RESUMEN
PURPOSE: To compare the endothelial coverage of different stents in porcine carotid arteries. Research problem: How effective are polyurethane stents (PU) and PU + rapamycin (PU + RAPA) compared to bare-metal stents on endothelial coverage by neointima in pigs after 28 days? METHODS: The methodology had two phases for an interventional, experimental, prospective study, with three Moura pigs, 12 weeks old and weighing between 19 and 22.5 kg. In phase I, eight stents were implanted in carotid arteries; three stents coated with PU, three coated with PU + RAPA, and two without coating. After 28 days, phase II was carried out, consisting of euthanasia, removal of the stents, to evaluate the exposed area of the stent struts, and the percentage of endothelialization through optical microscopy and scanning electron microscopy. RESULTS: The eight stents implanted with ultrasound sizing and post-dilation with a larger diameter balloon were analyzed by Doppler ultrasound, intravascular ultrasound, and angiography after 28 days. CONCLUSIONS: This study showed complete endothelial coverage by the endoluminal neointima of the stent struts, good integration and coverage with the arterial wall, with no exposed struts showing the presence of intimal hyperplasia (whitish tissue).
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Stents Liberadores de Fármacos , Sirolimus , Animales , Sirolimus/administración & dosificación , Sirolimus/farmacología , Porcinos , Arterias Carótidas/cirugía , Arterias Carótidas/efectos de los fármacos , Neointima/patología , Microscopía Electrónica de Rastreo , Poliuretanos , Estudios Prospectivos , Endotelio Vascular/efectos de los fármacos , Reproducibilidad de los Resultados , Polímeros , Modelos Animales , Factores de Tiempo , Materiales Biocompatibles RevestidosRESUMEN
BACKGROUND: The long-term impact of drug-coated balloon (DCB) angioplasty for the treatment of patients with de novo coronary artery lesions remains uncertain. We aimed to assess the non-inferiority of DCB angioplasty with rescue stenting to intended drug-eluting stent (DES) deployment for patients with de novo, non-complex coronary artery lesions. METHODS: REC-CAGEFREE I was an open-label, randomised, non-inferiority trial conducted at 43 sites in China. After successful lesion pre-dilatation, patients aged 18 years or older with de novo, non-complex coronary artery disease (irrespective of target vessel diameter) and an indication for percutaneous coronary intervention were randomly assigned (1:1), via a web-based centralised system with block randomisation (block size of two, four, or six) and stratified by site, to paclitaxel-coated balloon angioplasty with the option of rescue stenting due to an unsatisfactory result (DCB group) or intended deployment of second-generation thin-strut sirolimus-eluting stents (DES group). The primary outcome was the device-oriented composite endpoint (DoCE; including cardiovascular death, target vessel myocardial infarction, and clinically and physiologically indicated target lesion revascularisation) assessed at 24 months in the intention-to-treat (ITT) population (ie, all participants randomly assigned to treatment). Non-inferiority was established if the upper limit of the one-sided 95% CI for the absolute risk difference was smaller than 2·68%. Safety was assessed in the ITT population. This study is registered with ClinicalTrials.gov, NCT04561739. It is closed to accrual and extended follow-up is ongoing. FINDINGS: Between Feb 5, 2021, and May 1, 2022, 2272 patients were randomly assigned to the DCB group (1133 [50%]) or the DES group (1139 [50%]). Median age at the time of randomisation was 62 years (IQR 54-69), 1574 (69·3%) of 2272 were male, 698 (30·7%) were female, and all patients were of Chinese ethnicity. 106 (9·4%) of 1133 patients in the DCB group received rescue DES after unsatisfactory DCB angioplasty. As of data cutoff (May 1, 2024), median follow-up was 734 days (IQR 731-739). At 24 months, the DoCE occurred in 72 (6·4%) of 1133 patients in the DCB group and 38 (3·4%) of 1139 in the DES group, with a risk difference of 3·04% in the cumulative event rate (upper boundary of the one-sided 95% CI 4·52; pnon-inferiority=0·65; two-sided 95% CI 1·27-4·81; p=0·0008); the criterion for non-inferiority was not met. During intervention, no acute vessel closures occurred in the DCB group and one (0·1%) of 1139 patients in the DES group had acute vessel closure. Periprocedural myocardial infarction occurred in ten (0·9%) of 1133 patients in the DCB group and nine (0·8%) in the DES group. INTERPRETATION: In patients with de novo, non-complex coronary artery disease, irrespective of vessel diameter, a strategy of DCB angioplasty with rescue stenting did not achieve non-inferiority compared with the intended DES implantation in terms of the DoCE at 2 years, which indicates that DES should remain the preferred treatment for this patient population. FUNDING: Xijing Hospital and Shenqi Medical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
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Angioplastia Coronaria con Balón , Enfermedad de la Arteria Coronaria , Stents Liberadores de Fármacos , Paclitaxel , Humanos , Masculino , Femenino , Persona de Mediana Edad , Angioplastia Coronaria con Balón/métodos , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Enfermedad de la Arteria Coronaria/terapia , Anciano , Sirolimus/uso terapéutico , Sirolimus/administración & dosificación , Resultado del Tratamiento , Materiales Biocompatibles Revestidos , China/epidemiología , Intervención Coronaria Percutánea/métodosRESUMEN
BACKGROUND: Vascular malformations (VaMs) are caused by errors in vascular morphogenesis. Diagnosis and treatment can be complex. Few specialized centers care for these patients, and limited literature exists regarding their characteristics and clinical course. The vascular anomalies clinic (VAC) at the Instituto Nacional de Pediatría (National Institute for Pediatrics) is a multidisciplinary team and has been a reference center for patients with VaMs since 2012. We sought to describe the characteristics of patients cared for at the VAC, types of VaMs, treatments used, and clinical course. METHODS: This was a descriptive, observational, retrospective, and cross-sectional study conducted from 2012 to 2022. RESULTS: We included 435 patients with VaMs; the median age of presentation was 1 month. The most frequent signs and symptoms were increased volume (97.2%), superficial color change (65.5%), and pain (43.3%). The most common VaMs were lymphatic (36.7%) and venolymphatic (18.3%). Sclerotherapy was the most frequent treatment (73.4%), followed by medical treatment with sirolimus (18.5%); response to both was excellent/good in > 85% of cases. CONCLUSION: In this retrospective study of children with VaMs, we found that low-flow malformations were the most common, and sclerotherapy and sirolimus were the most frequently used treatments. The therapeutic response was excellent/good in most cases.
INTRODUCCIÓN: Las malformaciones vasculares (MaV) son secundarias a errores en la morfogénesis vascular. El diagnóstico y tratamiento puede ser complejo. Existen pocos centros especializados en su atención y escasa literatura respecto a características y evolución clínica. La Clínica de Anomalías Vasculares (CAV) del Instituto Nacional de Pediatría es un equipo multidisciplinario y centro de referencia para estos pacientes desde 2012. Buscamos describir las características de los pacientes atendidos en la CAV, tipo de MaV, tratamiento y evolución clínica. MÉTODOS: Estudio descriptivo, observacional, retrospectivo y transversal del periodo 2012 al 2022. RESULTADOS: Se incluyeron 435 pacientes con MaV, con edad mediana de presentación de 1 mes de vida. Los síntomas y signos más reportados fueron aumento de volumen (97.2%), cambio en coloración de la piel (65.5%) y dolor (43.3%). Las MaV más comunes fueron linfáticas (36.7%), siguiéndoles las venolinfáticas (18.3%). La escleroterapia fue el tratamiento más frecuente (73.4%) y el tratamiento médico más utilizado fue sirolimus (18.5%), ambos con excelente/buena respuesta en > 85% de los pacientes. CONCLUSIONES: En este estudio retrospectivo de niños con MaV encontramos que las más frecuentes son de bajo flujo y el tratamiento más usado escleroterapia y sirolimus. La respuesta terapéutica de la mayoría fue excelente/buena.
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Escleroterapia , Malformaciones Vasculares , Humanos , Estudios Retrospectivos , Malformaciones Vasculares/terapia , Malformaciones Vasculares/diagnóstico , Lactante , Masculino , Femenino , Estudios Transversales , Preescolar , Niño , Recién Nacido , Escleroterapia/métodos , Sirolimus/administración & dosificación , Adolescente , Resultado del TratamientoAsunto(s)
Rabdomioma , Sirolimus , Humanos , Femenino , Embarazo , Rabdomioma/diagnóstico por imagen , Rabdomioma/tratamiento farmacológico , Rabdomioma/embriología , Sirolimus/uso terapéutico , Sirolimus/administración & dosificación , Adulto , Intercambio Materno-Fetal , Antibióticos Antineoplásicos/uso terapéuticoRESUMEN
Rationale: Autism spectrum disorder (ASD) represents a complex neurodevelopmental condition lacking specific pharmacological interventions. Given the multifaced etiology of ASD, there exist no effective treatment for ASD. Rapamycin (RAPA) can activate autophagy by inhibiting the mTOR pathway and has exhibited promising effects in treating central nervous system disorders; however, its limited ability to cross the blood-brain barrier (BBB) has hindered its clinical efficacy, leading to substantial side effects. Methods: To address this challenge, we designed a drug delivery system utilizing red blood cell membrane (CM) vesicles modified with SS31 peptides to enhance the brain penetration of RAPA for the treatment of autism. Results: The fabricated SCM@RAPA nanoparticles, with an average diameter of 110 nm, exhibit rapid release of RAPA in a pathological environment characterized by oxidative stress. In vitro results demonstrate that SCM@RAPA effectively activate cellular autophagy, reduce intracellular ROS levels, improve mitochondrial function, thereby ameliorating neuronal damage. SS31 peptide modification significantly enhances the BBB penetration and rapid brain accumulation of SCM@RAPA. Notably, SCM@RAPA nanoparticles demonstrate the potential to ameliorate social deficits, improve cognitive function, and reverse neuronal impairments in valproic acid (VPA)-induced ASD models. Conclusions: The therapeutic potential of SCM@RAPA in managing ASD signifies a paradigm shift in autism drug treatment, holding promise for clinical interventions in diverse neurological conditions.
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Trastorno del Espectro Autista , Autofagia , Barrera Hematoencefálica , Nanopartículas , Estrés Oxidativo , Sirolimus , Sirolimus/administración & dosificación , Sirolimus/farmacología , Estrés Oxidativo/efectos de los fármacos , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/metabolismo , Animales , Autofagia/efectos de los fármacos , Nanopartículas/química , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Ratones , Humanos , Sistemas de Liberación de Medicamentos/métodos , Modelos Animales de Enfermedad , Masculino , Materiales Biomiméticos/administración & dosificación , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Biomimética/métodos , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Péptidos/administración & dosificación , Especies Reactivas de Oxígeno/metabolismo , Ácido Valproico/administración & dosificación , Ácido Valproico/farmacologíaRESUMEN
Purpose: Ovarian cancer has the highest mortality rate and lowest survival rate among female reproductive system malignancies. There are treatment options of surgery and chemotherapy, but both are limited. In this study, we developed and evaluated micelles composed of D-α-tocopheryl polyethylene-glycol (PEG) 1000 succinate (TPGS) and Soluplus® (SOL) loaded with olaparib (OLA), a poly(ADP-ribose)polymerase (PARP) inhibitor, and rapamycin (RAPA), a mammalian target of rapamycin (mTOR) inhibitor in ovarian cancer. Methods: We prepared micelles containing different molar ratios of OLA and RAPA embedded in different weight ratios of TPGS and SOL (OLA/RAPA-TPGS/SOL) were prepared and physicochemical characterized. Furthermore, we performed in vitro cytotoxicity experiments of OLA, RAPA, and OLA/RAPA-TPGS/SOL. In vivo toxicity and antitumor efficacy assays were also performed to assess the efficacy of the mixed micellar system. Results: OLA/RAPA-TPGS/SOL containing a 4:1 TPGS:SOL weight ratio and a 2:3 OLA:RAPA molar ratio showed synergistic effects and were optimized. The drug encapsulation efficiency of this formulation was >65%, and the physicochemical properties were sustained for 180 days. Moreover, the formulation had a high cell uptake rate and significantly inhibited cell migration (**p < 0.01). In the in vivo toxicity test, no toxicity was observed, with the exception of the high dose group. Furthermore, OLA/RAPA-TPGS/SOL markedly inhibited tumor spheroid and tumor growth in vivo. Conclusion: Compared to the control, OLA/RAPA-TPGS/SOL showed significant tumor inhibition. These findings lay a foundation for the use of TPGS/SOL mixed micelles loaded with OLA and RAPA in the treatment of ovarian cancer.
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Micelas , Neoplasias Ováricas , Ftalazinas , Piperazinas , Polietilenglicoles , Polivinilos , Sirolimus , Vitamina E , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Piperazinas/química , Piperazinas/farmacología , Polietilenglicoles/química , Humanos , Animales , Línea Celular Tumoral , Vitamina E/química , Vitamina E/farmacología , Sirolimus/química , Sirolimus/farmacología , Sirolimus/administración & dosificación , Sirolimus/farmacocinética , Ftalazinas/química , Ftalazinas/farmacología , Ftalazinas/administración & dosificación , Ftalazinas/farmacocinética , Polivinilos/química , Polivinilos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/administración & dosificación , Ratones , Portadores de Fármacos/química , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Desnudos , Ratones Endogámicos BALB C , Supervivencia Celular/efectos de los fármacosRESUMEN
The activation of tumor cell immunogenicity through oxaliplatin (OXP)-induced immunogenic cell death (ICD) has significant implications in cancer treatment. However, the anti-tumor effect of OXP monotherapy still has many shortcomings, and the systemic administration of OXP leads to low drug concentration at the tumor site, which is susceptible to systemic toxic side effects. In this study, a combined therapeutic strategy using folate-modified nanoliposomes co-delivered with rapamycin (Rapa) and OXP (abbreviated as FA@R/O Lps) is proposed for the treatment of colorectal cancer (CRC). Rapa and OXP can directly inhibit tumor cell proliferation and induce apoptosis. OXP induces ICD by triggering the release of danger signals, such as HMGB1, ATP, and calreticulin. FA@R/O Lps with a particle size of about 134.1±1.8â¯nm and a small dispersion were successfully prepared. This novel liposomal system can be used to target and increase drug accumulation in tumors. In-vivo experiments showed that FA@R/O Lps successfully inhibit CRC growth and liver metastasis, and simultaneously reduce off-target toxicity. In particular, FA@R/O Lps showed greater therapeutic effects than free Rapa/OXP and R/O Lps. Taken together, this study provides a novel combination of Rapa and OXP, and a nano-delivery system for enhanced anti-CRC efficacy. The results suggest that FA@R/O Lps could be a promising strategy for the treatment of CRC.
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Proliferación Celular , Neoplasias Colorrectales , Liposomas , Ratones Endogámicos BALB C , Oxaliplatino , Sirolimus , Oxaliplatino/farmacología , Oxaliplatino/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Animales , Sirolimus/farmacología , Sirolimus/administración & dosificación , Humanos , Proliferación Celular/efectos de los fármacos , Ratones , Línea Celular Tumoral , Ratones Desnudos , Apoptosis/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Compuestos Organoplatinos/farmacología , Compuestos Organoplatinos/administración & dosificación , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Ácido Fólico/química , Ácido Fólico/administración & dosificación , MasculinoRESUMEN
INTRODUCTION: Percutaneous coronary intervention (PCI) with drug-eluting stents (DES) in complex coronary artery disease (CAD) has been established as the standard of care, but stent-related events are not uncommon. Sirolimus-Coated Balloon (SCB)-based angioplasty is an emerging technology, although it needs to be thoroughly evaluated compared with DES in the complex PCI setting. This study aimed to investigate the safety and efficacy of SCB-based angioplasty compared with new-generation DES in complex PCI. METHODS: Net adverse cardiovascular events (NACE: all-cause death, target lesion revascularization, non-fatal myocardial infarction, and major bleedings according to BARC classification), as a primary study endpoint was compared between SCB and new-generation DES for complex coronary lesions. RESULTS: Among 1782 patients with complex CAD, 1076 were treated with a sirolimus-coated balloon (EASTBOURNE Registry) and 706 with new-generation DES (COMPLEX Registry). After propensity score matching, a total of 512 patients in both groups were analyzed. NACE occurred more significantly in the DES group during the 1-year follow-up (10.5% vs. 3.9%, p = 0.003), mainly due to a higher risk of bleeding (6.6% vs. 0.4%, p = 0.001). The Cox model adjusted for lesion length showed a significantly lower hazard of NACE (HR: 0.23, CI [0.10, 0.52], p < 0.001) and all-cause mortality (HR: 0.07, CI [0.01, 0.66], p = 0.020) in SCB compared to DES group. CONCLUSIONS: SCB angioplasty has an advantage over DES for the treatment of complex CAD regarding NACE, significantly reducing the incidence of major bleeding without increasing ischemic endpoints. SCB may be an alternative to DES in selected patients with complex coronary lesions.
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Angioplastia Coronaria con Balón , Enfermedad de la Arteria Coronaria , Stents Liberadores de Fármacos , Puntaje de Propensión , Sirolimus , Humanos , Sirolimus/administración & dosificación , Masculino , Femenino , Anciano , Persona de Mediana Edad , Enfermedad de la Arteria Coronaria/cirugía , Enfermedad de la Arteria Coronaria/terapia , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Angioplastia Coronaria con Balón/métodos , Angioplastia Coronaria con Balón/instrumentación , Angioplastia Coronaria con Balón/efectos adversos , Sistema de Registros , Estudios de Seguimiento , Resultado del Tratamiento , Materiales Biocompatibles RevestidosRESUMEN
In the realm of arterial disease interventions, drug-eluting stents (DES) have become a vital therapeutic choice in preventing atherosclerotic plaque formation and restenosis and facilitating vessel healing. Sirolimus-encapsulated poly Lactic-co-Glycolic acid (PLGA) Microparticles (MPs) were developed using solvent evaporation. MPs were freeze-dried with a cryoprotectant and coated on the stent surface using an efficient and reproducible nitrogen-assisted spray coating technique. The MPs displayed a uniform distribution particle size of 4.38 ± 1.1 µm, span value of 0.88 ± 0.02, coating mass transfer efficiency of 13.45 ± 1.1 % on the stent, and a coating time of ≤ 2 min per stent. Post sterilization, the particle size and morphology of the coated stents remained unchanged. Accelerated in vitro drug release profiles were evaluated under different conditions, indicating significant influences based on dissolution methods ranging from 28.2 %±4.3 %, 42.5 %±5.3 %, 76.6 %±4.7 %, and 84.25 %±3.1 % for dialysis bag (DB), vessel simulating flow-through cell (vFTC), flow-through cell (FTC), and sample and separate (SS) technique respectively for 48 h. The drug release mechanism from the coated stents is governed by the combination of the Korsmeyer Peppas and Higuchi models. The developed dissolution method exhibited discriminative effectiveness when evaluated with critical formulation attributes and process parameter variations. The 48 h accelerated drug release studies correlated well with the 6-month real-time release rate with an R2 value of 0.9142 and Pearson's R2 of 0.9561. Ex-vivo studies demonstrated the permeation of MPs into artery tissues. Stability studies confirmed that MPs coated stents maintained desired properties at 4 °C and 30 °C/65 % RH for 6 months. Overall, these findings contribute to advancing stent technology, suggesting the potential for improvement of arterial interventions and enhanced patient outcomes.
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Liberación de Fármacos , Stents Liberadores de Fármacos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Sirolimus , Sirolimus/administración & dosificación , Sirolimus/farmacocinética , Sirolimus/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Tamaño de la PartículaRESUMEN
Dose optimization of sirolimus may further improve outcomes in allogeneic hematopoietic cell transplant (HCT) patients receiving post-transplantation cyclophosphamide (PTCy) to prevent graft-versus-host disease (GVHD). Sirolimus exposure-response association studies in HCT patients (i.e., the association of trough concentration with clinical outcomes) have been conflicting. Sirolimus has important effects on T-cells, including conventional (Tcons) and regulatory T-cells (Tregs), both of which have been implicated in the mechanisms by which PTCy prevents GVHD, but there is an absence of validated biomarkers of sirolimus effects on these cell subsets. Considering the paucity of existing biomarkers and the complexities of the immune system, we conducted a literature review to inform a quantitative systems pharmacology (QSP) model of GVHD. The published literature presented multiple challenges. The sirolimus pharmacokinetic models insufficiently describe sirolimus distribution to relevant physiological compartments. Despite multiple publications describing sirolimus effects on Tcons and Tregs in preclinical and human ex vivo models, consistent parameters relating sirolimus concentrations to circulating Tcons and Tregs could not be found. Each aspect presents a challenge in building a QSP model of sirolimus and its temporal effects on T-cell subsets and GVHD prevention. To optimize GVHD prevention regimens, phase I studies and systematic studies of immunosuppressant concentration-effect association are needed for QSP modeling.
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Ciclofosfamida , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Inmunosupresores , Sirolimus , Humanos , Sirolimus/administración & dosificación , Enfermedad Injerto contra Huésped/prevención & control , Enfermedad Injerto contra Huésped/inmunología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Ciclofosfamida/efectos adversos , Inmunosupresores/administración & dosificación , Inmunosupresores/farmacocinética , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Animales , Modelos BiológicosAsunto(s)
Angioplastia Coronaria con Balón , Paclitaxel , Sirolimus , Animales , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Sirolimus/administración & dosificación , Sirolimus/uso terapéutico , Conejos , Angioplastia Coronaria con Balón/instrumentación , Angioplastia Coronaria con Balón/métodos , Modelos Animales de Enfermedad , Stents Liberadores de Fármacos , Materiales Biocompatibles Revestidos , Vasos Coronarios/diagnóstico por imagen , Vasos Coronarios/efectos de los fármacosAsunto(s)
Paclitaxel , Sirolimus , Animales , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Sirolimus/administración & dosificación , Conejos , Angioplastia Coronaria con Balón/instrumentación , Angioplastia Coronaria con Balón/métodos , Stents Liberadores de Fármacos , Modelos Animales de Enfermedad , Materiales Biocompatibles RevestidosRESUMEN
BACKGROUND: Evidence suggests that drug-coated balloons may benefit in-stent restenosis (ISR) treatment. However, the efficacy of new-generation sirolimus-coated balloon (SCB) compared with the latest generation drug-eluting stents (DESs) has not been studied in this setting. METHODS: All patients in the EASTBORNE (The All-Comers Sirolimus-Coated Balloon European Registry) and DEB-DRAGON (DEB vs Thin-DES in DES-ISR: Long Term Outcomes) registries undergoing percutaneous coronary intervention for DES-ISR were included in the study. The primary study end point was target lesion revascularization at 24 months. Secondary end points were major adverse cardiovascular events, all-cause death, myocardial infarction, and target vessel revascularization at 24 months. Our goal was to evaluate the efficacy and safety of SCB versus thin-struts DES in ISR at long-term follow-up. RESULTS: A total of 1545 patients with 1679 ISR lesions were included in the pooled analysis, of whom 621 (40.2%) patients with 621 lesions were treated with thin-strut DES and 924 (59.8%) patients with 1045 lesions were treated with SCB. The unmatched cohort showed no differences in the incidence of target lesion revascularization (10.8% versus 11.8%; P=0.568); however, there was a trend toward lower rates of myocardial infarction (7.4% versus 5.0%; P=0.062) and major adverse cardiovascular events (20.8% versus 17.1%; P=0.072) in the SCB group. After propensity score matching (n=335 patients per group), there were no significant differences in the rates of target lesion revascularization (11.6% versus 11.8%; P=0.329), target vessel revascularization (14.0% versus 13.1%; P=0.822), myocardial infarction (7.2% versus 4.5%; P=0.186), all-cause death (5.7% versus 4.2%; P=0.476), and major adverse cardiovascular event (21.5% versus 17.6%; P=0.242) between DES and SCB treatment. CONCLUSIONS: In patients with ISR, angioplasty with SCB compared with thin-struts DES is associated with comparable rates of target lesion revascularization, target vessel revascularization, myocardial infarction, all-cause death, and major adverse cardiovascular events at 2 years.
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Fármacos Cardiovasculares , Materiales Biocompatibles Revestidos , Reestenosis Coronaria , Stents Liberadores de Fármacos , Sistema de Registros , Sirolimus , Humanos , Masculino , Femenino , Sirolimus/administración & dosificación , Sirolimus/efectos adversos , Anciano , Persona de Mediana Edad , Resultado del Tratamiento , Reestenosis Coronaria/etiología , Reestenosis Coronaria/diagnóstico por imagen , Reestenosis Coronaria/mortalidad , Reestenosis Coronaria/terapia , Factores de Tiempo , Fármacos Cardiovasculares/administración & dosificación , Fármacos Cardiovasculares/efectos adversos , Factores de Riesgo , Angioplastia Coronaria con Balón/instrumentación , Angioplastia Coronaria con Balón/efectos adversos , Angioplastia Coronaria con Balón/mortalidad , Intervención Coronaria Percutánea/efectos adversos , Intervención Coronaria Percutánea/instrumentación , Intervención Coronaria Percutánea/mortalidad , Diseño de Prótesis , Europa (Continente) , Infarto del Miocardio/mortalidad , Infarto del Miocardio/etiología , Catéteres Cardíacos , Enfermedad de la Arteria Coronaria/terapia , Enfermedad de la Arteria Coronaria/mortalidad , Enfermedad de la Arteria Coronaria/diagnóstico por imagenAsunto(s)
Angioplastia Coronaria con Balón , Reestenosis Coronaria , Intervención Coronaria Percutánea , Sirolimus , Humanos , Reestenosis Coronaria/diagnóstico por imagen , Reestenosis Coronaria/etiología , Sirolimus/administración & dosificación , Sirolimus/efectos adversos , Angioplastia Coronaria con Balón/instrumentación , Angioplastia Coronaria con Balón/efectos adversos , Intervención Coronaria Percutánea/instrumentación , Intervención Coronaria Percutánea/efectos adversos , Materiales Biocompatibles Revestidos , Stents Liberadores de Fármacos , Resultado del Tratamiento , Fármacos Cardiovasculares/administración & dosificación , Fármacos Cardiovasculares/efectos adversos , Catéteres CardíacosRESUMEN
Rapamycin slows cystogenesis in murine models of polycystic kidney disease (PKD) but failed in clinical trials, potentially due to insufficient drug dosing. To improve drug efficiency without increasing dose, kidney-specific drug delivery may be used. Mesoscale nanoparticles (MNP) selectively target the proximal tubules in rodents. We explored whether MNPs can target cystic kidney tubules and whether rapamycin-encapsulated-MNPs (RapaMNPs) can slow cyst growth in Pkd1 knockout (KO) mice. MNP was intravenously administered in adult Pkd1KO mice. Serum and organs were harvested after 8, 24, 48 or 72 h to measure MNP localization, mTOR levels, and rapamycin concentration. Pkd1KO mice were then injected bi-weekly for 6 weeks with RapaMNP, rapamycin, or vehicle to determine drug efficacy on kidney cyst growth. Single MNP injections lead to kidney-preferential accumulation over other organs, specifically in tubules and cysts. Likewise, one RapaMNP injection resulted in higher drug delivery to the kidney compared to the liver, and displayed sustained mTOR inhibition. Bi-weekly injections with RapaMNP, rapamycin or vehicle for 6 weeks resulted in inconsistent mTOR inhibition and little change in cyst index, however. MNPs serve as an effective short-term, kidney-specific delivery system, but long-term RapaMNP failed to slow cyst progression in Pkd1KO mice.
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Modelos Animales de Enfermedad , Ratones Noqueados , Nanopartículas , Enfermedades Renales Poliquísticas , Sirolimus , Animales , Sirolimus/administración & dosificación , Sirolimus/farmacología , Ratones , Enfermedades Renales Poliquísticas/tratamiento farmacológico , Enfermedades Renales Poliquísticas/metabolismo , Enfermedades Renales Poliquísticas/genética , Enfermedades Renales Poliquísticas/patología , Nanopartículas/administración & dosificación , Serina-Treonina Quinasas TOR/metabolismo , Canales Catiónicos TRPP/genética , Canales Catiónicos TRPP/metabolismo , Riñón/metabolismo , Riñón/efectos de los fármacos , Riñón/patología , Sistemas de Liberación de Medicamentos , MasculinoAsunto(s)
Angioplastia Coronaria con Balón , Enfermedad de la Arteria Coronaria , Sistema de Registros , Sirolimus , Humanos , Enfermedad de la Arteria Coronaria/terapia , Sirolimus/uso terapéutico , Sirolimus/administración & dosificación , Resultado del Tratamiento , Angioplastia Coronaria con Balón/instrumentación , Angioplastia Coronaria con Balón/métodos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Stents Liberadores de FármacosRESUMEN
INTRODUCTION: The DESyne novolimus-eluting coronary stent (NES) is a new-generation drug-eluting stent (DES) that is widely used, but clinical data are rarely reported for this stent. We compared the safety and effectiveness of the DESyne NES and the Orsiro bioresorbable polymer sirolimus-eluting stent (SES) in patients undergoing percutaneous coronary intervention (PCI). METHODS: This was a retrospective, single-center, observational study. Between July 2017 and December 2022, patients who presented with chronic or acute coronary syndrome undergoing PCI with DESyne NES or Orsiro SES were consecutively enrolled in the present study. The primary endpoint, major adverse cardiovascular event (MACE), was a composite of cardiovascular death, target-vessel myocardial infarction, or clinically driven target-lesion revascularization. RESULTS: A total of 776 patients (age 68.8 ± 12.2; 75.9% male) undergoing PCI were included. Overall, 231 patients with 313 lesions received NES and 545 patients with 846 lesions received SES. During a follow-up duration of 784 ± 522 days, the primary endpoint occurred in 10 patients (4.3%) in the NES group and in 36 patients (6.6%) in the SES group. After multivariate adjustment, the risk of MACE did not significantly differ between groups (NES vs. SES, hazard ratio 0.74, 95% CI, 0.35-1.55, p = 0.425). The event rate of individual components of the primary endpoint was comparable between the two groups. CONCLUSIONS: Favorable and similar clinical outcomes were observed in patients undergoing PCI with either NES or SES in a medium-term follow-up duration. Future studies with adequately powered clinical endpoints are required for further evaluation.
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Stents Liberadores de Fármacos , Intervención Coronaria Percutánea , Diseño de Prótesis , Sirolimus , Humanos , Masculino , Femenino , Sirolimus/administración & dosificación , Estudios Retrospectivos , Anciano , Intervención Coronaria Percutánea/métodos , Intervención Coronaria Percutánea/instrumentación , Resultado del Tratamiento , Enfermedad de la Arteria Coronaria/terapia , Factores de Tiempo , Estudios de Seguimiento , Síndrome Coronario Agudo/terapia , Factores de Riesgo , Persona de Mediana Edad , Angiografía Coronaria , MacrólidosRESUMEN
OBJECTIVES: Our objective was to explore the safety and efficacy of a graphene oxide-loaded rapamycin-coated self-expandable metallic airway stent (GO@RAPA-SEMS) in a rabbit model. METHODS: The dip coating method was used to develop a GO@RAPA-SEMS and a poly(lactic-co-glycolic)-acid loaded rapamycin-coated self-expandable metallic airway stent (PLGA@RAPA-SEMS). The surface structure was evaluated using a scanning electronic microscope. The in vitro drug-release profiles of the 2 stents were explored and compared. In the animal study, a total of 45 rabbits were randomly divided into 3 groups and underwent 3 kinds of stent placements. Computed tomography was performed to evaluate the degree of stenosis at 1, 2 and 3 months after the stent operation. Five rabbits in each group were sacrificed after the computed tomography scan. The stented trachea and blood were collected for further pathological analysis and laboratory testing. RESULTS: The in vitro drug-release study revealed that GO@RAPA-SEMS exhibited a sudden release on the first day and maintained a certain release rate on the 14th day. The PLGA@RAPA-SEMS exhibited a longer sustained release time. All 45 rabbits underwent successful stent placement. Pathological results indicated that the granulation tissue thickness in the GO@RAPA-SEMS group was less than that in the PLGA@RAPA-SEMS group. The TUNEL and hypoxia-inducible factor-1α staining results support the fact that the granulation inhibition effect in the GO@RAPA-SEMS group was greater than that in the PLGA@RAPA-SEMS group. CONCLUSIONS: GO@RAPA-SEMS effectively inhibited stent-related granulation tissue hyperplasia.
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Stents Liberadores de Fármacos , Tejido de Granulación , Grafito , Sirolimus , Animales , Conejos , Grafito/administración & dosificación , Sirolimus/administración & dosificación , Sirolimus/farmacología , Tejido de Granulación/efectos de los fármacos , Tejido de Granulación/patología , Hiperplasia/prevención & control , Stents Metálicos Autoexpandibles , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Materiales Biocompatibles Revestidos , Modelos Animales de Enfermedad , Tráquea/efectos de los fármacos , Tráquea/patologíaRESUMEN
Drug delivery systems based on biomimetic peptide nanoparticles are steadily gaining prominence in the treatment of diverse medical conditions. This study focused on the development of peptides that depend on ligand-receptor interactions to load rapamycin (RAPA). Furthermore, a multifunctional peptide was engineered to target oxidized low-density lipoprotein (oxLDL) within atherosclerotic plaques, facilitating the localized delivery of RAPA. The interactions between peptides and RAPA/oxLDL were analyzed by simulations and experimental approaches. Results show that the main amino acid residues on the mammalian target of rapamycin that bind to RAPA are constructed as peptides (P1 and P2), which have specific interactions with RAPA and can effectively improve the loading efficiency of RAPA. The encapsulation and drug loading efficiencies of P1/P2 were 68.0/47.9% and 48.3/36.5%, respectively. In addition, the interaction force of the multifunctional peptide (P3) and oxLDL surpassed that of their interaction with human umbilical vein endothelial cells by a factor of 3.6, conclusively establishing the specific targeting of oxLDL by these nanoparticles. The encapsulation and drug loading efficiencies of P3 for RAPA were determined to be 60.2% and 41.5%. P3 can effectively load RAPA and target oxLDL within the plaque, suggesting that P3 has potential as a therapeutic agent for atherosclerotic disease.
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Células Endoteliales de la Vena Umbilical Humana , Lipoproteínas LDL , Nanopartículas , Péptidos , Placa Aterosclerótica , Sirolimus , Lipoproteínas LDL/química , Lipoproteínas LDL/metabolismo , Sirolimus/administración & dosificación , Sirolimus/química , Sirolimus/farmacología , Humanos , Placa Aterosclerótica/tratamiento farmacológico , Péptidos/química , Péptidos/farmacología , Péptidos/administración & dosificación , Nanopartículas/química , Nanopartículas/administración & dosificación , Sistemas de Liberación de Medicamentos , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Portadores de Fármacos/químicaRESUMEN
Intractable lymphatic malformations (iLM) pose a significant threat to affected children, demonstrating limited responses to conventional treatments. Sirolimus, effectively inhibiting endothelial cell proliferation in lymphatic vessels, plays a crucial role in iLM treatment. However, the drug's narrow therapeutic window and substantial interindividual variability necessitate customized dosing strategies. This study aims to establish a Population Pharmacokinetic Model (PopPK model) for sirolimus in pediatric iLM patients, identifying quantitative relationships between covariates and sirolimus clearance and volume of distribution. Initial dosages are recommended based on a target concentration range of 5-15 ng/mL. Retrospective data from our institution, encompassing 53 pediatric patients with 275 blood concentration results over the past five years (average age: 4.64 ± 4.19 years), constituted the foundation of this analysis. The final model, adopting a first-order absorption and elimination single-compartment model, retained age as the sole covariate. Results indicated a robust correlation between apparent clearance (CL/F) at 5.56 L/h, apparent volume of distribution (V/F) at 292.57 L, and age. Monte Carlo simulation guided initial dosages for patients aged 0-18 years within the target concentration range. This study presents the first PopPK model using a large Therapeutic Drug Monitoring (TDM) database to describe personalized sirolimus dosing for pediatric iLM patients, contributing to pharmacokinetic guidance and potentially improving long-term clinical outcomes.