Drug Dosing Regimens Research Articles

The acquisition order of leukemic drug resistance mutations is directed by the selective fitness associated with each resistance mechanism

In Chronic Myeloid Leukemia, the transition from drug sensitive to drug resistant disease is poorly understood. Here, we used exploratory sequencing of gene transcripts to determine the mechanisms of drug resistance in a dasatinib resistant cell line model. Importantly, cell samples were collected sequentially during drug exposure and dose escalation, revealing several resistance mechanisms which fluctuated over time. BCR::ABL1 overexpression, BCR::ABL1 kinase domain mutation, and overexpression of the small molecule transporter ABCG2, were identified as dasatinib resistance mechanisms. The acquisition of mutations followed an order corresponding with the increase in selective fitness associated with each resistance mechanism. Additionally, it was demonstrated that ABCG2 overexpression confers partial ponatinib resistance. The results of this study have broad applicability and help direct effective therapeutic drug usage and dosing regimens and may be useful for clinicians to select the most efficacious therapy at the most beneficial time.

SAFETY OF HYPOGLYCEMIC THERAPY IN CASES OF PATIENTS WITH POLYMORBID PATHOLOGIES

Impairment of the excretory function of the kidneys was revealed in 69% of patients with type 2 diabetes admitted to the hospital in therapeutic departments. A decrease of GFR below 30 ml/min/1,73 m2, which can significantly affect the choice and dosage regimen of hypoglycemic drugs, was recorded in 35% of patients. According to the anamnesis, sulfonylurea derivatives took 66.3% of hospitalized patients, biguanides in monotherapy - 25%, a combination of drugs from these two groups was prescribed in 35% cases. According to the analysis of the pharmacotherapy, 8.2% of patients with type 2 diabetes mellitus required correction of hypoglycemic therapy because of the functional state of the kidneys. According to the results of laboratory research methods , during hospitalization 3% of patients had episodes of hypoglycemia ( blood glucose level 3.9 mmol/L) or boundary values of glucose (blood glucose level = 4.0-4.1 mmol/L), but endocrinologist consultations and drug therapy correction hadn't been carried out. Therefore the lack of care of 'non-endocrinologists' regarding the risk of hypoglycemia in patients with type 2 diabetes with renal dysfunction leads to the absence of pharmacotherapy correction during hospitalization.

Real-world Performance of a New Strategy for Off-Label Use of Guselkumab in Moderate to Severe Psoriasis: Super-Responder Patients as the Epitome of Efficacy and Optimisation.

Guselkumab is a drug used to treat moderate to severe plaque psoriasis. However, real-life clinical data on its off-label use are limited, especially regarding the optimal drug dosage regimen for different patient profiles. The main objective of this real-world, single-centre, retrospective study was to identify the off-label guselkumab dosing regimen used in clinical practice. The study also aimed to evaluate the drug's efficacy, safety, and survival, as well as the proportion of super-responders (SR) based on a newly proposed definition. The study included 69 patients who started treatment with guselkumab between March 2019 and July 2021. Patients were followed up until April 2022, during which time their efficacy, safety, persistence, and use of guselkumab were recorded. Patients were aged ≥ 18 years and had moderate to severe plaque psoriasis. The mean disease duration was 18.6 years, and 59% of patients had received at least one biologic treatment before guselkumab with a mean of 1.3 biologics per patient. The initial absolute Psoriasis Area and Severity Index(PASI) was 10.1 and decreased to 2.1 between Week 11-20 without significant changes in the PASI value throughout the 90 weeks of follow-up. The cumulative probability of drug survival was 93.5% at Week 52. No differences were found in terms of efficacy and survival associated with the off-label drug dosage regimens compared to the doses described in the Summary of Product Characteristics (SmPC). The greatest adjustments in the drug administration regimen were achieved in the subgroups of bio-naïve and SR patients, with a reduction in the number of administrations by 40% and 47% compared to the regimen described in the SmPC. Super-response to guselkumab was mainly associated with patients naïve to previous biologic treatment. The study demonstrated that off-label use of guselkumab was safe and effective in real-life clinical practice. The findings suggest that adjustments to the drug administration regimen may be necessary to optimise its use in different patient profiles, especially in SR and bio-naïve patients. Further studies are needed to confirm these findings.

Monitoring islet specific immune responses in type 1 diabetes clinical immunotherapy trials.

The number of immunotherapeutic clinical trials in type 1 diabetes currently being conducted is expanding, and thus there is a need for robust immune-monitoring assays which are capable of detecting and characterizing islet specific immune responses in peripheral blood. Islet- specific T cells can serve as biomarkers and as such can guide drug selection, dosing regimens and immunological efficacy. Furthermore, these biomarkers can be utilized in patient stratification which can then benchmark suitability for participation in future clinical trials. This review focusses on the commonly used immune-monitoring techniques including multimer and antigen induced marker assays and the potential to combine these with single cell transcriptional profiling which may provide a greater understanding of the mechanisms underlying immuno-intervention. Although challenges remain around some key areas such as the need for harmonizing assays, technological advances mean that multiparametric information derived from a single sample can be used in coordinated efforts to harmonize biomarker discovery and validation. Moreover, the technologies discussed here have the potential to provide a unique insight on the effect of therapies on key players in the pathogenesis of T1D that cannot be obtained using antigen agnostic approaches.

Implementation of 2D barcode medication labels and smart pumps in pediatric acute care: Lessons learned.

In pediatric intensive care, prescription, administration, and interpretation of drug doses are weight-dependent. The use of standardized concentrations simplifies the preparation of drugs and increases safety. For safe administration as well as easy interpretation of intravenous drug dosing regimens with standardized concentrations, the display of weight-related dose rates on the infusion device is of pivotal significance. We report on challenges in the implementation of a new information technology-supported medication workflow. The workflow was introduced on eight beds in the pediatric heart surgery intensive care unit as well as in the pediatric anesthesia at the University of Bonn Medical Center. The proposed workflow utilizes medication labels generated from prescription data from the electronic health record. The generated labels include a 2D barcode to transfer data to the infusion devices. Methods Clinical and technical processes were agilely developed. The reliability of the system under real-life conditions was monitored. User satisfaction and potential for improvement were assessed. In addition, a structured survey among the nursing staff was carried out. The questionnaire addressed usability as well as the end-users' perception of effects on patient safety. The workflow has been applied 44111 times during the pilot phase. A total of 114 known failures in the technical infrastructure were observed. The survey showed good ratings for usability and safety (median "school grade" 2 or B for patient safety, intelligibility, patient identification and handling). The medical management of the involved acute care facilities rated the process as clearly beneficial regarding patient safety, suggesting a rollout to all pediatric intensive care areas. A medical information technology-supported medication workflow can increase user satisfaction and patient safety as perceived by the clinical end-users in pediatric acute care. The successful implementation benefits from an interdisciplinary team, active investigation of possible associated risks, and technical redundancy.

SARS-CoV-2 infection dysregulates the expression of clinically relevant drug metabolizing enzymes in Vero E6 cells and membrane transporters in human lung tissues.

SARS-CoV-2-mediated interactions with drug metabolizing enzymes and membrane transporters (DMETs) in different tissues, especially lung, the main affected organ may limit the clinical efficacy and safety profile of promising COVID-19 drugs. Herein, we investigated whether SARS-CoV-2 infection could dysregulate the expression of 25 clinically relevant DMETs in Vero E6 cells and postmortem lung tissues from COVID-19 patients. Also, we assessed the role of 2 inflammatory and 4 regulatory proteins in modulating the dysregulation of DMETs in human lung tissues. We showed for the first time that SARS-CoV-2 infection dysregulates CYP3A4 and UGT1A1 at the mRNA level, as well as P-gp and MRP1 at the protein level, in Vero E6 cells and postmortem human lung tissues, respectively. We observed that at the cellular level, DMETs could potentially be dysregulated by SARS-CoV-2-associated inflammatory response and lung injury. We uncovered the pulmonary cellular localization of CYP1A2, CYP2C8, CYP2C9, and CYP2D6, as well as ENT1 and ENT2 in human lung tissues, and observed that the presence of inflammatory cells is the major driving force for the discrepancy in the localization of DMETs between COVID-19 and control human lung tissues. Because alveolar epithelial cells and lymphocytes are both sites of SARS-CoV-2 infection and localization of DMETs, we recommend further investigation of the pulmonary pharmacokinetic profile of current COVID-19 drug dosing regimen to improve clinical outcomes.

Critical observation of WHO recommended multidrug therapy on the disease leprosy through mathematical study

Leprosy is a skin disease and it is characterized by a disorder of the peripheral nervous system which occurs due to the infection of Schwann cells. In this research article, we have formulated a four-dimensional ODE-based mathematical model which consists of the densities of healthy Schwann cells, infected Schwann cells, M. leprae bacteria, and the concentration of multidrug therapy (MDT). This work primarily aims on exploring the dynamical changes and interrelations of the system cell populations during the disease progression. Also, evaluating a critical value of the drug efficacy rate of MDT remains our key focus in this article so that a safe drug dose regimen for leprosy can be framed more effectively and realistically. We have examined the stability scenario of different equilibria and the occurrence of Hopf-bifurcation for the densities of our system cell populations with respect to the drug efficacy rate of MDT to gain insight on the precise impact of the efficiency rate on both the infected Schwann cell and the bacterial populations. Also, a necessary transversality condition for the occurrence of the bifurcation has been established. Our analytical and numerical investigations in this research work precisely explores that the process of demyelination, nerve regeneration, and infection of the healthy Schwann cells are the three most crucial factors in the leprosy pathogenesis and to control the M. leprae-induced infection of Schwann cells successfully, a more flexible version of MDT regime with efficacy rate varying in the range η∈(0.025,0.059) for 100−120 days in PB cases and 300 days in MB cases obtained in this research article should be applied. All of our analytical outcomes have been verified through numerical simulations and compared with some existing clinical findings.

POLYPRAGMASIA AND DRUG LOAD DEPENDING ON THE STATE OF KIDNEY FUNCTION OF PATIENTS SUFFERING FROM DIABETES MELLITUS

Type 2 diabetes mellitus is often combined with other diseases, which increases the likelihood of polypragmasia. For the correct dosage regimen of drugs, it is necessary to take into account the state of kidney function, the change of which may be associated with diabetic nephropathy. The aim of the study was to determine the structure of comorbid pathology in patients with type 2 diabetes mellitus and to evaluate the dosage regimen of hypoglycemic drugs taking into account the state of the kidneys. A retrospective analysis of 100 medical records of patients hospitalized in the endocrinology department of the Russian Railways Medicine Clinical Hospital from January to April 2022 was carried out. Patients were divided into groups depending on the presence or absence of CRD (chronic renal disease). Hypoglycemic therapy was evaluated by calculating the drug burden index (DBI) in DDD units for 10 days of pharmacotherapy with oral hypoglycemic and insulin drugs.
 It was found that arterial hypertension (85%), dyslipidemia (67%), obesity (62%) prevailed in the structure of comorbid pathology in patients with diabetes mellitus. Polypragmasia was detected in 87% of patients. Decrease of glomerular filtration rate (GFR40 ml/min) was found in 61% of patients.
 The study showed that while maintaining kidney function (GFR 60 ml/min) in the selected cohort of patients, the average DBI value for oral drugs reached 34 DDD units for 10 days of pharmacotherapy, for insulin preparations - 13 DDD units for 10 days of pharmacotherapy. In patients with reduced GFR40 ml/min, the average DBI value for oral medications was significantly lower, reaching 8.6 DDD units for 10 days of pharmacotherapy, for insulin preparations 7.6 DDD units for 10 days of pharmacotherapy, indicating a decrease in the number of drug prescriptions.

Quantitative systems pharmacology model of GITR-mediated T cell dynamics in tumor microenvironment.

T cell interaction in the tumor microenvironment is a key component of immuno-oncology therapy. Glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) is expressed on immune cells including regulatory T cells (Tregs) and effector T cells (Teffs). Preclinical data suggest that agonism of GITR in combination with Fc-γ receptor-mediated depletion of Tregs results in increased intratumoral Teff:Treg ratio and tumor shrinkage. A novel quantitative systems pharmacology (QSP) model was developed for the murine anti-GITR agonist antibody, DTA-1.mIgG2a, to describe the kinetics of intratumoral Tregs and Teffs in Colon26 and A20 syngeneic mouse tumor models. It adequately captured the time profiles of intratumoral Treg and Teff and serum DTA-1.mIgG2a and soluble GITR concentrations in both mouse models, and described the response differences between the two models. The QSP model provides a quantitative understanding of the trade-off between maximizing Treg depletion versus Teff agonism, and offers insights to optimize drug design and dose regimen.

Pharmacogenetic Aspects of Drug Metabolizing Enzymes and Transporters in Pediatric Medicine: Study Progress, Clinical Practice and Future Perspectives.

As the activity of certain drug metabolizing enzymes or transporter proteins can vary with age, the effect of ontogenetic and genetic variation on the activity of these enzymes is critical for the accurate prediction of treatment outcomes and toxicity in children. This makes pharmacogenetic research in pediatrics particularly important and urgentlyneeded, but also challenging. This review summarizes pharmacogenetic studies on the effects of genetic polymorphisms on pharmacokinetic parameters and clinical outcomes in pediatric populations for certain drugs, which are commonly prescribed by clinicians across multiple therapeutic areas in a general hospital, organized from those with the most to the least pediatric evidence among each drug category. We also further discuss the research status of the gene-guided dosing regimens and clinical implementation of pediatric pharmacogenetics. More and more drug-gene interactions are demonstrated to have clinical validity for children, and pharmacogenomics in pediatrics have shown evidence-based benefits to enhance the efficacy and precision of existing drug dosing regimens in several therapeutic areas. However, the most important limitation to the implementation is the lack of high-quality, rigorous pediatric prospective clinical studies, so adequately powered interventional clinical trials that support incorporation of pharmacogenetics into the care of children are still needed.

Review of the latest solutions in the use of contact lenses as controlled release systems for ophthalmic drugs.

In recent years, there has been a great interest in the potential use of contact lenses as eye drug delivery systems. Static (individual layers of the cornea, sclera and retina) as well as dynamic barriers (blood flow) pose a serious challenge to the effective delivery of the drug substance to the eyeball. The current ophthalmic systems are not optimal for patients, especially in the form of eye drops, where almost 95% of the drug contained in them is lost through the process of absorption through the conjunctiva or tear drainage. This article describes in vitro experiments that examined the use of contact lenses in the context of drug treatment in infectious, inflammatory, allergic, and glaucomatous diseases. Various techniques used to modify the materials as well as their impact on drug release kinetics were discussed. It has also been demonstrated that these methods can be used in practice during in vivo research, both in animal models as well as in sick and healthy people. The advantages of using controlled-release drug systems in the form of contact lenses are the drug dosing regimen, bioavailability and the prolonged residence time of drugs in the eyeball.

Влияние кистевого теппинга на частоту эпилептических приступов и качество жизни у 30-летнего мужчины со структурной фокальной эпилепсией

Aim: To present a clinical case of the use of the wrist tapping method in a 30-year-old patient with structural focal epilepsy (SFE). Key points. During 4 visits, we examined patient N., 30 years old, suffering from SFE, which developed against the background of a gunshot wound to the skull, with frequent focal seizures (FS) and bilateral tonic-clonic seizures (BTCS). After 6 months from the start of wrist tapping sessions (4th visit), using the application, the patient noted a 55% increase in quality of life due to the ability to stop AF and prevent the development of BTK. In 87.5% of cases, he was able to stop incipient motor hemifacial FS and prevent its transformation into BTCS. With regular use of the application by the patient, the incidence of FS decreased by 65.4% on the 4th visit compared to that on the 2nd visit. The patient highly rated the effectiveness and safety of the wrist tapping method (97.6%). Conclusion. The use of the application allowed a young man with treatment-resistant post-traumatic SFE, without changing the dosage regimen and dose of the antiepileptic drug, to reduce the frequency of FS by 65.4% from baseline and significantly reduce the number of BTCS, significantly improving the quality of life. Keywords: structural focal epilepsy, wrist tapping.

The problem of antibiotic resistance of microorganisms in Ukraine and the world

Basically, antibiotic resistance develops due to the incorrect use of antibiotics in various branches of animal husbandry, both during the treatment or prevention of diseases, and due to their long-term use as growth stimulants. As a result, costs for the treatment of farm animals and companion animals are increasing. Antibiotic resistance among microorganisms is a threat to every person, every patient, medical and veterinary worker. Also, this is a big challenge for the field of health care, veterinary medicine and agriculture as a whole. It is very difficult to solve the problem of resistance, because it is not one-sided. Medicines that were effective a few years ago are losing their positions today, and their use is being forced to be limited. According to data from the World Health Organization, the rapid increase in the resistance of microorganisms to antibacterial drugs threatens the scientific gains made by scientists during the last 50-70 years. The formation of antibiotic resistance is due to the genetic properties of microorganisms, as a result of their acquisition of new genetic information, or due to a change in the level of expression of the bacterial cell's own genes. An important factor in the fight against the spread of antibiotic resistance is the pharmacodynamic substantiation of the dosing regimens of antibacterial drugs and their use for specific microorganisms.There are guiding documents that control and recommend the reliability of determining the sensitivity of microorganisms to antibiotics, in particular - methodological recommendations of the European organization EUCAST, the data and material of which are periodically (annually) updated. These documents are developed primarily for routine use in clinical laboratories that do not cover technical procedures for identifying resistance mechanisms at the molecular level. However, a significant part of the given data, research on determining the sensitivity of microorganisms to antibiotics, is performed in national reference laboratories. There is a change in the sensitivity of the micro-flora to antibiotics, which is not covered by the screening of multi-resistant microorganisms, or the direct detection of resistance in clinical samples. Therefore, the study of the problem remains relevant and expedient. Key words: microorganisms, resistance, antibiotics, gram-positive bacteria, gram-negative bacteria, control, disease, spread, problem, treatment, animals.

A Review of Therapeutic Drug Monitoring and Model-Informed Precision Dosing in Personalized Medicine

Therapeutic drug monitoring (TDM) and model-informed precision dosing (MIPD) have become effective methods in determining and adjusting dose regimens of various drugs in clinical practice. With the latest development in technology, particularly in computer science, drug individualization has evolved to be more flexible and precise. However, these methods still have certain drawbacks and have not been applied on a grand scale. This review shall present the most basic concept of TDM and MIPD as well as current issues in their application.
 
 
 

Opioid versus non-opioid analgesia for spine surgery: a systematic review and meta-analysis of randomized controlled trials.

Opioids are the primary analgesics used in patients undergoing spine surgery. Postoperative pain is common despite their liberal use and so are opioid-associated side effects. Non-opioid analgesics are gaining popularity as alternative to opioids in spine surgery. This systematic review evaluated current evidence regarding opioid and non-opioid intraoperative analgesia and their influence on immediate postoperative pain and adverse events in spine surgery. A total of 10,459 records were obtained by searching Medline, EMBASE and Web of Science databases and six randomized controlled trials were included. Differences in postoperative pain scores between opioid and non-opioid groups were not significant at 1h: 4 studies, mean difference (MD) = 0.65 units, 95% confidence intervals (CI) [-0.12 to 1.41], p = 0.10, but favored non-opioid at 24h after surgery: 3 studies, MD = 0.75 units, 95%CI [0.03 to 1.46], p = 0.04. The time for first postoperative analgesic requirement was shorter (MD = -45.06min, 95%CI [-72.50 to -17.62], p = 0.001), and morphine consumption during first 24h after surgery was higher in opioid compared to non-opioid group (MD = 4.54mg, 95%CI [3.26 to 5.82], p < 0.00001). Adverse effects of postoperative nausea and vomiting (Relative risk (RR) = 2.15, 95%CI [1.37 to 3.38], p = 0.0009) and shivering (RR = 2.52, 95%CI [1.08 to 5.89], p = 0.03) were higher and bradycardia was lower (RR = 0.35, 95%CI [0.17 to 0.71], p = 0.004) with opioid analgesia. The certainty of evidence on GRADE assessment is low for studied outcomes. Available evidence supports intraoperative non-opioid analgesia for overall postoperative pain outcomes in spine surgery. More research is needed to find the best drug combination and dosing regimen. Prospero Registration: CRD42020209042.

Pharmacokinetic-pharmacodynamic model to predict drug concentrations and intraocular pressure lowering effect for a bimatoprost six-month slow-release system.

Ophthalmic drug product development and dosing regimen selection depend on animal eye drug concentration-effect relationships since human eye tissues cannot be sampled for drug quantification. This study hypothesized that a pharmacokinetic-pharmacodynamic (PK-PD) mathematical model developed based on dog studies can be applied to the human eye of different ages, based on physiological parameter adjustment, to predict drug concentrations and effects in response to a new 6-month slow-release, intracameral, intraocular pressure (IOP) lowering, anti-glaucoma bimatoprost implant. Using previously reported dog concentration-effect relationship data at various doses, and the physiological parameters of dog eye, a PK-PD model was designed to predict dog aqueous humor drug concentrations and IOP lowering effects simultaneously for a given dose. After validating the model using the dog IOP data, it was applied to the human eye. Using a drug release rate constant of 0.0002 h-1, the model predicted the dog IOP lowering effect with an error less than 6% or less at various doses (Observed = 0.91*Predicted + 2.35; R2 = 0.98). Considering literature reported aqueous humor volumes and flow rates in old (over 60 years) and young (20 to 30 years) humans, aqueous humor elimination rate constant was estimated to be 0.9 and 0.68 h-1, respectively. The model when modified using the older human eye parameters, predicted the IOP lowering effects reported in a clinical trial with 63-year-old adults, with an error of 6.2% or less. The model, when used for young adult eye not previously tested in clinical trials, predicted lower drug concentrations and effects, possibly due to 54% higher aqueous humor volume relative to older adults. The model predicted an IOP reduction of 26.3 and 30.6%, at 10 and 15 microgram doses, respectively, in young adults. The PK-PD model developed is useful for product design and patient dosing by predicting eye drug concentration and effect time-courses in response to implant administration at various doses, frequencies, and release rates.

Optimisation of treatments for oral Neisseria gonorrhoeae infection: Pharmacokinetics Study (STI-PK project) – study protocol for non-randomised clinical trial

IntroductionNeisseria gonorrhoeae infections are common and incidence increasing. Oropharyngeal infections are associated with greater treatment failure compared with other sites and drive transmission to anogenital sites through saliva. Gonococcal resistance...

The investigation of the complex population-drug-drug interaction between ritonavir-boosted lopinavir and chloroquine or ivermectin using physiologically-based pharmacokinetic modeling.

Therapy failure caused by complex population-drug-drug (PDDI) interactions including CYP3A4 can be predicted using mechanistic physiologically-based pharmacokinetic (PBPK) modeling. A synergy between ritonavir-boosted lopinavir (LPVr), ivermectin, and chloroquine was suggested to improve COVID-19 treatment. This work aimed to study the PDDI of the two CYP3A4 substrates (ivermectin and chloroquine) with LPVr in mild-to-moderate COVID-19 adults, geriatrics, and pregnancy populations. The PDDI of LPVr with ivermectin or chloroquine was investigated. Pearson's correlations between plasma, saliva, and lung interstitial fluid (ISF) levels were evaluated. Target site (lung epithelial lining fluid [ELF]) levels of ivermectin and chloroquine were estimated. Upon LPVr coadministration, while the chloroquine plasma levels were reduced by 30, 40, and 20%, the ivermectin plasma levels were increased by a minimum of 425, 234, and 453% in adults, geriatrics, and pregnancy populations, respectively. The established correlation equations can be useful in therapeutic drug monitoring (TDM) and dosing regimen optimization. Neither chloroquine nor ivermectin reached therapeutic ELF levels in the presence of LPVr despite reaching toxic ivermectin plasma levels. PBPK modeling, guided with TDM in saliva, can be advantageous to evaluate the probability of reaching therapeutic ELF levels in the presence of PDDI, especially in home-treated patients.

Chemotherapeutic drug screening in 3D-Bioengineered human myobundles provides insight into taxane-induced myotoxicities

SummaryTwo prominent frontline breast cancer (BC) chemotherapies commonly used in combination, doxorubicin (DOX) and docetaxel (TAX), are associated with long-lasting cardiometabolic and musculoskeletal side effects. Whereas DOX has been linked to mitochondrial dysfunction, mechanisms underlying TAX-induced myotoxicities remain uncertain. Here, the metabolic and functional consequences of TAX ± DOX were investigated using a 3D-bioengineered model of adult human muscle and a drug dosing regimen designed to resemble in vivo pharmacokinetics. DOX potently reduced mitochondrial respiratory capacity, 3D-myobundle size, and contractile force, whereas TAX-induced acetylation and remodeling of the microtubule network led to perturbations in glucose uptake, mitochondrial respiratory sensitivity, and kinetics of fatigue, without compromising tetanic force generation. These findings suggest TAX-induced remodeling of the microtubule network disrupts glucose transport and respiratory control in skeletal muscle and thereby have important clinical implications related to the cardiometabolic health and quality of life of BC patients and survivors.

Rapamycin nanoparticles improves drug bioavailability in PLAM treatment by interstitial injection

BackgroundPulmonary lymphangiomyomatosis (PLAM) is a rare interstitial lung disease characterized by diffuse cystic changes caused by the destructive proliferation of smooth muscle-like cells or LAM cells. PLAM is more common in young women than other people, and a consensus is lacking regarding PLAM treatment. The clinical treatment of PLAM is currently dominated by rapamycin. By inhibiting the mTOR signaling pathway, rapamycin can inhibit and delay PLAM’s occurrence and development. However, the application of rapamycin also has shortcomings, including the drug’s low oral bioavailability and a high binding rate to hemoglobin, thus significantly decreasing the amount of drug distributed to the lungs.Methods and resultsHere, we developed a new mode of rapamycin administration in which the drug was injected into the intrathecal space after being nanosized; the directional flow characteristics of the liquid in the intrathecal space were exploited to increase the drug content in the interstitial fluid to the greatest extent possible. We studied the rapamycin content in the interstitial fluid and blood after intervaginal space injection (ISI). Compared with oral administration, ISI significantly increased the drug concentration in the lung interstitial fluid.ConclusionsThese results provided new ideas for treating PLAM and optimizing the dosing regimens of drugs with similar characteristics to rapamycin.