parasitemia within 13 days post-infection during the treatment. The translational potential of antileishmanial and antichagasic hits, as well as further identification of their molecular targets, will be assessed in future research.

Financial realities of fighting cancer: A close look at patient responsibility with part D coverage.

12 Background: Medicare Part D, a prescription drug plan offered by government-contracted private payers, provides coverage for prescription drugs. The plan design encompasses the deductible, initial coverage (IC), coverage gap (CG), and catastrophic coverage (CC) phases. In the earlier phases, patients bear a significant financial burden for drug costs (100% of the deductible, 25% of drug costs during IC and CG) until they reach the out-of-pocket threshold (OOPT) and transition to the CC phase, where the responsibility decreases to 5% of the drug cost with no upper limit. Additionally, Medicare subsidizes or assumes full responsibility for low-income patients through the Low-Income Cost Subsidy (LICS) benefit. We analyzed the patient responsibility (PR) for cancer patients under Medicare Part D and the impact of Part D Anti-Neoplastics (PDAN). Methods: Using Medicare Part D prescription data for 15 practices in The US Oncology Network, we obtained and evaluated the gross drug costs below (GDCB) and above (GDCA) the OOPT, LICS and estimated PR for prescriptions over a 6-year period (July 2016 – June 2022). Results: The analysis of 5.12 million prescriptions for 99,623 cancer patients reveals that 1 in every 5 patients surpassed the OOPT and transitioned to the CC phase. Among the patients receiving PDAN drugs, 3 in every 4 crossed the OOPT. Table 1 provides the percentage of patients entering the CC phase and the estimated per patient, per year PR amounts. Within the PDAN drug recipient group, 85% of patients who reached the OOPT did so within the first 3 months of initiating therapy, often after just 2 prescription dispenses, resulting in a significant portion of the PR being incurred upfront. Approximately 45% of the PR was accumulated prior to crossing the OOPT. Interestingly, only 1 in every 5 patients receiving generic PDAN drugs surpassed the OOPT, in contrast to every patient receiving a branded PDAN. Additionally, patients receiving generic PDAN incurred lower PR costs. About 1 in every 6 patients benefited from the LICS, with 60% of the LICS amounts being paid within the first 3 months of starting therapy, aligning with the timing of patients entering the CC phase. Conclusions: Cancer patients, particularly those taking PDAN drugs, face significant PR costs. The proposed changes to the Part D plan design outlined in the Inflation Reduction Act (IRA) aim to alleviate this burden by reducing PR. These changes include reducing PR in the CC phase to 0%, capping PR in the earlier phases at $2000 and changing cost-sharing between plans, manufacturers, and Medicare. However, the potential effects of these adjustments on Part D plan premiums remain uncertain and require further examination. Without PDAN Drugs With PDAN Drugs Total % of patients Not crossing OOPT 94% 22% 80% Crossing OOPT 6% 78% 20% Patient Responsibility for Patients Not crossing OOPT $292 $1,787 $373 Crossing OOPT $2,448 $6,525 $5,555 Total $422 $5,489 $1,424

Changes in drug crystallinity in a commercial tacrolimus amorphous formulation result in variable pharmacokinetics

Tacrolimus capsules contain the drug as the amorphous form. It is well known that drug crystallinity is a risk factor for the performance of amorphous formulations. This study investigated the impact of varying levels of crystalline drug on the pharmacokinetics of tacrolimus following oral dosing of a 5 mg capsule under fasting conditions. Two treatments with percent crystallinity of 20% and 50% were achieved by exposing a marketed generic tacrolimus product to open dish storage conditions of 35 °C and 75% relative humidity (RH) for up to 20 days. Crystallinity was monitored with X-ray powder diffraction. Prograf®, the reference listed drug (RLD), an amorphous generic drug product, and generic drug products containing 20% and 50% crystalline tacrolimus were evaluated. All four treatments were administered to healthy participants in a randomized, single-dose, four-treatment, four-period, four-way crossover study. Blood sampling occurred over 24 h. The amorphous generic tacrolimus product was determined not to be bioequivalent to the RLD. The capsules containing both 20% and 50% crystalline tacrolimus also failed the bioequivalence recommendations when compared to the amorphous generic or to the RLD. Both levels of crystalline tacrolimus resulted in BE failure for both Cmax and AUC parameters. The impact of tacrolimus crystallization was greater for maximum blood concentration (Cmax) values relative to the area-under-the-curve (AUC) values. This study demonstrates that crystalline tacrolimus formed in a marketed generic product and these changes resulted in variable pharmacokinetics which could be of significant clinical concern.

Biowaiver monographs for immediate-release solid oral dosage forms: Lemborexant

Lemborexant is a dual orexin receptor antagonist assigned to class II of the Biopharmaceutics Classification System (BCS). Thus, the ICH M9 Guideline excludes immediate-release (IR) solid oral dosage forms containing lemborexant from BCS-based biowaivers, irrespective of their in vitro dissolution behavior. By contrast, classification of lemborexant according to the refined Developability Classification System (rDCS) falls into class I, indicating few biopharmaceutics risks. Customized rDCS investigations identify dissolution as the main risk factor, in line with clinical data in humans which suggest that the absorption of lemborexant is limited neither by solubility nor by permeability. Instead, any risks lie in dissolution. Analysis by the rDCS coupled with biorelevant dissolution testing thus provides a way forward for manufacturers to mitigate the risks associated with changes in formulation or introduction of a generic version prior to running clinical bioequivalence (BE) studies. As a way forward regarding biowaivers for lemborexant and similar cases, where justifying BE based on the current BCS-based approach is not possible, a four-step pathway towards establishing BE virtually could be adopted as follows: (i) rDCS analysis to identify critical bioavailability attributes, (ii) comparative (biorelevant) dissolution testing, (iii) Physiologically Based Biopharmaceutics Modeling (PBBM), and (iv) virtual BE assessment.

Self-guided Knowledge-Injected Graph Neural Network for Alzheimer's Diseases.

Graph neural networks (GNNs) are proficient machine learning models in handling irregularly structured data. Nevertheless, their generic formulation falls short when applied to the analysis of brain connectomes in Alzheimer's Disease (AD), necessitating the incorporation of domain-specific knowledge to achieve optimal model performance. The integration of AD-related expertise into GNNs presents a significant challenge. Current methodologies reliant on manual design often demand substantial expertise from external domain specialists to guide the development of novel models, thereby consuming considerable time and resources. To mitigate the need for manual curation, this paper introduces a novel self-guided knowledge-infused multimodal GNN to autonomously integrate domain knowledge into the model development process. We propose to conceptualize existing domain knowledge as natural language, and devise a specialized multimodal GNN framework tailored to leverage this uncurated knowledge to direct the learning of the GNN submodule, thereby enhancing its efficacy and improving prediction interpretability. To assess the effectiveness of our framework, we compile a comprehensive literature dataset comprising recent peer-reviewed publications on AD. By integrating this literature dataset with several real-world AD datasets, our experimental results illustrate the effectiveness of the proposed method in extracting curated knowledge and offering explanations on graphs for domain-specific applications. Furthermore, our approach successfully utilizes the extracted information to enhance the performance of the GNN.

Optical Activities of Organic Crystals: Crystal Orbital Formulation of Anisotropic Gyration.

To describe the optical activities of crystals, gyration tensors are necessary for all wavelengths of incident light. To date, few studies on direct calculations of gyration tensors from Bloch states have been conducted. Herein, a practical procedure to obtain gyration tensors of organic crystals is presented using the crystal orbital method. The extended Hückel method was adopted to evaluate the gyration tensors, epitomizing the one-electron formulation. To confirm the validity of the formulation, the optical rotatory power of alanine and γ-glycine was examined. The reproduced profiles of the optical rotatory power were consistent with the results of recent experiments. This is a general formulation of the one-electron theory of optical activities for three-dimensional crystals. In principle, the optical rotatory strength tensor is not invariant with translation. For systems with small unit cells, however, the formalism is quasi-invariant with respect to translation. The quasi origin-independent formalism is sufficiently substantial to be applicable to modern crystal optics.

Analisa mutu tablet ibuprofen generik berlogo dan generik bermerek yang diproduksi industri X di Gresik

Ibuprofen tablets are one of the most widely used antipyretic analgesic drugs for self-medication in pharmacies. According to the Biopharmaceutical Classification System (BCS), Ibuprofen is included in Class II or drugs with low solubility, but high permeability. This study was carried out to determine the physical quality of branded generic and branded generic ibuprofen drugs. This research was carried out by dissolution testing on ibuprofen tablets. The results obtained from the physical quality test met the specified requirements. The dissolution test showed that Q30 had dissolved more than 70%. The conclusion is that the drug meets the requirements and there is no difference between generic drugs with the logo and branded generics.

Slab assignment to non-identical reheat furnaces running in parallel mode

This article analyses a slab assignment problem for non-identical reheat furnaces in the steelmaking industry. We tackle the problem of assigning slabs to different types of reheat furnaces, a walking beam and a pusher type furnace. Furthermore, we need to determine the feed-in as well as the residence time for each slab. The aim is to (i) reduce the energy consumption, (ii) increase the production rate and (iii) the heating quality of the slabs which depends on the assigned furnace and to what extent the slabs are overheated. Moreover, the subsequent production stage (Hot Rolling Mill), needs to be synchronized with the furnaces which is essential for a smooth production. We specify the problem as a mixed integer optimization formulation that is solved with iterative parameter adjustment. Rapid convergence leads to a novel two-phase solution method that yields furnace schedules that are optimal for the adjusted parameter values in reasonable time. The results show that our proposed method performs better than an industry benchmark by increasing the production rate and increasing the reheating quality. Furthermore, the new generic problem formulation allows using standard software and can be applied to identical or non-identical furnaces highlighting its broad applicability across steel-making companies.