Drug Distribution Research Articles

Whole-body distribution of tenofovir, emtricitabine and dolutegravir in non-human primates.

One major barrier to HIV cure is the persistence of virus, possibly linked to an insufficient antiretroviral drug (ARV) distribution into tissues. To draw the whole-body distribution of three antiretroviral drugs-tenofovir disoproxil fumarate, emtricitabine and dolutegravir-in non-human primates (NHPs). Eight uninfected NHPs received a single injection of a solution containing the three ARVs. Forty-five different tissues were sampled 24 h after injection. Median tissue penetration factors (TPFs) were 45.4, 5.8 and 0.5 for tenofovir, emtricitabine and dolutegravir, respectively, and were statistically different between the three ARVs. Tissues were grouped by system, because TPFs were consistent according to these groups, and ranked in order of decreasing TPFs. The digestive system was the system with the highest tissue concentrations. Next came the two main sites of elimination, the liver and the kidney, as well as the tissues of the cardiopulmonary and urinary systems. Then, it was the whole lymphatic system. The next group included the reproductive system, the adipose tissue and the skin. The last two systems were the muscle and the CNS. The intra-tissue variability was rather low with a median coefficient of variation of the concentrations around 15% and no value greater than 80%. Overall, this study determines the first whole-body distribution in a validated NHP model. These data have important implications for future preclinical and clinical studies for the development of novel HIV therapies towards an HIV cure.

Recent Updates on Interaction Studies and Drug Delivery of Antimalarials with Serum Albumin Proteins.

This review focuses on recent trends in the binding study of various antimalarial agents with serum albumins in detail. Serum albumin has a significant role in the transport of drugs and endogenous ligands. The nature and magnitude of serum albumin and drug interactions have a tremendous impact on the pharmacological behavior and toxicity of that drug. Binding of drug to serum albumin not only controls its free and active concentration, but also provides a reservoir for a long duration of action. This ultimately affects drug absorption, distribution, metabolism, and excretion. Such interaction determines the actual drug efficacy as the drug action can be correlated with the amount of unbound drug. With the advancement in spectroscopic techniques and simulation studies, binding studies play an increasingly important role in biophysical and biomedical science, especially in the field of drug delivery and development. This review assesses the insight we have gained so far to improve drug delivery and discovery of antimalarials on the basis of a plethora of drug-serum protein interaction studies done so far.

The Neurologist's Guide to Drug Pricing in the United States.

As newer, innovative neurology drugs enter the US health care system, neurologists should consider the cost of these treatments in addition to their efficacy, safety, and tolerability. To do so thoughtfully requires an understanding of how prescription drugs are priced in the United States. The process of drug pricing is linked to the distribution supply chain and the many stakeholders involved. Stakeholders include pharmaceutical manufacturers; wholesalers; pharmacies; pharmacy benefit managers; payers, including health insurers; hospital systems; neurologists and other clinicians; and patients. Drug pricing has taken center stage as the Inflation Reduction Act of 2022 has set maximum out-of-pocket expenses for Medicare beneficiaries for the first time in the program's history and limits drug price increases for a select group of Medicare Part D drugs. This article describes the US drug distribution supply chain and its stakeholders and introduces key drug pricing terms; a brief description of how rebates are generally estimated will also be discussed. Finally, as newer neurology outpatient drugs enter the market, the "value" of drugs will be described through cost-effectiveness terminology and their utility for the clinical neurologist.

Vehicle routing problem for cold-chain drug distribution with epidemic spread situation

We investigate a vehicle routing problem considering the influence of epidemic spread (VRP-ES) for the design of a novel cold-chain drug distribution system, in which the disease spread model is used to capture virus transmission characteristics and demand fluctuations. To this end, we aim to minimize the total travel time and transmission risk of the distribution network by incorporating realistic features including priority distribution and temperature control. We propose a hybrid tabu search heuristic (HTS) with a specifically designed initial solution, several neighborhood operators, and diversification strategies to solve this problem. A series of numerical experiments are conducted to test the proposed solution methodology. The virus spread model and vehicle routing results are discussed to analyze the VRP-ES optimization strategies through an empirical case study of Chongqing city in China. Sensitivity analysis is conducted to identify the impact of various parameters on the VRP-ES and provide some management implications as well.

Design of the distribution of iron oxide (Fe3O4) nano-particle drug in realistic cholangiocarcinoma model and the simulation of temperature increase during magnetic induction hyperthermia

The prognosis for Cholangiocarcinoma (CCA) is unfavorable, necessitating the development of new therapeutic approach such as magnetic hyperthermia therapy (MHT) which is induced by magnetic nano-particle (MNPs) drug to bridge the treatment gap. Given the deep location of CCA within the abdominal cavity and proximity to vital organs, accurately predict the individualized treatment effects and safety brought by the distribution of MNPs in tumor will be crucial for the advancement of MHT in CCA. The Mimics software was used in this study to conduct three-dimensional reconstruction of abdominal computed tomography (CT) and magnetic reso-nance imaging images from clinical patients, resulting in the generation of a realistic digital geometric model representing the human biliary tract and its adjacent structures. Subsequently, The COMSOL Multiphysics software was utilized for modeling CCA and calculating the heat transfer law resulting from the multi-regional distribution of MNPs in CCA. The temperature within the central region of irregular CCA measured approximately 46°C, and most areas within the tumor displayed temperatures surpassing 41°C. The temperature of the inner edge of CCA is only 39 ∼ 41℃, however, it can be ameliorated by adjusting the local drug concentration through simulation system. For CCA with diverse morphologies and anatomical locations, the multi-regional distribution patterns of intratumoral MNPs and a slight overlap of drug distribution areas synergistically enhance intratumoral temperature while ensuring treatment safety. The present study highlights the practicality and imperative of incorporating personalized intratumoral MNPs distribution strategy into clinical practice for MHT, which can be achieved through the development of an integrated simulation system which incorporates medical image data and numerical calculations.

A Stereolithography-Based Modified Spin-Casting Method for Faster Laboratory-Scale Production of Dexamethasone-Containing Dissolving Microneedle Arrays.

Microneedle arrays (MNAs) consist of a few dozens of submillimeter needles, which tend to penetrate through the stratum corneum layer of the skin and deliver hardly penetrating drugs to the systemic circulation. The application of this smart dosage form shows several advantages, such as simple use and negligible pain caused by needle punctures compared to conventional subcutaneous injections. Dissolving MNAs (DMNAs) represent a promising form of cutaneous drug delivery due to their high drug content, biocompatibility, and ease of use. Although different technologies are suitable to produce microneedle arrays (e.g., micromilling, chemical etching, laser ablation etc.), many of these are expensive or hardly accessible. Following the exponential growth of the 3D-printing industry in the last decade, high-resolution desktop printers became accessible for researchers to easily and cost-effectively design and produce microstructures, including MNAs. In this work, a low force stereolithography (LFS) 3D-printer was used to develop the dimensionally correct MNA masters for the spin-casting method. The present study aimed to develop and characterize drug-loaded DMNAs using a two-level, full factorial design for three factors focusing on the optimization of DMNA production and adequate drug content. For the preparation of DMNAs, carboxymethylcellulose and trehalose were used in certain amounts as matrices for dexamethasone sodium phosphate (DEX). Investigation of the produced DexDMNAs included mechanical analysis via texture analyzer and optical microscopy, determination of drug content and distribution with HPLC and Raman microscopy, dissolution studies via HPLC, and ex vivo qualitative permeation studies by Raman mapping. It can be concluded that a DEX-containing, mechanically stable, biodegradable DexDMNA system was successfully developed in two dosage strengths, of which both efficiently delivered the drug to the lower layers (dermis) of human skin. Moreover, the ex vivo skin penetration results support that the application of DMNAs for cutaneous drug delivery can be more effective than that of a conventional dermal gel.

Enhancing HIV treatment and support: a qualitative inquiry into client and healthcare provider perspectives on differential service delivery models in Uganda

BackgroundHIV/AIDS continues to be a significant contributor to illness and death, particularly in sub-Saharan Africa. In this study, we conducted a qualitative assessment to understand Client and Healthcare Provider Perspectives on Differential Service Delivery Models in Uganda. The purpose was to establish strengths and weaknesses within the services delivery models, inform policy and decision-making, and to facilitate context specific solutions.MethodsBetween February and April 2023, a qualitative cross-sectional study was utilised to gather insights from a targeted selection of individuals, including People Living with HIV (PLHIV), healthcare workers, HIV focal persons, community retail pharmacists, and various stakeholders. The data collection process included eleven in-depth interviews, nine key informant interviews, and eight focus group discussions carried out across eight districts in Central Uganda. The collected data was analyzed through inductive thematic analysis with the aid of Excel.ResultsThe various Differentiated Service Delivery Models (DSDMs), notably Community-Client-Led Drug Distribution (CCLAD), Community Drug Distribution Point (CDDP), Community Retail Pharmacy Drug Distribution Point (CRPDDP), and the facility-based Facility Based Individual Model (FBIM), were reported to have several positive impacts. These included improved treatment adherence, efficient management of antiretroviral (ARV) supplies, reduced exposure to infectious diseases, enhanced healthcare worker hospitality, minimized travel time for ART refills, stigma reduction, and decreased waiting times. Concern was raised about the lack of improvement in HIV status disclosure, opportunistic infection treatment, adherence to seasonal appointments, and sustainability due to the overreliance of the DSDMs on donor funding, suggesting potential discontinuation without funding. Doubts about health workers’ commitment surfaced. Notably, the CCLAD model displayed self-sustainability, with clients financially supporting group members to collect medicines.ConclusionCommunity-based DSDMs, such as CCLAD and CDDP, improve ART refill convenience, social support, and client experiences. These models reduce travel and waiting times, lowering infection risks. Addressing challenges and enhancing facility-based models is vital. In order to maintain funding after donor funding ends, sustainability measures like cross-subsidization can be used. If well implemented, the DSDMs have the potential to produce better or comparable ART outcomes compared to the FBIM model.

Global occurrence, distribution, and ecological risk assessment of psychopharmaceuticals and illicit drugs in surface water environment: A meta-analysis

Psychopharmaceuticals and illicit drugs (PIDs) in aquatic environments can negatively impact ecosystem and human health. However, data on the sources, distribution, drivers, and risks of PIDs in global surface waters are limited. We compiled a dataset of 331 records spanning 23 PIDs in surface waters and sediments across 100 countries by conducting a systematic review and meta-analysis of 108 studies published between 2005 and 2022. Most PIDs were sewage-derived, as wastewater treatment rarely achieved complete removal. The highest total PID levels were in Ethiopia, Australia, and Armenia, with many highly contaminated samples from low- and middle-income countries with minimal prior monitoring. Socioeconomic factors (population, GDP) and environmental variables (water stress) influenced the distribution of PIDs. 3,4-Methylenedioxy amphetamine hydrochloride (MDA), Δ9-tetrahydrocannabinol (THC), and 11- Δ9‑hydroxy-tetrahydrocannabinol (THCOH) posed the greatest ecological risks, especially in Oceania and North America. PIDs in surface waters present risks to aquatic organisms. Our findings elucidate the current status and future directions of PID research in surface waters and provide a scientific foundation for evaluating ecological risks and informing pollution control policies.

Proteomic Profiling Reveals Age-Related Changes in Transporter Proteins in the Human Blood-Brain Barrier.

The Blood-Brain Barrier (BBB) is a crucial, selective barrier that regulates the entry of molecules including nutrients, environmental toxins, and therapeutic medications into the brain. This function relies heavily on brain endothelial cell proteins, particularly transporters and tight junction proteins. The BBB continues to develop postnatally, adapting its selective barrier function across different developmental phases, and alters with aging and disease. Here we present a global proteomics analysis focused on the ontogeny and aging of proteins in human brain microvessels (BMVs), predominantly composed of brain endothelial cells. Our proteomic profiling quantified 6,223 proteins and revealed possible age-related alteration in BBB permeability due to basement membrane component changes through the early developmental stage and age-dependent changes in transporter expression. Notable changes in expression levels were observed with development and age in nutrient transporters and transporters that play critical roles in drug disposition. This research 1) provides important information on the mechanisms that drive changes in the metabolic content of the brain with age and 2) enables the creation of physiologically based pharmacokinetic models for CNS drug distribution across different life stages.

Determination of doxorubicin in plasma and tissues of mice by UPLC-MS/MS and its application to pharmacokinetic study

A rapid and sensitive ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was established for the simultaneous determination of doxorubicin (DOX) in mouse plasma and tissues, including the heart, liver, spleen, lung, kidney and tumor, and to investigate the pharmacokinetics and distribution in mice. In this study, daunorubicin (DNR) was used as an internal standard, and the mobile phase consisted of ammonium formate 2 mM containing 0.1 % formic acid (A) and acetonitrile (B), the chromatographic column was ACQUITY UPLC BEHTM C18 with a gradient elution at a flow rate of 0.2 mL/min. Electrospray ionization (ESI) in positive ion pattern was utilized for the ion separation of DOX, with the ions used for quantitative analysis being DOX m/z 544.28 → 397.10 and DNR m/z 528.35 → 321.08, respectively. The results showed that a good linear relationship in the calibration curve range of 1–800 ng/mL in mouse plasma and 1–2500 ng/g in tissues (R2 > 0.99) with the limits of quantification of 1 ng/mL in plasma and tissues. The method exhibited good matrix effect and extraction recovery, with the intra-day and inter-day precision of plasma and tissue were less than 10.3 % and 15.4 %, and the relative error (RE) were both less than ±14.8 % and ±18.9 %, respectively. The stability results under different conditions were found to be accurate. It also revealed the distribution of DOX in various tissues of mice, with the concentration ranking as liver > heart > kidney > spleen > lung > tumor. This method was successfully used to the study for the pharmacokinetics in plasma and drug distribution in tissues of BALB/c mice.

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC): Why it will Transform Cancer Surgery

Abstract Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) represents an innovative method for delivering chemotherapy directly into the abdominal cavity, offering a targeted, effective, and less toxic treatment option for patients with non-resectable peritoneal metastasis (PM). PIPAC is increasingly adopted due to its benefits over traditional therapies, including enhanced drug penetration, reduced systemic toxicity, and improved efficacy in chemoresistant PM. Performed laparoscopically, PIPAC is minimally invasive, often outpatient, and well-tolerated, preserving patients' quality of life. So far, PIPAC has been mainly used in advanced PM from ovarian, gastric, and colorectal cancers, where it can be effective even after other treatments have failed. The repeatable nature of PIPAC offers opportunities for maintenance therapy and long-term disease control. A recent meta-analysis of PIPAC studies reported a 4% non-access rate and 39% of patients completing three or more cycles, with only 4% experiencing severe toxicities. Pathological responses were observed in 68% of cases, indicating reliable efficacy. A first randomized trial showed PIPAC’s superiority in objective response rates and quality of life compared to intravenous chemotherapy for platinum-resistant ovarian cancer. Research in PIPAC is dynamic and multidisciplinary, aiming to refine the technique, minimize side effects, and expand its applicability to various cancers. Studies focus on the efficacy of aerosolized drug delivery, including nanoparticles and RNA-based therapies, which offer targeted treatment options with promising therapeutic potential. Innovations such as electrostatic precipitation PIPAC (ePIPAC) combine enhanced drug distribution with increased tissue penetration, representing significant advancements in PM treatment. Future developments will focus on optimizing aerosol characteristics, drug formulations, and personalized medicine approaches.

Reduction-Responsive Polyprodrug Nanoplatform Based on Curcumin for Tumor-Targeted Therapy.

Polymer prodrug nanoparticles have become an emerging drug delivery system in cancer therapy due to their high drug loading. However, their poor drug release and lack of tumor cell targeting limit their clinical application. This study aimed to prepare targeted and reduction-reactive polyprodrug nanocarriers based on curcumin (CUR) for co-delivery of doxorubicin (DOX), labeled as DOX/HAPCS NPs, and to investigate their anticancer activity. The polymer was synthesized and characterized by chemical method. The drug loading and drug release behavior of DOX and CUR in polymer nanoparticles were determined. Moreover, the antitumor effects of polymer nanoparticles were evaluated using an MTT experiment and tumor inhibition experiment, and the synergistic effect of co-delivered DOX and CUR was explored. The particle size of DOX/HAPCS NPs was 152.5nm, and the potential was about -26.74 mV. The drug-carrying capacity of DOX and CUR was about 7.56% and 34.75%, respectively, indicating high drug-carrying capacity and good stability. DOX and CUR released over 90% within 24 hours in the tumor environment. Compared with free DOX, DOX/HAPCS NPs demonstrated significantly enhanced cell and tumor inhibitory effects (P< 0.05) in vivo and in vitro and changed drug distribution to avoid toxic side effects on normal tissues. The combined index showed that DOX and CUR showed synergistic anticancer effects at a set ratio. The prepared reduction-responsive targeted polymer nanomedical DOX/HAPCS NPs exhibited a synergistic anti-cancer effect, with high drug loading capacity and the ability to release drugs in proportion, making it a promising polymer nanoparticle drug delivery system.

What matters for drug delivery to tumor by nanoparticles: Gaining insights from PBPK/PD simulation of drug nanocrystals

Background and purpose: In our previous studies, drug nanocrystals were directly prepared by solution crystallization, possessing uniform particle size and morphology suitable for intravenous (IV) injection. These nanocrystals accumulated in a small percentage of their injected dose in tumor-bearing mice but showed similar anti-tumor effectiveness and much-reduced side effects compared with current commercial solubilized and encapsulated delivery systems. Experimental approach: In this study, we aimed to delineate possible controlling factors for the pharmacokinetics (PK) and biodistribution behaviors of paclitaxel (PTX) nanocrystals tested in mice by applying physiologically based pharmacokinetics (PBPK) modeling, coupled with pharmacodynamics (PD) simulation, to the data. Key Results: Our results show that clearance of the drug plays a significant, if not the most important, role in determining tissue distribution, including tumor accumulation of PTX nanocrystals. Surface treatment of drug nanocrystals with polymeric surfactants also appeared to affect PK profiles and PD outcomes. Importantly, when scaled to model human parameters, our PK/PD simulations suggest that drug distribution in humans, as opposed to animal models, was significantly influenced by tissue partitioning rather than drug clearance. This finding could facilitate the design and development of future drug delivery systems. Conclusion: Drug nanocrystals deposited in tissues, including tumors, could therefore act as depots, releasing the drug back into the circulation, possibly contributing to extended treatment, as well as any detrimental effects.

The Role of Inhaled Chitosan-Based Nanoparticles in Lung Cancer Therapy.

Lung cancer is the leading cause of cancer-related mortality worldwide, largely due to the limited efficacy of anticancer drugs, which is primarily attributed to insufficient doses reaching the lungs. Additionally, patients undergoing treatment experience severe systemic adverse effects due to the distribution of anticancer drugs to non-targeted sites. In light of these challenges, there has been a growing interest in pulmonary administration of drugs for the treatment of lung cancer. This route allows drugs to be delivered directly to the lungs, resulting in high local concentrations that can enhance antitumor efficacy while mitigating systemic toxic effects. However, pulmonary administration poses the challenge of overcoming the mechanical, chemical, and immunological defenses of the respiratory tract that prevent the inhaled drug from properly penetrating the lungs. To overcome these drawbacks, the use of nanoparticles in inhaler formulations may be a promising strategy. Nanoparticles can assist in minimizing drug clearance, increasing penetration into the lung epithelium, and enhancing cellular uptake. They can also facilitate increased drug stability, promote controlled drug release, and delivery to target sites, such as the tumor environment. Among them, chitosan-based nanoparticles demonstrate advantages over other polymeric nanocarriers due to their unique biological properties, including antitumor activity and mucoadhesive capacity. These properties have the potential to enhance the efficacy of the drug when administered via the pulmonary route. In view of the above, this paper provides an overview of the research conducted on the delivery of anticancer drug-loaded chitosan-based nanoparticles incorporated into inhaled drug delivery devices for the treatment of lung cancer. Furthermore, the article addresses the use of emerging technologies, such as siRNA (small interfering RNA), in the context of lung cancer therapy. Particularly, recent studies employing chitosan-based nanoparticles for siRNA delivery via the pulmonary route are described.

Population pharmacokinetic modeling of sufentanil in adult Korean patients undergoing cardiopulmonary bypass surgery.

Sufentanil is frequently used as an anesthetic agent in cardiac surgery owing to its cardiovascular safety and favorable pharmacokinetics. However, the pharmacokinetics profiles of sufentanil in patients undergoing cardiopulmonary bypass (CPB) surgery remain less understood, which is crucial for achieving the desired level of anesthesia and mitigating surgical complications. Therefore, this study aimed to develop a population pharmacokinetic model of sufentanil in patients undergoing CPB surgery and elucidate the clinical factors affecting its pharmacokinetic profile. Adult patients who underwent cardiac surgery with CPB and were administered sufentanil for anesthesia were enrolled. Arterial blood samples were collected to quantify plasma concentrations of sufentanil and clinical laboratory parameters, including inflammatory cytokines. A population pharmacokinetic model was established using nonlinear mixed-effects modeling. Simulations were performed using the pharmacokinetic parameters of the final model. Overall, 20 patients were included in the final analysis. Sufentanil pharmacokinetics were modeled using a two-compartment model, accounting for CPB effects. Sufentanil clearance increased 2.80-fold during CPB and warming phases, while the central compartment volume increased 2.74-fold during CPB. CPB was a significant covariate affecting drug clearance and distribution volume. No other significant covariates were identified despite increased levels of the inflammatory cytokines, including IL-6, IL-8, and TNF-α during CPB. The simulation indicated a 30 μg loading dose and 40 μg/h maintenance infusion for target-controlled infusion. Additionally, a bolus dose of 60 μg was added at CPB initiation to adjust for exposure changes during this phase. Considering the target sufentanil concentrations, a uniform dosing regimen was acceptable for effective analgesia.

Research on molecular characteristics of ADME-related genes in kidney renal clear cell carcinoma

Genes involved in drug absorption, distribution, metabolism, and excretion (ADME) are named ADME genes. However, the comprehensive role of ADME genes in kidney renal clear cell carcinoma (KIRC) remains unclear. Using the clinical and gene expression data of KIRC patients downloaded from The Cancer Genome Atlas (TCGA), ArrayExpress, and the Gene Expression Omnibus (GEO) databases, we cluster patients into two patterns, and the population with a relatively poor prognosis demonstrated higher level of immunosuppressive cell infiltration and higher proportion of glycolytic subtypes. Then, 17 ADME genes combination identified through the least absolute shrinkage and selection operator algorithm (LASSO, 1000 times) was utilized to calculate the ADME score. The ADME score was found to be an independent predictor of prognosis in KIRC and to be tightly associated with the infiltration level of immune cells, metabolic properties, tumor-related signaling pathways, genetic variation, and responses to chemotherapeutics. Our work revealed the characteristics of ADME in KIRC. Assessing the ADME profiles of individual patients can deepen our comprehension of tumor microenvironment (TME) features in KIRC and can aid in developing more personalized and effective therapeutic strategies.

Advancements in Lipid Nanoparticle Technologies for Precision Targeting in Therapeutic Delivery

<img src=” https://s3.amazonaws.com/production.scholastica/article/121633/large/prnano_1412024bg2.jpeg?1721676909”> Lipid nanoparticles (LNPs) are at the forefront of targeted therapeutic delivery, serving as an innovative platform for precisely delivering therapeutic agents directly to specific cells or tissues. Therapeutic delivery seeks to enhance drug efficacy and safety by controlling the distribution of drugs within the body, thereby minimizing off-target effects while maximizing therapeutic impact. This review delves into advancements and innovations in LNP design to achieve unprecedented targeting precision, surmount biological barriers, and diminish off-target interactions. It encom-passes exploring targeting strategies, including passive targeting that leverages the enhanced permeability and retention effect, active targeting via receptor-ligand interactions, and stimuli-responsive methodologies for the controlled release of therapeutics. With a focus on novel tar-geting techniques, including endogenous targeting and strategic de-targeting, to enhance LNP de-livery specificity and therapeutic efficacy. This review articulates the critical role of lipid com-position, nanoparticle characterization, and surface engineering in tailoring LNPs for therapeutic applications. Through evaluating the forefront of LNP technology in drug delivery and gene therapy, this review forecasts the trajectory of nanoparticle-based therapeutics, envisioning their pivotal role in the advent of personalized medicine, thereby providing a foundation for future explorations aimed at refining and optimizing LNP systems for clinical applications.

Mass Spectrometry Imaging Combined with Sparse Autoencoder Method Reveals Altered Phosphorylcholine Distribution in Imipramine Treated Wild-Type Mice Brains.

Mass spectrometry imaging (MSI) is essential for visualizing drug distribution, metabolites, and significant biomolecules in pharmacokinetic studies. This study mainly focuses on imipramine, a tricyclic antidepressant that affects endogenous metabolite concentrations. The aim was to use atmospheric pressure matrix-assisted laser desorption/ionization (AP-MALDI)-MSI combined with different dimensionality reduction methods to examine the distribution and impact of imipramine on endogenous metabolites in the brains of treated wild-type mice. Brain sections from both control and imipramine-treated mice underwent AP-MALDI-MSI. Dimensionality reduction methods, including principal component analysis, multivariate curve resolution, and sparse autoencoder (SAE), were employed to extract valuable information from the MSI data. Only the SAE method identified phosphorylcholine (ChoP) as a potential marker distinguishing between the control and treated mice brains. Additionally, a significant decrease in ChoP accumulation was observed in the cerebellum, hypothalamus, thalamus, midbrain, caudate putamen, and striatum ventral regions of the treated mice brains. The application of dimensionality reduction methods, particularly the SAE method, to the AP-MALDI-MSI data is a novel approach for peak selection in AP-MALDI-MSI data analysis. This study revealed a significant decrease in ChoP in imipramine-treated mice brains.

The Comparison of the Clinical Efficacy and Drug Tissue Distribution of Furazolidone and Tetracycline-quadruple Therapy in Helicobacter pylori Eradication: A Randomized Controlled Trial.

Helicobacter pylori (H. Pylori) is considered a main causative organism of gastric ulcers, gastric cancer and duodenal ulcers. The current treatment relies on a combination of antimicrobial agents and acid suppressant agents, but the eradication effect is not satisfactory. To clarify the concentration of antibiotics at the lesion site, we investigate the clinical efficacy and drug tissue distribution of the combination therapy of furazolidone and tetracycline in eradicating H. Pylori. Patients with H. pylori infection (n = 60) were randomized to either group A or B. Bismuth potassium citrate capsules 220mg, omeprazole enteric-coated capsules 20mg, amoxicillin capsules 1000mg, each twice per day, and furazolidone tablets 500mg were administered to group A. Group B was treated with bismuth potassium citrate capsules 220mg, omeprazole enteric-coated capsules 20mg, amoxicillin capsules 1000mg, and tetracycline tablets 500mg each twice per day for 2 weeks. The serum and gastric juice, gastric antrum, gastric horn, and gastric body samples were taken under a gastroscope on the 14th day. The antimicrobial concentrations in serum and tissue samples were determined by high-performance liquid chromatography. In the negative group of furazolidone, the concentrations of gastric antrum, gastric body, and gastric angle were significantly higher than those in the positive group (P = 0.017, 0.015, and 0.028). The concentrations of furazolidone in gastric fluid, gastric antrum, gastric angle, and gastric body were ∼421 times, 82 times, 17 times, and 51 times higher than those in serum, respectively. The concentrations of tetracycline in the serum and gastric angle of the tetracycline negative group were significantly higher than those in the positive group (P = 0.036 and 0.042), and the tetracycline concentrations in the gastric horn and gastric body were about 4 and 6 times higher than those in the serum, respectively. The concentration of amoxicillin in group B was higher than that in group A, especially in serum, gastric juice, gastric angle, and gastric body (P < 0.05). Furazolidone is mainly concentrated and sequentially distributed in gastric juice, gastric antrum, and gastric body tissue, and tetracycline is mainly distributed in serum, gastric angle, and gastric body, whereas amoxicillin is mainly distributed in serum, gastric juice, gastric angle, and gastric body. Improving the concentration and tissue distribution of antibacterial drugs in the human gastric mucosa is the key to ensuring the ideal eradication rate of quadruple therapy.

Hemp-based psychoactive use and risk among young adults: Trend theory, policy, and regulation beyond legality

BackgroundHemp-based psychoactives comprise a burgeoning legal substance market with rising trends in use across the U.S. and Canada as well as parts of Europe. Currently, scant empirical research on the use of these Novel Psychoactive Substances (NPS) exists. By examining policy, market conditions, consumer uptake, and related risks, this research extends theory on drug trends by describing the regulatory environments that shape the emergence and popularity of psychoactive hemp-based products among young adults. MethodsRelying on ethnographic fieldwork of hemp-based markets across 3 U.S. state hemp and cannabis policy contexts as well as in-depth interviews with 40 young adult cannabis consumers recruited across 10 U.S. states, we examined how regulatory conditions shape hemp-based psychoactive markets, trends in their use, and associated risks. ResultsYoung adults are motivated to consume hemp-based psychoactives due to the regulatory and market environments that facilitate the production of highly potent products that are inexpensive and easily accessible. States that regulate hemp-based psychoactives as cannabis, do not provide hemp markets with a competitive advantage and as such see minimal uptake. In the absence of hemp specific policies, substantial variations in product potencies, insufficient dosing information, and unscrupulous product packaging practices may increase related risks. ConclusionTrend theory provides insight into the complex relationships that exist between drug policy, markets, and the proliferation of legal highs. Understanding the contextual significance that both market and regulatory conditions have on legal drug production, distribution, and consumption may better inform approaches to reduce the risks commonly associated with novel psychoactive substances like hemp-based psychoactives.