journal
https://read.qxmd.com/read/38605261/machine-learning-exploration-of-the-relationship-between-drugs-and-the-blood-brain-barrier-guiding-molecular-modification
#1
JOURNAL ARTICLE
Qi Yang, Lili Fan, Erwei Hao, Xiaotao Hou, Jiagang Deng, Zhongshang Xia, Zhengcai Du
OBJECTIVE: This study aimed to improve the efficiency of pharmacotherapy for CNS diseases by optimizing the ability of drug molecules to penetrate the Blood-Brain Barrier (BBB). METHODS: We established qualitative and quantitative databases of the ADME properties of drugs and derived characteristic features of compounds with efficient BBB penetration. Using these insights, we developed four machine learning models to predict a drug's BBB permeability by assessing ADME properties and molecular topology...
April 11, 2024: Pharmaceutical Research
https://read.qxmd.com/read/38589647/a-refined-thin-film-model-for-drug-dissolution-considering-radial-diffusion-simulating-powder-dissolution
#2
JOURNAL ARTICLE
Karthik Salish, Chi So, Seong Hoon Jeong, Hao Helen Hou, Chen Mao
PURPOSE: We aim to present a refined thin-film model describing the drug particle dissolution considering radial diffusion in spherical boundary layer, and to demonstrate the ability of the model to describe the dissolution behavior of bulk drug powders. METHODS: The dissolution model introduced in this study was refined from a radial diffusion-based model previously published by our laboratory (So et al. in Pharm Res. 39:907-17, 2022). The refined model was created to simulate the dissolution of bulk powders, and to account for the evolution of particle size and diffusion layer thickness during dissolution...
April 8, 2024: Pharmaceutical Research
https://read.qxmd.com/read/38561581/antibiotic-development-lessons-from-the-past-and-future-opportunities
#3
REVIEW
Michael S Kinch, Zachary Kraft, Tyler Schwartz
The challenge of antimicrobial resistance is broadly appreciated by the clinical and scientific communities. To assess progress in the development of medical countermeasures to combat bacterial infections, we deployed information gleaned from clinical trials conducted from 2000 to 2021. Whereas private sector interest in cancer grew dramatically over this period, activity to combat bacterial infections remained stagnant. The comparative ambivalence to antimicrobial resistance is reflected in the number of investigative drugs under clinical investigation, their stage of development and most troublingly, a declining number of organizations that are actively involved in the development of new products to treat bacterial infections...
April 1, 2024: Pharmaceutical Research
https://read.qxmd.com/read/38561580/combating-alcohol-adduct-impurity-in-immunosuppressant-drug-product-manufacturing-a-scientific-investigation-for-enhanced-process-control
#4
JOURNAL ARTICLE
Vasanthakumar Sekar, Devarajan Vedhachalam, ArunKumar Vb, Sivananthan Sivaraman, Venkatakrishnan Janakarajan, Sai Sethuraman, Sandeep G Shiroor, Jean-Marie M Geoffroy
OBJECTIVE: This research aims to elucidate critical impurities in process validation batches of tacrolimus injection formulations, focusing on identification and characterization of previously unreported impurity at RRT 0.42, identified as the tacrolimus alcohol adduct. The potential root causes for the formation of new impurity was determined using structured risk assessment by cause and effect fishbone diagram. The primary objective was to propose mitigation plan and demonstrate the control of impurities with 6 month accelerated stability results in development batches...
April 1, 2024: Pharmaceutical Research
https://read.qxmd.com/read/38561579/development-and-validation-of-matrix-of-chemistry-manufacturing-and-control-mocmc-system-for-intramammary-drug-products-imm
#5
JOURNAL ARTICLE
Nada A Helal, Marilyn N Martinez, David G Longstaff, Ziyaur Rahman, Mohammad T H Nutan, Mansoor A Khan
PURPOSE: Products formulated for intramammary (IMM) infusion are intended for the delivery of therapeutic moieties directly into the udder through the teat canal to maximize drug exposure at the targeted clinical site, the mammary gland, with little to no systemic drug exposure. Currently, to our knowledge, there has been no in-vitro matrix system available to differentiate between IMM formulations. Our goal is to develop A custom tailored in-vitro "Matrix of Chemistry, Manufacturing and Control" (MoCMC) System to be a promising future tool for identifying inequivalent IMM formulations...
April 1, 2024: Pharmaceutical Research
https://read.qxmd.com/read/38538971/the-use-of-global-sensitivity-analysis-to-assess-the-oral-absorption-of-weakly-basic-compounds-a-case-example-of-dipyridamole
#6
JOURNAL ARTICLE
Siddharth S Kesharwani, Guillaume Louit, Fady Ibrahim
OBJECTIVE: To utilize the global system analysis (GSA) in oral absorption modeling to gain a deeper understanding of system behavior, improve model accuracy, and make informed decisions during drug development. METHODS: GSA was utilized to give insight into which drug substance (DS), drug product (DP), and/or physiological parameter would have an impact on peak plasma concentration (Cmax ) and area under the curve (AUC) of dipyridamole as a model weakly basic compound...
March 27, 2024: Pharmaceutical Research
https://read.qxmd.com/read/38538970/pharmacokinetics-of-pegasparaginase-in-infants-with-acute-lymphoblastic-leukemia
#7
JOURNAL ARTICLE
Leiah J Brigitha, Veerle Mondelaers, Yiwei Liu, Birgitte K Albertsen, Beata Zalewska-Szewczyk, Carmelo Rizzari, Rishi S Kotecha, Rob Pieters, Alwin D R Huitema, Inge M van der Sluis
BACKGROUND: PEGasparaginase is known to be a critical drug for treating pediatric acute lymphoblastic leukemia (ALL), however, there is insufficient evidence to determine the optimal dose for infants who are less than one year of age at diagnosis. This international study was conducted to identify the pharmacokinetics of PEGasparaginase in infants with newly diagnosed ALL and gather insight into the clearance and dosing of this population. METHODS: Infants with ALL who received treatment with PEGasparaginase were included in our population pharmacokinetic assessment employing non-linear mixed effects modelling (NONMEM)...
March 27, 2024: Pharmaceutical Research
https://read.qxmd.com/read/38536615/quantification-of-unencapsulated-drug-in-target-tissues-demonstrates-pharmacological-properties-and-therapeutic-effects-of-liposomal-topotecan-ff-10850
#8
JOURNAL ARTICLE
Toshifumi Kimura, Ken Okada, Yasushi Morohashi, Yukio Kato, Mikinaga Mori, Hiroshi Kato, Takeshi Matsumoto, Susumu Shimoyama
PURPOSE: Quantifying unencapsulated drug concentrations in tissues is crucial for understanding the mechanisms underlying the efficacy and safety of liposomal drugs; however, the methodology for this has not been fully established. Herein, we aimed to investigate the enhanced therapeutic potential of a pegylated liposomal formulation of topotecan (FF-10850) by analyzing the concentrations of the unencapsulated drug in target tissues, to guide the improvement of its dosing regimen. METHODS: We developed a method for measuring unencapsulated topotecan concentrations in tumor and bone marrow interstitial fluid (BM-ISF) and applied this method to pharmacokinetic assessments...
March 27, 2024: Pharmaceutical Research
https://read.qxmd.com/read/38519817/a-high-threshold-of-biotherapeutic-aggregate-numbers-is-needed-to-induce-an-immunogenic-response-in-vitro-in-vivo-and-in-the-clinic
#9
JOURNAL ARTICLE
Joseph R Cohen, Stephen R Brych, Siddharth Prabhu, Vivian Bi, Ahmed Elbaradei, Joshua M Tokuda, Cathie Xiang, Martha Hokom, Xiaohong Cui, Claudia Ly, Nathan Amos, Jilin Sun, Dominador Calamba, Jonathan Herskovitz, Allyson Capili, Kimya Nourbakhsh, Anthony Merlo, Julia Carreon, Jette Wypych, Linda O Narhi, Vibha Jawa, Marisa K Joubert
BACKGROUND AND PURPOSE: There is concern that subvisible aggregates in biotherapeutic drug products pose a risk to patient safety. We investigated the threshold of biotherapeutic aggregates needed to induce immunogenic responses. METHODS AND RESULTS: Highly aggregated samples were tested in cell-based assays and induced cellular responses in a manner that depended on the number of particles. The threshold of immune activation varied by disease state (cancer, rheumatoid arthritis, allergy), concomitant therapies, and particle number...
March 22, 2024: Pharmaceutical Research
https://read.qxmd.com/read/38519816/pharmacokinetic-profile-of-brepocitinib-with-topical-administration-in-atopic-dermatitis-and-psoriasis-populations-strategy-to-inform-clinical-trial-design-in-adult-and-pediatric-populations
#10
JOURNAL ARTICLE
Farzaneh Maleki, Cheng Chang, Vivek S Purohit, Timothy Nicholas
INTRODUCTION: Topical brepocitinib, a tyrosine kinase (TYK)2/Janus kinase (JAK)1 inhibitor, is in development for psoriasis (PsO) and atopic dermatitis (AD). Quantitative analyses of prior clinical trial data were used to inform future clinical trial designs. METHODS: Two phase 2b studies in patients with AD and PsO were used to characterize the amount of topical brepocitinib and the resultant systemic trough concentration (CTrough ) using a linear mixed-effects regression (LMER)...
March 22, 2024: Pharmaceutical Research
https://read.qxmd.com/read/38519815/predicting-drug-drug-interactions-involving-rifampicin-using-a-semi-mechanistic-hepatic-compartmental-model
#11
JOURNAL ARTICLE
Jingxi Li, Xue Li, Keheng Wu, Sihui Long, Youni Zhao, Xiong Jin, Mengjun Zhang, Xinyi Wu, Zhijun Huang, Zhou Zhou, Jack Liu, Bo Liu
AIMS: To develop a semi-mechanistic hepatic compartmental model to predict the effects of rifampicin, a known inducer of CYP3A4 enzyme, on the metabolism of five drugs, in the hope of informing dose adjustments to avoid potential drug-drug interactions. METHODS: A search was conducted for DDI studies on the interactions between rifampicin and CYP substrates that met specific criteria, including the availability of plasma concentration-time profiles, physical and absorption parameters, pharmacokinetic parameters, and the use of healthy subjects at therapeutic doses...
March 22, 2024: Pharmaceutical Research
https://read.qxmd.com/read/38519814/evaluation-of-pharmacokinetic-and-pharmacodynamic-pk-pd-of-novel-fluorenylmethoxycarbonyl-phenylalanine-antimicrobial-agent
#12
JOURNAL ARTICLE
Avinash Y Gahane, Devesh Pratap Verma, Swagata Sarkar, Ashwani K Thakur
OBJECTIVE: To assess the pharmacokinetic profile, in-vivo toxicity, and efficacy of 9-Fluorenylmethoxycarbonyl-L-phenylalanine (Fmoc-F) as a potential antibacterial agent, with a focus on its suitability for clinical translation. METHODS: An RP-HPLC-based bio-analytical method was developed and qualified to quantify Fmoc-F levels in mouse plasma for pharmacokinetic analysis. Oral bioavailability was determined, and in-vivo toxicity was evaluated following intra-peritoneal administration...
March 22, 2024: Pharmaceutical Research
https://read.qxmd.com/read/38519813/identification-of-surfactant-impact-on-a-monoclonal-antibody-characterization-via-hplc-separation-based-and-biophysical-methods
#13
JOURNAL ARTICLE
Kaizhu Guo, Jing Song, Petra Bennington, Alexander J Pavon, Jameson R Bothe, Hanmi Xi, Rico C Gunawan
PURPOSE OR OBJECTIVE: Surfactants, including polysorbates and poloxamers, play a crucial role in the formulation of therapeutic proteins by acting as solubilizing and stabilizing agents. They help prevent protein aggregation and adsorption, thereby enhancing the stability of drug substance and products., However, it is important to note that utilizing high concentrations of surfactants in protein formulations can present significant analytical challenges, which can ultimately affect the product characterization...
March 22, 2024: Pharmaceutical Research
https://read.qxmd.com/read/38509321/nonlinear-pharmacokinetics-of-topical-flurbiprofen-gel-in-a-phase-i-study-among-chinese-healthy-adults
#14
JOURNAL ARTICLE
Wending Xiao, Zhihong Zhu, Feifan Xie, Feiyan Liu, Zeneng Cheng
INTRODUCTION: PDX-02 (Flurbiprofen sodium) is a topical nonsteroidal anti-inflammatory drug in gel formulation for local analgesia and anti-inflammation. A Phase I clinical trial was conducted to assess the safety, tolerability, and pharmacokinetics of single and multiple doses of PDX-02 gel in Chinese healthy adults. METHODS: The trial comprised three parts: (1) a single-dose ascending study with three dose levels (0.5%, 1% to 2% PDX-02 gel) applied on a 136 cm2 skin area; (2) a multiple-dose study with either 1% or 2% PDX-02 gel applied on a 136 cm2 skin area for 7 consecutive days; and (3) a high dose group with 2% PDX-02 gel on an 816 cm2 skin area and a frequent multiple dose group with 2% PDX-02 gel on a 272 cm2 skin area four times a day for 7 consecutive days...
March 20, 2024: Pharmaceutical Research
https://read.qxmd.com/read/38504074/peptide-acylation-in-aliphatic-polyesters-a-review-of-mechanisms-and-inhibition-strategies
#15
REVIEW
Mojgan Sheikhi, Nasrin Nemayandeh, Mehrnoosh Shirangi
Biodegradable polyesters are widely employed in the development of controlled release systems for peptide drugs. However, one of the challenges in developing a polyester-based delivery system for peptides is the acylation reaction between peptides and polymers. Peptide acylation is an important factor that affects formulation stability and can occur during storage, in vitro release, and after drug administration. This review focuses on the mechanisms and parameters that influence the rate of peptide acylation within polyesters...
March 19, 2024: Pharmaceutical Research
https://read.qxmd.com/read/38485855/conversion-of-olmesartan-to-olmesartan-medoxomil-a-prodrug-that-improves-intestinal-absorption-confers-substrate-recognition-by-oatp2b1
#16
JOURNAL ARTICLE
Naomi Fukazawa, Tomohiro Nishimura, Keisuke Orii, Saki Noguchi, Masatoshi Tomi
PURPOSE: Olmesartan medoxomil (olmesartan-MX), an ester-type prodrug of the angiotensin II receptor blocker (ARB) olmesartan, is predominantly anionic at intestinal pH. Human organic anion transporting polypeptide 2B1 (OATP2B1) is expressed in the small intestine and is involved in the absorption of various acidic drugs. This study was designed to test the hypothesis that OATP2B1-mediated uptake contributes to the enhanced intestinal absorption of olmesartan-MX, even though olmesartan itself is not a substrate of OATP2B1...
March 14, 2024: Pharmaceutical Research
https://read.qxmd.com/read/38472610/when-will-the-glomerular-filtration-rate-in-former-preterm-neonates-catch-up-with-their-term-peers
#17
JOURNAL ARTICLE
Yunjiao Wu, Karel Allegaert, Robert B Flint, Sebastiaan C Goulooze, Pyry A J Välitalo, Matthijs de Hoog, Hussain Mulla, Catherine M T Sherwin, Sinno H P Simons, Elke H J Krekels, Catherijne A J Knibbe, Swantje Völler
AIMS: Whether and when glomerular filtration rate (GFR) in preterms catches up with term peers is unknown. This study aims to develop a GFR maturation model for (pre)term-born individuals from birth to 18 years of age. Secondarily, the function is applied to data of different renally excreted drugs. METHODS: We combined published inulin clearance values and serum creatinine (Scr) concentrations in (pre)term born individuals throughout childhood. Inulin clearance was assumed to be equal to GFR, and Scr to reflect creatinine synthesis rate/GFR...
March 12, 2024: Pharmaceutical Research
https://read.qxmd.com/read/38472609/importance-of-considering-fed-state-gastrointestinal-physiology-in-predicting-the-reabsorption-of-enterohepatic-circulation-of-drugs
#18
JOURNAL ARTICLE
Kohei Nakamura, Atsushi Kambayashi, Satomi Onoue
PURPOSE: The purpose of this study was to develop a simulation model for the pharmacokinetics (PK) of drugs undergoing enterohepatic circulation (EHC) with consideration to the environment in the gastrointestinal tract in the fed state in humans. The investigation particularly focused on the necessity of compensating for the permeability rate constant in the reabsorption process in consideration of drug entrapment in bile micelles. METHODS: Meloxicam and ezetimibe were used as model drugs...
March 12, 2024: Pharmaceutical Research
https://read.qxmd.com/read/38443633/clinical-investigation-of-large-volume-subcutaneous-delivery-up-to-25-ml-for-lean-and-non-lean-subjects
#19
JOURNAL ARTICLE
Xiangnan Dang, Han Shih, Rakesh Sharma, Daneen T Angwin-Kaerner, Kathleen Lin, Shiven Kapur, Nagarajan R Thyagarajapuram, Galen H Shi, David S Collins
PURPOSE: To evaluate the clinical feasibility and tolerability of large volume subcutaneous delivery at different injection depths for lean and non-lean subjects. METHODS: A single-center, randomized, subject-blinded, crossover study in 62 healthy subjects was conducted to evaluate delivery of a 10-cP solution containing hyaluronic acid. Subjects were separated into lean and non-lean cohort by SC thickness. A syringe pump was used to study the effect of different volumes (5, 12, 25 mL) of a viscous placebo solution and needle lengths (6, 9 and 12 mm) delivered at 0...
March 5, 2024: Pharmaceutical Research
https://read.qxmd.com/read/38443632/healthcare-systems-and-artificial-intelligence-focus-on-challenges-and-the-international-regulatory-framework
#20
JOURNAL ARTICLE
Alessia Romagnoli, Francesco Ferrara, Roberto Langella, Andrea Zovi
BACKGROUND: Nowadays, healthcare systems are coping with the challenge of countering the exponential growth of healthcare costs worldwide, to support sustainability and to guarantee access to treatment for all patients. METHODS: Artificial Intelligence (AI) is the technology able to perform human cognitive functions through the creation of algorithms. The value of AI in healthcare and its ability to address healthcare delivery issues has been a subject of discussion within the scientific community for several years...
March 5, 2024: Pharmaceutical Research
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