Amount Of Drug Research Articles

Completeness and quality of comprehensive managed care data compared with fee-for-service data in national Medicaid claims from 2001 to 2019.

To evaluate the completeness and quality of Medicaid comprehensive managed care (CMC) data in national MAX/TAF research files. This observational study compared CMC with fee-for-service (FFS) enrollee data in 2001-2019 Medicaid MAX/TAF inpatient, outpatient, and pharmacy files. Completeness was assessed as the proportion of enrollees with any claim and mean claims per enrollee with any claim. Quality was assessed as the proportion of inpatient and outpatient claims with primary diagnosis and procedure codes and the proportion of prescription drug claims with fill dates, National Drug Codes (NDC), days supplied, and quantity dispensed. Acceptable ranges for each study measure were defined as the national FFS mean ± 2 standard deviations. We analyzed secondary data on 45 states from 2001 to 2013 (MAX) and 50 states and DC from 2014 to 2019 (TAF). The sample included adults aged 18-64 with continuous calendar-year enrollment who were eligible for full Medicaid benefits and ineligible for Medicare. We determined CMC enrollment rates and assessed data completeness and quality among state-years with ≥10% CMC penetration, comparing CMC with FFS enrollees. Across 891 state-years, 194,364,647 enrollees met inclusion criteria. Of 540 state-years (60.6%) with ≥10% CMC enrollment, CMC data were largely comparable to national FFS distributions for all inpatient (n = 430; 79.6%), outpatient (n = 467, 86.5%), and prescription (n = 459, 85.0%) completeness criteria and for all inpatient (n = 449, 83.1%), outpatient (n = 511, 94.6%), and prescription (n = 528, 97.8%) quality criteria. Overall completeness (92.3%) and quality (84.6%) improved substantially by 2019. Completeness and quality of CMC data were largely comparable to FFS data, with increasing state-years meeting criteria over time. Further research on national Medicaid populations should assess and address differences in data completeness and quality by plan type across states, over time, and in relation to specific study samples and measures of interest.

Multifunctional Ru(III)/Fe3O4/DNA nanoplatform for photothermal-enhanced photodynamic and chemodynamic cancer therapy

Among the many cancer treatment methods, there have been many reports on the use of nanoplatforms with single treatment methods such as photothermal, photodynamic or chemodynamic for cancer treatment. In this study, Ru(III) with photodynamic effect and Fe3O4 nanoparticles with photothermal and chemodynamic effects are connected through long DNA chains with efficient active targeting rolling circle amplification to construct Ru(III)/Fe3O4/DNA nano-platform realizes the combination of photothermal, photodynamic and chemodynamic treatment, which significantly improves the therapeutic effect of the nano-platform. Its multiple active targeting capabilities reduce the damage to normal cells. Ru(III) has excellent photodynamic effect and can catalyze the respiration product NADH (Nicotinamide adenine dinucleotide)to produce highly oxidizing H2O2. Fe3O4 NPs has weak absorption at 808 nm indicates that it can perform mild photothermal treatment, and the Fe2+ in it can react with H2O2 to produce ·OH and participate in chemodynamic treatment. Each repeating unit on the rolling circle amplified DNA long chain is connected to the AS1411 aptamer that can actively target cancer cells. Unlike the passive targeting of other nanomedicines, active and efficient targeting is achieved, and a small amount of drugs can achieve high efficacy. The therapeutic effect also reduces the damage to normal cells. The comprehensive killing effect of Ru(III)/Fe3O4/DNA can reach 85.1 %. Its high targeting of cancer cells can also be used for imaging detection of cancer cells. This new nanoplatform provides an idea for the synergy of multiple cancer treatments.

Design of solid lipid nanoparticles for skin photoprotection through the topical delivery of caffeic acid-phthalimide

Exposure of the skin to ultraviolet (UV) radiation is associated with many pathological conditions such as premature aging and skin cancer. Furthermore, members of Nicotinamide Adenine Dinucleotide Phosphate-oxidase (NADPH oxidase or NOX) enzyme family can produce UV-induced reactive oxygen species (ROS), even after cessation of radiation exposure. The caffeic acid-phthalimide (CF) compound is a potent antioxidant, which reduces the generation of ROS. However, its high lipophilicity may hamper its permeation through the skin. Solid lipid nanoparticles (SLNs) can ensure close contact and increase the amount of drug absorbed into the skin. The present work aims to develop and optimize SLNs containing CF to achieve enhanced skin photoprotection along with antioxidant and anti-aging effects. SLNs were prepared by the hot homogenization method using Compritol 888 ATO as the lipid matrix, and Tween 80 and Pluronic® F-127 as the surfactants to stabilize nanoparticle dispersion. The particles had high stability for at least 30 days. Physicochemical characterizations of the selected SLNs formulations showed sizes in the range 150–180 nm, polydispersity index (PDI) of 0.2, and a negative zeta potential (≅ −25 mV). The SLNs had high CF entrapment efficiency (96–97 %) and showed a controlled drug‐release profile. The in vitro study revealed low cytotoxic properties of CF-loaded SLNs towards fibroblasts and a photoprotective effect, reflected from the increased viability of UVB-irradiated fibroblasts treated with CF-SLNs. Moreover, the CF-SLNs induced fibroblast migration and closure, showing that these nanosystems offer not only biological photoprotection, but also stimulate wound healing.

Medication Disposal within Reach: Assessing Implementation of Permanent Disposal Receptacles in Community Pharmacies

Availability of medication disposal receptacles is critical to curbing nonmedical opioid use and diversion; however, availability in community pharmacies is sparse. The objective of this study was to describe implementation of the community pharmacy medication disposal program offered by the HEALing Communities Study in Kentucky (HCS-KY) using the EPIS (Exploration, Preparation, Implementation, and Sustainment) framework. Sixteen counties participated in the HCS-KY from 1/1/2020-12/31/2023. Exploration and Preparation included gathering and review of evidence-based literature, state/community data, and key opinion leader input to develop a detailed implementation plan. Implementation and Sustainment were assessed using implementation outcome data collected (e.g., number of receptacles placed, amount of drug returned) and semi-structured qualitative interviews to evaluate common themes, including barriers and facilitators related to implementation and sustainment. Disposal receptacles were placed in 59 pharmacies within the 16 HCS-KY counties. Following implementation, the median number of receptacles per participating county increased significantly from 2.5 to 4.5 (p<0.001). A total of 8019.9 pounds of drug were returned during the study period, with a median per-county return rate of 230.5 pounds per year. Twenty-one pharmacy representatives participated in qualitative interviews. Most (70.0 %) reported weekly receptacle usage; however, few (35.0 %) reported routinely discussing disposal with patients. While 42.9 % reported no barriers, the most frequently reported barrier (33.3 %) was receptacle limitations (e.g., only available during business hours, dosage form restrictions). Implementation of the HCS-KY community pharmacy medication disposal program led to notable increases in disposal locations that were highly utilized by communities.

Analysis of Drug Inventory Control Using ABC Method (Always Better Control), EOQ (Economic Order Quantity), And ROP (Reorder Point) At Untada General Hospital, Palu

The procurement of pharmaceutical supplies, including drugs, is the part that uses the largest budget in the hospital. The use of this large budget requires the hospitals to control drug stocks to prevent the possibility of emptiness or over stocks that can cause losses. The uncertainty in planning of drug necessity, encourages the application of a method in controlling drug inventory. The aim of this study was to determine the amount and investment value of drugs included in groups A, B, C and to determine the EOQ and ROP values of the drugs. This study was a quantitative study with a retrospective approach using secondary data in the form of drug procurement during January-December 2022 owned by Undata Hospital Palu. The results of the analysis using the ABC method obtained that group A had 64 items (11%) with investment value IDR 11,048,130,440 (75%), group B had 142 items (25%) with investment value IDR 2,976,402,576 (20%), and group C had 364 items (64%) with investment value IDR 737,979,346 (5%). The optimum amount of medicine ordered based on the EOQ method was around 1-100 items at most. The minimum amount of medicine stock to be reordered based on the ROP method is around 1-100 items at most

Is the shift in treatment patterns towards new, more expensive drugs still driving the increase in pharmaceutical expenditure? A decomposition analysis of expenditure data in Sweden 1990–2022

ABSTRACT Background Pharmaceutical expenditures (PE) are increasing worldwide, raising concerns about sustainability. However, the current price index provides an incomplete picture of this trend due to the rapid introduction of new drugs on the market. Objective The aim of this study is to decompose PE into their components and investigate the development in Sweden from 1990 to 2022. Methods The PE index was broken down into separate indices for price, quantity, and a residual. The residual reflects changes in expenditure driven by shifts in drug treatment patterns. Results PE increased by 227% during the study period. The decomposition showed that this increase was mainly driven by the residual (215%). Drug quantity increased by 105%, while the relative prices decreased by 50%. When dividing the whole study period into three 11-year-subperiods, the increase in real drug expenditure, drug quantity, and the residual was the highest from 1990 to 2000. Conclusions The finding that the residual is the main driver indicates that the increase in PE is due to the introduction of and shift to more expensive pharmaceutical treatments, while existing treatments tend to become cheaper. Further research is needed to determine whether newer, more expensive drugs are indeed worth the extra cost.

Jet versus vibrating mesh nebulizer for tobramycin aerosol in spontaneously breathing children with tracheostomies - a simulation study.

Tracheostomy tubes act as foreign bodies, predisposing the surrounding airway to respiratory infections. Initial treatment for infections is topical - nebulized tobramycin - although guidelines for standardized treatment are lacking. To quantify tobramycin delivery to simulated, tracheostomized children to inform future administration guidelines. A breathing simulator was programmed for volume-controlled ventilation at 6 mL.kg-1, for a 3 kg and a 16 kg child representing under or over 6-yrs, respectively. Nebulized tobramycin doses based on current guidelines for non-tracheostomized children (80 mg, or 300 mg, under and over 6-yrs, respectively) were delivered using standard hospital protocol, collected on filters, and assayed with chromatography to quantify average tobramycin delivered dose from six replicate measurements. The jet nebulizer delivered more tobramycin than the vibrating mesh nebulizer from an 80 mg (ages <6-yrs) dose for both a 3 kg child: 2.1 vs. 0.7 mg (3 mm, p = 0.047) and a 16 kg child: 8.7 vs. 3.5 mg (5 mm size, p = 0.022), 11.4 vs. 8.3 mg (4 mm size, p = 0.2). The jet nebulizer delivered more tobramycin than the vibrating mesh nebulizer for both a 3 kg child: 8.4 vs. 3.7 mg (3 mm, p = 0.00076) and a 16 kg child: 33.2 vs. 25 mg (5 mm, p = 0.2) but not for a 16 kg child: 39.4 vs. 46.5 mg (4 mm, p = 0.18) The low amount and poor distribution of drug delivered warrants consideration and review of dosing regimens for treatment. Future research should investigate improving the efficiency of drug delivery to tracheostomized children and the safety and efficacy of higher-dosage regimens.

Advances in Canine Anesthesia: Physiologically Based Pharmacokinetic Modeling for Predicting Propofol Plasma Profiles in Canines with Hepatic Impairment.

Background: A PBPK model allows the prediction of the concentration of drug amounts in different tissues and organs over time and can be used to simulate and optimize different therapeutic protocols in healthy and sick individuals. The objective of this work was to create a PBPK model to predict propofol doses for healthy canines and canines with hepatic impairment. Methods: The study methodology was divided into two major phases, in which the first phase consisted of creating the PBPK model for healthy canines, and in the second phase, this model was adjusted for canines with hepatic impairment. The model for healthy canines presented good predictive performance, evidenced by the value of the performance measure of the geometric mean fold error that ranged from 0.8 to 1.25, meeting the double error criterion. The simulated regimen for healthy canines, i.e., of 5 mg/kg (administered as a bolus) followed by a continuous infusion at a rate of 0.13 mg/kg/min, was sufficient and ensured that all simulated subjects achieved the target plasma concentration. Canines with 60% and 40% liver function had infusion rate adjustments to ensure that individuals did not exceed the therapeutic window for maintenance of anesthesia. Results: The results presented in this manuscript are suggestive of the effectiveness and practicality of a PBPK model for propofol in canines, with a particular focus on hepatic impairment.

Prevalence and influencing factors of medication-related burden among patients with late-life depression in typical city of eastern China: a cross-sectional study

AimTo evaluate the medication-related burden (MRB) of patients with late-life depression (LLD) and its influencing factors in China using the Living with Medicines Questionnaire-3 (LMQ-3), providing reference for reducing the MRB of those patients.MethodA cross-sectional study was conducted between September 2023 and January 2024 on 588 patients with LLD. LMQ-3 and MRB factors questionnaire were used for data collection. The distribution of variables was assessed using descriptive analysis, while analyses of Mann-Whitney and Kruskal-Wallis were performed to evaluate inter-group differences. To explore the MRB among patients with LLD and influencing factors, multiple linear regression analysis was performed.ResultsThe median (IQR) LMQ-3 score of 588 participants was 102 (18), indicating a moderate MRB level. Regression analysis revealed a significant trend toward higher perceived burden among patients aged 70–79 years old, living in rural areas, receiving more medical insurance settlements, using all cash, taking more than 5 drugs each time, and taking medicine more than 3 times a day (p < 0.05), which were risk factors for higher MRB. Conversely, patients who lived with their children, had an annual household income (including adult children) more than 50,000 Chinese Yuan, and no adverse drug reactions had lower LMQ-3 scores (p < 0.05), which were protective factors. Patients’ concerns about medicine, their lack of autonomy in medicine regimens, and the lack of communication between patients and doctors on treatment regimens were the main causes of the burden.ConclusionsResults of this study provided preliminary evidence of the MRB among patients with LLD. Age, residence, living status, annual household income, type of drug payment, quantity and frequency of medication, and adverse reactions significantly affected the perceived medication burden. It is advisable for health policy makers and health care providers to implement appropriate intervention strategies and burden reduction programs for this vulnerable group.

Nanocomposites Based on Iron Oxide and Carbonaceous Nanoparticles: From Synthesis to Their Biomedical Applications.

Nanocomposites based on Fe3O4 and carbonaceous nanoparticles (CNPs), including carbon nanotubes (CNTs) and graphene derivatives (graphene oxide (GO) and reduced graphene oxide (RGO)), such as Fe3O4@GO, Fe3O4@RGO, and Fe3O4@CNT, have demonstrated considerable potential in a number of health applications, including tissue regeneration and innovative cancer treatments such as hyperthermia (HT). This is due to their ability to transport drugs and generate localized heat under the influence of an alternating magnetic field on Fe3O4. Despite the promising potential of CNTs and graphene derivatives as drug delivery systems, their use in biological applications is hindered by challenges related to dispersion in physiological media and particle agglomeration. Hence, a solid foundation has been established for the integration of various synthesis techniques for these nanocomposites, with the wet co-precipitation method being the most prevalent. Moreover, the dimensions and morphology of the composite nanoparticles are directly correlated with the value of magnetic saturation, thus influencing the efficiency of the composite in drug delivery and other significant biomedical applications. The current demand for this type of material is related to the loading of a larger quantity of drugs within the hybrid structure of the carrier, with the objective of releasing this amount into the tumor cells. A second demand refers to the biocompatibility of the drug carrier and its capacity to permeate cell membranes, as well as the processes occurring within the drug carriers. The main objective of this paper is to review the synthesis methods used to prepare hybrids based on Fe3O4 and CNPs, such as GO, RGO, and CNTs, and to examinate their role in the formation of hybrid nanoparticles and the correlation between their morphology, the dimensions, and optical/magnetic properties.

Synthesis, Characterisation, Computational ADME studies, Pharmacological screening and In-vitro Hydrolysis studies of potential novel mutual prodrugs of N-(2,3-xylyl anthranillic acid)

In the present work we report Synthesis, Computational ADME study, Pharmacological evaluation and In-vitro hydrolysis study of new mutual prodrugs of N-(2,3-xylyl anthranillic acid) prepared with and without spacer using Dicyclohexylcarbodiimide (DCC) as coupling agent. The structures of mutual prodrugs formed were confirmed by advanced spectroscopic techniques. The title compounds were tested for analgesic activity by Eddy’s hot plate and tail-flick method; for anti-inflammatory activity by carrageenan induced rat paw edema method and for ulcerogenicity and acute oral toxicity. Title compounds exhibited promising analgesic and anti-inflammatory activity. The compounds were found to be devoid of ulcerogenicity at the test dose level and presented significant values of the ADME properties studied, obeying Lipinski Rule of five violations, good oral absorption and lipophilicity. Hydrolysis studies revealed that the compounds were sufficiently stable at pH 1.2, indicating that no appreciable hydrolysis to the free acids might occur in the stomach. The amount of free drug released on hydrolysis in 80% human plasma (pH 7.4) was greater than that released in aqueous buffers, suggesting that the rate of hydrolysis of compounds in 80% human plasma was markedly accelerated compared with that in aqueous buffers.

Need for individualized counseling regarding psoriasis systemic therapy in women of childbearing age: analysis of the PsoFem study at the University Medical Center Hamburg.

For patients with moderate-to-severe psoriasis and current childbearing/pregnancy, the choice of therapy is limited. The present study compared the disease burden and treatment choices in women of childbearing age (WoCBA) with and without a current wish for pregnancy. Female patients aged 18 to 45 years, with moderate-to-severe psoriasis vulgaris, were consecutively recruited. The patients reported on sociodemographic/reproductive characteristics and quality of life impairments. The physicians assessed disease severity, comorbidities, and current treatment(s). Both patients' and dermatologists' perceptions of shared decision-making for the current systemic treatment were surveyed. Participants were 145 WoCBA with psoriasis: 73 were pregnant or reported a desire to conceive (group CB+) and 72 reported no wish to have (more) children (group CB-). Patients without childbearing wishes were older and often had previous children; no significant differences in clinical features or quality of life impairments were found. A significantly higher proportion of patients in the CB+ group were prescribed tumor necrosis factor alpha blockers, particularly certolizumab pegol. This treatment option was associated with previous children and the desire to conceive, but not with disease variables. Family planning was more often discussed and considered in the clinical decision for the CB+ group, but patient-doctor agreement for shared decision-making was fair-to-moderate. The small sample size prevented comparative analyses between patients planning a pregnancy in the short- vs long-term future. In addition, specific variables related to the decision-making process for the current therapy need to be assessed and examined in more detail in further research. For WoCBA with childbearing wishes, tumor necrosis factor alpha blockers were most frequently prescribed, in accordance with current guidelines/recommendations. Decision-making for continuing or changing systemic therapy during pregnancy must take into account medication specificities and the vulnerable stages in pregnancy, as well as the limited amount of pregnancy-compatible drugs.

Electrochemical Sensor Based on Crafted Thia Polymeric Crown Ether for Determination of Carbamazepine and Ephedrine

Background: Direct analysis methods are considered some of the best and easiest tools to quickly determine the amount of active drug in some pharmaceutical preparations. Objectives: In this study, an ion electrode is prepared to determine the concentration of a sample of ephedrine (Eph) and carbamazepine (CBZ) in the medicines produced by some companies directly. Methods: CBZ and Eph drugs ion-selective electrode (ISE) based on Thia polymeric crown ether (SPCE-CZB and SPCE-Eph) as membrane carrier in polyvinyl chloride (PVC) matrix was successfully fabricated for the determination of CBZ and Eph drugs. Results: The electrode exhibited a liner Nernstian slope response over the range of 1×10-1 to 1×10-6 M, and 1×10-5 to 1×10-1 with a slope of 28 and 33±2 mV per decade charge, respectively, by using dimethyl phthalate plasticizer and a detection limit of 1×10-9 M. The response time of the sensor was 10 s. The ISE showed a greater preference for CBZ and Eph over other drugs with good precision. Conclusion: The selectivity coefficients of some drugs ranged from 1×10-5 to 1×10-1. Meanwhile, SPCE-CZB (ISE) was successfully used as an indicator electrode for the potentiometric determination of the CBZ drug pharmaceutical formulas.

Elterelésben résztvevők szerhasználati szokásai és motivációja kvalitatív vizsgálatok tükrében

The aim of our study to show the diversion system in Hungary and the motivation of clients who have been diverted. The institution of diversion was introduced in our country in 1993, which offers treatment to drug users instead of punishment in case of possession of a small amount of drugs. During our empirical investigations, our goal was to explore the substance use habits and motivation of diverted clients. For this purpose, we conducted semi-structured interviews with ten people starting diversion, which we supplemented with the inclusion of a diagnostic test for measuring motivation (URICA). The results of our research support the results of previous research on the topic, according to which the clients willingness to cooperate and motivation is low, which can thus lead to the ineffectiveness of the diversion.

Bioadhesive film for the delivery of local anesthetics to the buccal mucosa: ex-vivo and in-vivo evaluation

The aim of this work was the preparation and characterization of two bioadhesive films (with different drug loadings) containing a combination of lidocaine and prilocaine hydrochloride to be applied on the buccal mucosa to reduce the pain sensation associated with needle insertion during dental procedures. The films were tested ex-vivo to determine the amount of drug permeated/retained in buccal mucosa, and, in-vivo to assess the extent and duration of anesthetic effect on the mucosa and pharmacokinetic parameters. As a reference, the commercial formulation EMLA® cream was used. Ex-vivo studies were conducted on porcine esophageal epithelium, an accepted model for buccal mucosa, and in-vivo studies on human volunteers. The ex-vivo results obtained show that the retention of both drugs into the mucosa resulted comparable after the application of the films or EMLA® cream for 10 min; on the contrary, the amounts of drug permeated from the commercial formulation was higher, suggesting the possibility to achieve systemic effect. In-vivo experiments showed that the intensity of anesthesia, evaluated by VAS during needle insertion, was much higher for EMLA® cream (the median value was zero for EMLA® and 0.15–0.3 cm for the two films); however, the film and EMLA® cream resulted equivalent in terms of duration of anesthesia, from 25 to 40 min. The pharmacokinetic study showed that both films tested produced very low plasma concentration (zero for most of experimental data point), thus guaranteeing no risk of systemic effects, whereas EMLA® cream demonstrated measurable plasma levels for both drugs (lidocaine Cmax was 4 ng/ml, prilocaine Cmax was 1.5 ng/ml). Moreover, a correlation between ex-vivo drug tissue concentration and duration of the anesthetic effect in-vivo was found. Although this correlation is limited to a small number of formulations, it supports the validity of pig esophageal epithelium in the development of formulation to be used on human buccal mucosa.

Post-genomic illumination of paclitaxel biosynthesis.

Paclitaxel rapidly became one of the most effective anticancer drugs. However, the production of paclitaxel is hindered by substantial challenges, particularly considering the significant quantities of drug required and the inherently low concentration of paclitaxel and its intermediates in plants. Paclitaxel is currently produced in a so-called semi-synthesis in which baccatin III is extracted from Taxus species and chemically converted to paclitaxel. Despite the fact that many of the intermediates of paclitaxel biosynthesis are yet to be experimentally determined, a set of recent papers-facilitated by the sequencing and assembly of three Taxus genomes-has uncovered the minimal gene sets for both baccatin III and paclitaxel biosynthesis. Here we summarize the key milestones towards our understanding of paclitaxel biosynthesis and highlight recent advancements made possible by genome-level analysis of potential key genes involved. We argue that these studies will ultimately pave the way towards the elucidation of the entire paclitaxel biosynthetic pathway and facilitate the industrial production of paclitaxel via synthetic biology approaches. However, several major challenges lie ahead before we can fully tap into the amazing curative potential that taxanes provide.

Navigating the COVID-19 Risk Environment, Overdose Prevention, and Self Care Practices of People Who Use Illicit Opioids in New York City

Background The concurrent opioid overdose crisis and COVID-19 pandemic created a perfect storm of risk for drug overdose mortality and other negative health outcomes. Methods This study is based on semi-structured interviews with 29 adults in New York City who were using illicit opioids (heroin, fentanyl, and prescription opioids without prescription) between April and September 2020 to gain their perspectives on navigating COVID as the pandemic was unfolding. Interviews explored both challenges posed by the pandemic and participants’ navigation of these challenges to prevent overdose, procure drugs, manage drug use, and maintain their health and safety. Results Participants tried to adhere to best public health policies and practices and adapted as needed to protect their own and others’ health. They procured larger amounts of drugs to reduce travel, arranged drop-offs, and adhered to social distancing mandates during transactions. Homeless participants formed supportive and protective “bubbles” with network members to ensure safety and maximize resources. Participants addressed service access challenges by stockpiling MOUD, injection equipment and naloxone and reported using drugs when protected by naloxone and someone to administer when possible. Conclusions Despite the many challenges posed by COVID to people who use drugs in NYC, this research documents the ways people who use drugs drew on experiences of navigating stigma, structural violence, and social exclusion on a daily basis to enhance self-care and harm reduction practices. Powerful narratives of adaptation and resilience speak to the need to include people who use drugs in future public health and disaster planning initiatives.

Inhalation of itraconazole mitigates bleomycin-induced lung fibrosis via regulating SPP1 and C3 signaling pathway pivotal in the interaction between phagocytic macrophages and diseased fibroblasts

BackgroundIdiopathic pulmonary fibrosis (IPF) stands as a significant contributor to global mortality rates. Presently, there exists a dearth of effective anti-fibrotic treatments for this condition. While itraconazole (ITR) has exhibited potential in mitigating pulmonary fibrosis, its oral administration is hampered by unfavorable pharmacokinetics, which elevate the risk of adverse reactions, thus limiting its clinical utility.MethodsAn inhalable formulation of ITR were engineered which aimed at enhancing its pulmonary dispersion. First, pharmacokinetics were conducted to investigate the blood concentration and tissue residue of ITR after inhalation administration. In addition, bleomycin induced mouse pulmonary fibrosis model was used to compare the therapeutic effects of ITR administered by inhalation and intragastric administration. Finally, single-cell RNA sequencing (scRNAseq) was used to explore the mechanism of ITR inhalation administration.ResultsWe found that a large amount of drugs accumulated in the lung tissue for a long time after inhalation administration, thus maximizing the therapeutic effect of drugs. Inhalation of ITR daily at for 21 days significantly attenuated bleomycin-induced lung fibrosis and inflammation in murine models. Additionally, our findings revealed that ITR inhalation diminished the proportion of diseased fibroblasts while promoting reparative fibroblast populations in the murine model. Furthermore, it effectively reversed the proportion of activated phagocytic macrophages. Mechanistically, ITR inhalation exerted its effects by regulating SPP1 and C3 signaling pathway pivotal in the interaction between phagocytic macrophages and diseased fibroblasts.ConclusionsThese insights into the molecular mechanisms underlying ITR’s therapeutic effects on IPF underscore the favorable pharmacokinetic profile conferred by inhalation, thus presenting a promising formulation poised for clinical translation.

Exploring the potential of a pH-sensitive hydrogel sponge: interpenetrating network of tragacanth and pectin for controlled delivery of levosulpiride.

The development of drug delivery systems that allow precise control over drug release pattern has fetched significant attention in the pharmaceutical field. This research work investigates the potential of a pH-sensitive interpenetrating network (IPN) composed of tragacanth and pectin as a carrier for the controlled release of levosulpiride. To enhance the solubility of poorly soluble drug levosulpiride, inclusion complexes were formed with beta cyclodextrin (βCD). The IPN was prepared by cross-linking tragacanth with pectin by adopting a green chemistry approach. The resulting cross-linked polymeric network was subjected to repetitive freeze-drying cycles for preparation of spongy mass. The physicochemical properties of the resultant product were thoroughly characterized using a range of analytical techniques, including Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), thermal analyses (DSC/TGA), and X-ray diffraction (XRD). The physical parameters like sol-gel fraction (%), drug loading (%), swelling behavior, electrolyte responsiveness, and in vitro drug release profile of the developed sponge were systematically evaluated under varying pH conditions. Results of FTIR demonstrated the formation of cross-linked network, ruling out drug-excipient interaction. SEM analysis unveiled porous and rough geometry. Thermal analyses proved the hydrogel network thermally stable whereas, PXRD demonstrated the overall amorphous nature of the hydrogel sponge. The outcomes of physical parameters demonstrated an incremental trend in gel fraction from 63 to 85% on raising the molar concentration of cross-linker from TP1 to TP3. However, increasing tragacanth content escalation in gel fraction from 75 to 79% was noticed. While gel fraction was augmented from 79 to 83% with increasing pectin contents. The maximum drug loading formulation TP3 was computed to be 89%. Hydrogel sponges also demonstrated electrolyte responsiveness. The release profile indicated a pH-responsive behavior, with sustained release up to 10h observed in a buffer solution of pH 6.8 and 7.4. In an acidic medium, a minor amount of drug was released during 10h dissolution. Drug release kinetics was observed to be in zero order. The findings of this study highlight the promising potential of the tragacanth/pectin hydrogel sponge as a pH-sensitive dais for the controlled delivery of levosulpiride, emphasizing its potential application in personalized drug therapy and the treatment of gastrointestinal disorders.

Breaking the 500-Dalton Rule of Transdermal Drug Delivery by Locally Stretching Skin with Porous Micropost Array

Transdermal drug administration has been attracting attention for its variety of advantages, such as elimination of pain and its minimal invasiveness. However, the efficacy of transdermal drug delivery is limited by the stratum corneum, the outermost layer of the skin. The permeable molecular size through the stratum corneum is known to be roughly below 500 Da, which is known as the 500-Da rule in the area of transdermal drug delivery (1). Various techniques have been explored to enhance transdermal permeation, including, microneedles, thermal ablation, microdermabrasion, electroporation and cavitational ultrasound (2). Among them, microneedles, in particular, have been extensively studied and tested for clinical use.In this work, we discovered that the blunt frustoconical-shaped microneedles or microposts can increase the permeability of skin by locally stretching the stratum corneum without penetration (Figure 1a). Through testing with various molecular sizes, we successfully demonstrated that molecules with a size of approximately up to 10 kDa can be injected. Due to its minimally invasive nature, we propose this as an alternative noninvasive approach to conventional microneedle transdermal drug delivery.Porous frustoconical microneedle arrays (PMN) were fabricated using methacrylic-based materials with microscopic porous network structures (Figure 1b), based on our group’s protocol (3). Ions and molecules can pass through the network by applying weak electric field to introduce electrophoresis and electroosmosis. Using the developed micropost arrays, we conducted the following experiments. Firstly, we measured the transdermal electrical resistance of a pig skin with the PMN array pressed onto the skin. A non-penetrating frustoconical PMN array was found to reduce the transdermal resistance to a similar level as the sharp PMN array that physically penetrates stratum corneum, indicating that local stretching of the stratum corneum can enhance ion and molecular permeability of the skin even without penetration. Secondly, we applied a weak electric field to the PMN array to induce electroosmotic flow (EOF) inside the porous network and measured the drug permeabilities through pig skin using fluorescent-labeled drug molecules with different molecular sizes (Figure 1c). The amount of the permeated drug was evaluated by enzymatically degrading the skin samples and measuring its fluorescent intensity. We found that drug molecules could permeate only when the skin was stretched with the PMN array and EOF was present simultaneously. The synergy between the extension of the stratum corneum and EOF promotion enables the minimally invasive transdermal drug delivery that is even less invasive than the conventional sharp microneedles. We quantitatively confirmed that at least 10-kDa molecules can permeate through the stratum corneum with our developed frustoconical PMN array.In summary, we developed a porous micropost array that can locally stretch stratum corneum to enhance chemical and drug transdermal permeability. By measuring the electric resistance and using fluorescent imaging, we confirmed that drug molecules with a size of approximately 10 kDa can be delivered using a porous micropost array without penetrating the stratum corneum. Our approach of using micropost array significantly widens the window of possible drug molecular sizes for transdermal applications.Figure (a) Frustoconical microposts locally stretch the stratum corneum and increase drug permeability through the skin. Electroosmotic flow pumps out the drug molecules loaded in the porous structure. (b) Fabricated porous micropost array. (c) Fluorescent image of 10-kDa FITC-Dextran molecules permeating through the stratum corneum.References Bos JD & Meinardi MMHM (2000) The 500 Dalton rule for the skin penetration of chemical compounds and drugs. Exp Dermatol 9(3):165-169. Prausnitz MR & Langer R (2008) Transdermal drug delivery. Nat Biotechnol 26(11):1261-1268. Terutsuki D, Segawa R, Kusama S, Abe H, & Nishizawa M (2023) Frustoconical porous microneedle for electroosmotic transdermal drug delivery. J Control Release 354:694-700. Figure 1