Search Results (136)

Background: Sirolimus (SRL, rapamycin) is a clinically important mTOR inhibitor used in immunosuppression, oncology, and cardiovascular drug-eluting devices. Despite its long-standing FDA approval, the human metabolic profile of SRL remains incompletely characterized. SRL is primarily metabolized by CYP3A enzymes in the liver and intestine, but the diversity, pharmacokinetics, and biological activity of its metabolites have been poorly explored due to the lack of structurally identified standards. Methods: To investigate SRL metabolism, we incubated SRL with pooled human liver microsomes (HLM) and isolated the resulting metabolites. Structural characterization was performed using high-resolution mass spectrometry (HRMS) and ion trap MSⁿ. We also applied Density Functional Theory (DFT) calculations to assess the energetic favorability of metabolic transformations and conducted molecular dynamics (MD) simulations to model metabolite interactions within the CYP3A4 active site. Results: We identified 21 unique SRL metabolites, classified into five major structural groups: O-demethylated, hydroxylated, didemethylated, di-hydroxylated, and mixed hydroxylated/demethylated derivatives. DFT analyses indicated that certain demethylation and hydroxylation reactions were energetically preferred, correlating with metabolite abundance. MD simulations further validated these findings by demonstrating the favorable orientation and accessibility of key sites within the CYP3A4 binding pocket. Conclusions: This study provides a comprehensive structural map of SRL metabolism, offering mechanistic insights into the formation of its metabolites. Our integrated approach of experimental and computational analyses lays the groundwork for future investigations into the pharmacodynamic and toxicodynamic effects of SRL metabolites on the mTOR pathway. Full article

Background and Clinical Significance: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by pathogenic variants in TSC1 or TSC2. Cardiac rhabdomyoma is a common prenatal finding and can be associated with severe complications, including pericardial effusion. We administered prenatal sirolimus to mitigate pericardial effusion, which led to postnatal complications. Case Presentation: A 28-year-old pregnant woman with no significant family history underwent routine fetal ultrasound at 28.1 weeks of gestation, which identified a large right ventricular mass consistent with rhabdomyoma. Further fetal brain MRI revealed cortical-subcortical tubers and subependymal nodules, leading to a clinical diagnosis of TSC. At 30.4 weeks, oral sirolimus (3 mg/day) was started due to the significant pericardial effusion. The effusion remained after treatment, requiring pericardiocentesis at 33.6 weeks. The sirolimus dosage was raised to 6 mg/day at 35.6 weeks, reaching a plasma level of 3.76 ng/mL, but there was no discernible improvement because of the continued fluid accumulation. The mother did not experience any adverse side effects from the procedure. Genetic testing confirmed a pathogenic variant in TSC2 (c.1372C>T). After birth, the neonate received a single dose of sirolimus but subsequently developed necrotizing enterocolitis (NEC), highlighting the potential adverse effects and the need for cautious consideration of treatment options. Conclusions: This case illustrates the complexities of managing prenatal tuberous sclerosis complex (TSC). While sirolimus has been explored for fetal cardiac rhabdomyoma and associated complications, its effectiveness in resolving pericardial effusion remains uncertain. Additionally, the development of NEC postnatally raises concerns about the safety of mTOR inhibitors in this context. Further studies are necessary to assess the risks and benefits of this approach in fetal therapy. Full article

Background: Congenital hepatic hemangiomas (CHHs) are typically considered rapidly involuting tumors, similar to their cutaneous counterparts (RICHs). However, non-involuting tumors remain poorly characterized. This study examines the evolutionary patterns and management strategies for non-involuting congenital hepatic hemangiomas (NICHHs). Methods: We conducted a retrospective review of clinical, imaging, histological, and genetic data of children diagnosed with NICHH—defined as showing no signs of involution for at least 18 months—between 1991 and 2022. Results: Seven patients (five females, two males) were identified. The median age at diagnosis was 42 days (range: 0–1440). Five patients had asymptomatic lesions, predominantly located in the right hepatic lobe. Histologic confirmation was available in three cases, and a GNAQ gene mutation was identified in one. The median follow-up period was 75 months (range: 35–191). Three patients with giant NICHH were treated with sirolimus, resulting in partial response in two cases and lesion stabilization in one. The four untreated patients showed diverse evolutionary patterns, including delayed involution and tardive growth. Conclusions: NICHH lesions demonstrate distinct long-term evolution. Accurate diagnosis and regular monitoring are essential to avoid unnecessary interventions. Sirolimus may offer a promising non-surgical treatment for select patients, particularly those with giant lesions. Full article

Immunosuppressants are essential for preventing allograft rejection; however, they require therapeutic drug monitoring to maintain efficacy and to prevent severe complications such as opportunistic infections. Calcineurin inhibitors (CIs) are primarily distributed in red blood cells, whereas mycophenolic acid (MPA) and its metabolites are found in plasma. These differences necessitate separate analyses for each drug, increasing laboratory workload, analytical complexity, and patient burden. We developed a liquid chromatography–tandem mass spectrometry method for simultaneous quantification of CIs such as tacrolimus (Tac), everolimus (Eve), sirolimus (Sir), cyclosporine A (CycA) and MPA in 2.8-µL whole-blood samples, with a hematocrit-based correction to estimate plasma-equivalent MPA concentrations. Performance of this method was assessed by comparison with conventional immunoassay results using linear regression and Bland–Altman analyses, demonstrating excellent agreement, with strong linearity (R² > 0.995) at <2 to 35 ng/mL for three CIs, 26.0 to 1866 ng/mL for CycA, and 0.1 to 50 μg/mL for MPA. Furthermore, MPA and tacrolimus concentrations closely aligned with routine clinical results (R² > 0.900), indicating high accuracy and reproducibility. This new approach may be particularly beneficial for hospitalized patients with limited venous access, pediatric populations, and in remote care settings where frequent blood sampling is challenging because of simultaneous quantification and fewer sample volume requirements. Full article

Background/Objectives: The administration of human monoclonal antibodies (mAb) in preclinical pharmacokinetics and toxicology studies often triggers an immune response, leading to the formation of anti-drug antibodies (ADA). To mitigate this effect, we have recently performed and reported on studies using short-term immunosuppressive regimens to induce prolonged immune tolerance towards a human mAb, erenumab, in rats. Here, we report on the development of a semi-mechanistic modeling approach that quantitatively integrates pharmacokinetic and immunogenicity assessments from immune tolerance induction studies to provide a framework for the simulation-based evaluation of different immune induction scenarios for the maintenance of prolonged immune tolerance towards human mAbs. Methods: The integrated pharmacokinetic/pharmacodynamic (PK/PD) modeling approach combined a semi-mechanistic model of the adaptive immune system to predict ADA formation kinetics with a population pharmacokinetic model to assess the impact of the time course of the ADA magnitude on the PK of erenumab in rats. Model-derived erenumab concentration–time profiles served as input for a quantitative system pharmacology-style semi-mechanistic model of the adaptive immune system to conceptualize the ADA response as a function of the kinetics of CD4⁺ T helper cells and T regulatory cells. Results: The model adequately described the observed ADA magnitude–time profiles in all treatment groups and reasonably simulated the kinetics of selected immune cells responsible for ADA formation. It also successfully captured the impact of tacrolimus/sirolimus immunomodulation on ADA formation, demonstrating that the regimen effectively suppressed ADA formations and induced immune tolerance. Conclusions: This work demonstrates the utility of modeling approaches to integrate pharmacokinetic and immunogenicity assessment data for the prospective planning of long-term toxicology studies to support the preclinical development of mAbs. Full article

Background/Objectives: Prolonged use of immunosuppressive drugs (IMDs) is correlated with increased risk of cancer in transplant patients. However, detailed side-by-side analysis of cancer risk associated with individual IMDs in the same population is not available. The aim of this study was to identify drug-specific risks of cancer for commonly used transplant IMDs. Methods: We analyzed the risk of cancer for the IMDs commonly used in transplant patients (tacrolimus (TAC), cyclosporin (CY), sirolimus (SIR), mycophenolate (MMF), and their combinations) in Texas Medicare beneficiaries between 2007 and 2018. Results: Of 7721 transplant recipients receiving an IMD of interest, 2261 developed cancer. There was an increased risk of any cancer diagnosis with the use of TAC (HR: 1.49; 95% CI: 1.25–1.78) and CY (HR: 1.51; 95% CI: 1.19–1.92), and decreased risk with use of MMF (HR: 0.77; 95% CI: 0.67–0.89). Cancer-specific models revealed increased risk of liver cancer (HR: 5.25, 95% CI: 2.03–13.61) and decreased risk of ovarian/uterine cancer (HR: 0.25, 95% CI: 0.07–0.84) with TAC; increased risk of lung cancer with CY (HR: 5.06, 95% CI: 1.47–17.41); and increased risk of lymphoma associated with SIR (HR: 2.80, 95% CI: 1.00–7.81). Conclusions: TAC increases cancer risk, and MMF decreases cancer risk. Individual cancer types also vary in risk associated with individual IMDs. This study provides new information on IMD-specific cancer risk that can guide individualized screening/treatment decisions to reduce the risk associated with specific cancers after transplantation. Full article

The evolution of percutaneous coronary intervention (PCI) has led to significant advances in drug-coated balloon (DCB) technology, offering a stent-free alternative for treating coronary artery disease. While paclitaxel-coated balloons (PCBs) have been the standard, sirolimus-coated balloons (SCBs) are emerging as a viable alternative with distinct pharmacokinetic and clinical benefits. This review explores the mechanisms of action of paclitaxel and sirolimus, their impact on different plaque morphologies, and the clinical implications of DCB selection. Paclitaxel facilitates positive vascular remodeling and is particularly effective in fibrotic and lipid-rich plaques, but its poor penetration in calcified lesions remains a limitation. Sirolimus, with its homogeneous tissue distribution and anti-inflammatory properties, is better suited for unstable, lipid-rich, and inflammatory plaques, where it promotes plaque stabilization. Recent randomized trials and meta-analyses have compared SCBs vs. PCBs in both de novo lesions and in-stent restenosis, showing non-inferior outcomes. Additionally, DCBs demonstrate comparable efficacy to DES in small vessel disease, reducing the need for permanent metallic scaffolds. This review summarizes the current evidence on DCB selection based on plaque characteristics and highlights areas for further investigation in personalized PCI strategies. Given the narrative review design, the authors conducted a comprehensive literature search using databases such as PubMed and MEDLINE. Keywords included “drug-coated balloon”, “paclitaxel-coated balloon”, “sirolimus-coated balloon”, “in-stent restenosis”, and “plaque morphology”. Studies were selected based on relevance, including randomized controlled trials, registries, and meta-analyses. No formal inclusion/exclusion criteria or systematic screening were applied due to the nature of narrative synthesis. Full article

Globally, cardiovascular disease is a leading cause of disability and early death, affecting 422.7 million people and causing 17.9 million deaths (31% of global deaths) in 2015. Peripheral arterial disease, previously overlooked compared to coronary artery disease, is now recognised as a major contributor to cardiovascular morbidity and mortality, with distinct characteristics. After noninvasive methods, the femoropopliteal segment is frequently treated with revascularisation, which is recommended for claudication and chronic limb-threatening ischemia (CLTI). Challenges such as mechanical stresses, chronic occlusions, extensive plaque, and calcification affect procedural success and vessel patency. Innovations were needed to address these issues, and vascular drug delivery devices have become integral to endovascular treatment. We review the current literature concerning a diverse range of these devices in clinical use and their role in managing symptomatic patients. Full article

Pancreatic cancer is a deadly disease with a low survival rate, particularly in its advanced stages. Advanced pancreatic cancer remains a major clinical challenge due to limited treatment options. Surgical resection may not always be feasible, and traditional chemotherapy often shows restricted effectiveness. As a result, researchers are exploring a multifaceted therapeutic approach targeting the genetic and molecular drivers of the disease. A combination of molecular profiling and targeted therapies are being investigated to improve outcomes and address the shortcomings of traditional treatments. The focus of this review is to provide a summary of current and completed clinical trials for the treatment of advanced pancreatic cancer. This includes adagrasib (a KRAS inhibitor), olaparib (a PARP inhibitor for BRCA mutations), APG-1387 (an IAP antagonist), minnelide (an anti-stromal agent), arimastat (an MMP inhibitor), MK-0646 (an IGF1R inhibitor), sirolimus (an mTOR inhibitor), and metabolic inhibitors. These agents are being evaluated both as standalone treatments and in combination with standard therapy. Furthermore, we have summarized novel approaches such as cancer vaccines and ablation techniques as emerging strategies in the treatment of advanced pancreatic cancer. We have also examined the challenges in treating advanced pancreatic cancer and the factors contributing to therapeutic failure, which may offer valuable insights for developing more effective treatment strategies and innovative drug designs. Full article

Drug-eluting stents, which release antiproliferative agents such as sirolimus and everolimus, were developed to reduce the risk of restenosis associated with bare-metal stents. However, despite their proven clinical efficacy, concerns remain regarding in-stent restenosis due to delayed endothelial healing and the risk of late thrombotic events. In this study, we aimed to determine the vascular effects of sirolimus and everolimus on isolated human saphenous vein (SV) samples obtained from patients undergoing coronary artery bypass surgery. SV rings were subjected to sirolimus and everolimus in acute and pretreatment conditions in vitro. Increasing concentrations of sirolimus (10⁻⁸–10⁻⁵ M), everolimus (10⁻⁸–10⁻⁵ M), and their vehicle were administered to SV rings precontracted with phenylephrine (Phe,10⁻⁶–5 × 10⁻⁶ M) to evaluate their direct vascular effects. Additionally, SV rings were incubated (16 h) either with sirolimus (10⁻⁵ M), everolimus (10⁻⁶ M), or the vehicle. Thereafter, the contractile responses to Phe (10⁻⁸–10⁻⁴ M), and the endothelium-dependent and endothelium-independent relaxant responses to acetylcholine (ACh, 10⁻⁸–10⁻⁴ M) and sodium nitroprusside (SNP,10⁻⁸–10⁻⁴ M) were determined, respectively. Our findings demonstrated that sirolimus and everolimus did not exert direct relaxant and modulatory effects on vascular function in isolated human SVs. Hence, the preservation of contractile and relaxant responses with sirolimus and everolimus may have clinical implications in the context of DES implantation. Full article

Lymphatic malformations (LMs) are benign, congenital vascular anomalies caused by abnormal lymphangiogenesis during embryology, often presenting as fluid-filled cystic lesions. Though LMs can affect any part of the body except the brain, they primarily manifest in the head and neck or axilla regions of children. With a prevalence of approximately 1 in 4000 births, LMs are commonly diagnosed by age two, with symptoms varying based on lesion location and size. This paper reviews the classification of LMs and discusses the de Serres staging system, which aids in assessing prognosis based on lesion site. Mutations in the (PIK3CA) gene are implicated in most cases, and LMs are also associated with syndromic conditions like Turner and Noonan syndromes. They are diagnosed by ultrasound (USS) or magnetic resonance imaging (MRI), while a histologic analysis can confirm lymphatic origin. Treatment options range from conservative approaches, such as observation, to sclerotherapy, pharmacotherapy, and surgery. Sclerotherapy, particularly with agents like OK-432, bleomycin, and doxycycline, has shown significant efficacy in reducing LM size and symptoms with minimal side effects. Pharmacological therapies, such as sirolimus, that target the mTOR pathway are also increasingly being used, with a good effect on the burden of disease. While surgical excision remains a choice for symptomatic or large lesions, minimally invasive approaches are often preferred due to lower morbidity. Emerging techniques include gravity-dependent sclerotherapy, electrosclerotherapy, alpelisib, everolimus, and Wnt/β-catenin pathway stimulators (e.g., tankyrase inhibitors, porcupine inhibitors). Computational atomistic molecular dynamics (MD) and density functional tight binding (DFTB) techniques may offer an experimental approach to future therapeutic targets. This paper highlights a multidisciplinary approach to LM management, emphasising individualised treatment based on lesion characteristics and patient needs. Full article

Introduction: Percutaneous coronary intervention (PCI) with drug-eluting stents (DES) is a cornerstone of the management of ischemic heart disease. However, in-stent restenosis (ISR) remains a significant clinical challenge, occurring in approximately 5–10% of patients undergoing PCI. This study is designed to compare the efficacy and safety of the primary therapeutic approaches for DES-ISR, specifically drug-coated balloons (DCBs)—paclitaxel-coated balloons (PCBs) and sirolimus-coated balloons (SCBs)—with a new-generation everolimus-eluting stent (EES), contributing to the evolving field of personalized medicine. Methods and Analysis: This prospective, multicentre, randomised, non-inferiority trial aims to enroll 150 patients with DES-ISR, who will be randomised into one of the following: SCB, PCB, or EES. The primary endpoint comparing DCB and EES is late lumen loss (LLL) at 6 months, as measured by quantitative coronary angiography (QCA). Secondary endpoints comparing the three arms include a device-oriented composite endpoint, intraluminal gain, optical coherence tomography (OCT) measured LLL, and correlations between LLL and quantitative flow ratio (QFR). The primary endpoint will be analysed using a non-inferiority design, with a margin set at 0.25 mm, for which the sample size was calculated. Statistical analysis of the primary endpoint will be conducted on an intention-to-treat basis with a one-tailed Mann–Whitney U test with a significance level of 95. Secondary endpoints will be analysed via superiority testing using ANOVA, the Kruskal–Wallis test, logistic regression, or Fisher’s exact test, as appropriate. Ethics and Dissemination: The study protocol has been approved by the Medical Devices Department of the Hungarian National Institute of Pharmacy and Nutrition, ensuring compliance with ethical standards as outlined in the Declaration of Helsinki. All investigators declare no conflicts of interest related to this study. The trial is registered in ClinicalTrials.gov under the ID: NCT04862052. Full article

Background: mTOR-Is positively influence the occurrence and course of certain tumors after solid organ transplantation. mTOR-inhibitor (mTOR-I) treatment, either alone or in combination with Calcineurininhibitors (CNIs), significantly reduces the incidence of malignancies after organ transplantation. However, there is no information on which mTOR-I, Sirolimus (SIR) or Everolimus (ERL), has a stronger anti-tumoral effect. Methods: The current literature was searched for prospective randomized controlled trials in renal transplantation. There were 1.164 trials screened, of which 20 could be included (7465 patients). We performed a network meta-analysis to analyze the relative risk of different types of mTOR-I compared to CNI treatment on malignancies after transplantation. A minimum follow-up of 24 months was mandatory for inclusion. Results: Four different types of mTOR-I treatment were analyzed in network meta-analyses—SIR mono, ERL mono, SIR with CNI, and ERL with CNI. The average follow-up of all trials was 43.8 months. All four different mTOR-I regimes showed a significant reduced relative risk for malignancies compared to a regular CNI-treatment with the strongest effect under SIR in combination with a CNI (RR 0.23, CI 0.09–0.55, p = 0.001). This effect remained consistent for all tumor entities except non-melanoma skin cancer (RR 0.25, CI 0.07–0.90, p = 0.033). Conclusions: It is well known that an mTOR-I based treatment in transplant patients reduces the risk of tumor manifestation in comparison to CNI treatment. A combination of SIR and CNI seems to be the most potent mTOR-I therapy against malignancies. Full article

Lymphangioleiomyomatosis (LAM) is a rare, progressive, and poor-prognosis systemic disorder that primarily affects women of reproductive age, with a higher prevalence among individuals of Caucasian origin. However, there are limited reliable data on the prevalence of LAM during pregnancy. The fulminant respiratory clinical presentation that often includes progressive dyspnea on exertion, cough, or hemoptysis, frequently complicated by pneumothorax, and the increased risk of spontaneous abortion due to increased estrogen and progesterone production during gestation, are arguments that most often make the diagnosed woman avoid pregnancy. Elevated levels of vascular endothelial growth factor D (VEGF-D), decline in respiratory function, and radiological findings are sufficient arguments in favor of the diagnosis in the pregnant woman. Sirolimus, an mTOR inhibitor, has demonstrated effectiveness in slowing the decline of lung function. Although sirolimus treatment is often recommended to be discontinued before conception due to the increased risk of fetal growth restriction, maintaining a dose level of <5 pcg/mL, with serum drug levels of 3–5 pcg/L, has been considered safe. Given the potential risks, individualized decisions about pregnancy are advised for patients with LAM. For those who choose to proceed, close monitoring by a multidisciplinary team is essential to manage complications effectively. Ongoing research aims to provide clearer guidance to optimize outcomes for both mother and child. Full article

Background: Sirolimus-coated balloons (SCBs) have emerged as a promising alternative to paclitaxel-coated devices for the treatment of femoropopliteal lesions. However, real-world data on SCB performance in also complex peripheral arterial disease remains unknown. We sought to evaluate the safety and 12-month clinical outcomes of the Selution SLR™ balloon angioplasty in a challenging real-world patient cohort. Methods: This single-center, retrospective observational study with prospective follow-up included 21 patients with symptomatic peripheral arterial disease treated with the Selution SLR™ SCB (Med. Alliance, SA, Mont-sur-Rolle, Switzerland) after vessel preparation with rotational atherectomy, between October 2023 and November 2024. The primary endpoints were technical success, 12-month primary patency, and target lesion revascularization (TLR). Secondary endpoints included major adverse cardiac events (MACE), major adverse limb events (MALE), and changes in Rutherford classification and ankle-brachial index (ABI). Results: The median age was 79 years, with 47.6% of patients over 80 years old. Most patients presented with advanced peripheral atherosclerotic disease (PAD) (Rutherford category V, 47.6%). Lesions were predominantly occlusive (76.2%), with a median length of 130 mm and severe/moderate calcified in 71.4% of cases. Technical success was achieved in 95.2% of procedures. The 12-month primary patency was 95%, with a TLR-Rate of 5%. No major amputations or cardiovascular deaths occurred. Significant improvements in Rutherford category and ABI were maintained at 12 months. Conclusions: In this real-world cohort of patients with complex PAD, vessel preparation-assisted Selution SLR™ angioplasty demonstrated safety and promising 12-month outcomes. These findings support the use of SCBs in also challenging peripheral interventions, though larger-scale data and further follow up are needed in order to establish SCBs’ role as crucial in the treatment algorithm of PAD. Full article