RESUMO
AIMS: Among antirestenotic compounds, sirolimus displays a superior safety profile compared to paclitaxel, but its pharmacokinetic properties make it a challenging therapeutic candidate for single-time delivery. Herein we evaluate the feasibility of delivery, long-term retention and vascular effects of sirolimus nanoparticles delivered through a novel porous angioplasty balloon in normal porcine arteries and in a swine model of in-stent restenosis (ISR). METHODS AND RESULTS: Sirolimus nanoparticle formulation was delivered via porous balloon angioplasty to 753 coronary artery segments for pharmacokinetic studies and 26 segments for biological effect of sirolimus delivery in different clinical scenarios (de novo [n=8], ISR [n=6] and following stent implantation [n=12]). Sirolimus coronary artery concentrations were above the target therapeutic level of 1 ng/mg after 26 days, and were >100-fold higher in coronary artery treatment sites than in distal myocardium and remote tissues at all time points. At 28 days, reduction in percent stenosis in formulation-treated sites compared to balloon angioplasty treatment was noted in all three clinical scenarios, with the largest effect seen in the de novo study. CONCLUSIONS: Local coronary delivery of sirolimus nanoparticles in the porcine model using a novel porous balloon delivery system achieved therapeutic long-term intra-arterial drug levels without significant systemic residual exposure.
Assuntos
Angioplastia Coronária com Balão/instrumentação , Antibióticos Antineoplásicos/administração & dosagem , Reestenose Coronária/prevenção & controle , Sirolimo/administração & dosagem , Animais , Antibióticos Antineoplásicos/farmacocinética , Vasos Coronários/efeitos dos fármacos , Feminino , Masculino , Nanopartículas , Sirolimo/farmacocinética , SuínosRESUMO
Small molecules potentially mimicking the hormone erythropoietin have been discovered by screening of a library of rationally designed multicomponent reaction molecules in a functional cell-based assay.
Assuntos
Eritropoetina/química , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Interleucina-3/fisiologia , Camundongos , Modelos Moleculares , Conformação Molecular , Mimetismo Molecular , Receptores da Eritropoetina/efeitos dos fármacos , Proteínas RecombinantesRESUMO
OBJECTIVES: The ETHOS I trial was the first in-human experience evaluating the safety and efficacy of two different release formulations of the 17-beta estradiol-eluting R-Stent versus uncoated control stents for the treatment of patients with single de novo native coronary lesions. BACKGROUND: Estrogens were reported to inhibit neointimal proliferation and to accelerate endothelial regeneration after coronary angioplasty and thus could be an ideal compound to deliver on a stent for the purpose of reducing in-stent restenosis. METHODS: Ninety-five patients were randomized to receive a slow-release (n = 32) or the moderate release (n = 31) formulations or the bare metal stent (n = 32). The primary end point was the 6-month percent in-stent volume obstruction by intravascular ultrasound (IVUS). RESULTS: Diabetes was present in 29.5% of patients; the mean reference vessel diameter was 2.90 mm; and the mean lesion length was 13.5 mm. Primary endpoint, 6-month percent in-stent volume obstruction by IVUS, did not differ significantly between the 3 groups (31% +/- 14%, 33% +/- 11%, and 31% +/- 14%, P = 0.83). Secondary endpoints also did not differ significantly between the groups including 6-month rates of in-lesion binary angiographic restenosis (13.3%, 14.3%, and 12.5%, P = 0.98), in-stent late loss (0.82 +/- 0.49 mm, 0.86 +/- 0.53 mm, and 0.84 +/- 0.46 mm, P = 0.97), target lesion revascularization (12.5%, 6.9%, and 6.5%, P = 0.64), and major adverse cardiac events (18.8%, 10.3%, and 6.5%, P = 0.31). CONCLUSIONS: In this first-in-man randomized trial, the 17-beta estradiol-eluting R-Stent, in either slow- or moderate-release formulations, was well-tolerated, but showed no benefit for treatment of coronary lesions when compared to controls.
Assuntos
Estenose Coronária/terapia , Estradiol/administração & dosagem , Stents , Análise de Variância , Brasil , Angiografia Coronária , Reestenose Coronária/diagnóstico por imagem , Reestenose Coronária/patologia , Reestenose Coronária/prevenção & controle , Estenose Coronária/diagnóstico por imagem , Estenose Coronária/patologia , Método Duplo-Cego , Sistemas de Liberação de Medicamentos , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Polímeros , Estudos Prospectivos , Resultado do TratamentoRESUMO
The interaction of activated Ras with Raf initiates signaling cascades that contribute to a significant percentage of human tumors, suggesting that agents that specifically disrupt this interaction might have desirable chemotherapeutic properties. We used a subtractive forward two-hybrid approach to identify small molecule compounds that block the interaction of Ras with Raf. These compounds (MCP1 and its derivatives, 53 and 110) reduced serum-induced transcriptional activation of serum response element as well as Ras-induced transcription by way of the AP-1 site. They also inhibited Ras-induced Raf-1 activation in human embryonic kidney 293 cells, Raf-1 and mitogen-activated protein kinase kinase 1 activities in HT1080 fibrosarcoma cells, and epidermal growth factor-induced Raf-1 activation in A549 lung carcinoma cells. The MCP compounds caused reversion of ras-transformed phenotypes including morphology, in vitro invasiveness, and anchorage-independent growth of HT1080 cells. Decreased level of matrix metalloproteinases was also observed. Further characterization showed that MCP compounds restore actin stress fibers and cause flat reversion in NIH 3T3 cells transformed with H-Ras (V12) but not in NIH 3T3 cells transformed with constitutively active Raf-1 (RafDeltaN). Finally, we show that MCP compounds inhibit anchorage-independent growth of A549 and PANC-1 cells harboring K-ras mutation. Furthermore, MCP110 caused G(1) enrichment of A549 cells with the decrease of cyclin D level. These results highlight potent and specific effects of MCP compounds on cancer cells with intrinsic Ras activation.
Assuntos
Proteínas Proto-Oncogênicas c-raf/genética , Ativação Transcricional/efeitos dos fármacos , Proteínas ras/metabolismo , Células 3T3 , Animais , Células CHO , Cricetinae , Biblioteca Gênica , Humanos , Luciferases , Sistema de Sinalização das MAP Quinases , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fenótipo , Ligação Proteica , Elemento de Resposta Sérica , Fator de Transcrição AP-1/metabolismo , Transformação Genética , Células Tumorais Cultivadas , Proteínas ras/genéticaRESUMO
Objectives: The ETHOS I trial was the first in-human experience evaluating the safety and efficacy of two different release formulations of the 17-b estradiol-eluting RStent TM versus uncoated control stents for the treatment of patients with single de novo native coronary lesions. Background: Estrogens were reported to inhibit neointimal proliferation and to accelerate endothelial regeneration after coronary angioplasty and thus could be an ideal compound to deliver on a stent for the purpose of reducing in-stent restenosis. Methods: Ninety-five patients were randomized to receive a slowrelease (n = 32) or the moderate release (n = 31) formulations or the bare metal stent (n = 32). The primary end point was the 6-month percent in-stent volume obstruction by intravascular ultrasound (IVUS). Results: Diabetes was present in 29.5% of patients; the mean reference vessel diameter was 2.90 mm; and the mean lesion length was 13.5 mm. Primary endpoint, 6-month percent in-stent volume obstruction by IVUS, did not differ significantly between the 3 groups (31% 6 14%, 33% 6 11%, and 31% 6 14%, P = 0.83). Secondary endpoints also did not differ significantly between the groups including 6-month rates of in-lesion binary angiographic restenosis (13.3%, 14.3%, and 12.5%, P = 0.98), in-stent late loss (0.82 6 0.49 mm, 0.86 6 0.53 mm, and 0.84 6 0.46 mm, P = 0.97), target lesion revascularization (12.5%, 6.9%, and 6.5%, P = 0.64), and major adverse cardiac events (18.8%, 10.3%, and 6.5%, P = 0.31). Conclusions: In this first-in-man randomized trial, the 17-b estradiol-eluting R-StentTM, in either slowor moderate-release formulations, was well-tolerated, but showed no benefit for treatment of coronary lesions when compared to controls.
Assuntos
Doença da Artéria Coronariana , Reestenose Coronária , StentsRESUMO
Objectives: The ETHOS I trial was the first in-human experience evaluating the safety
and efficacy of two different release formulations of the 17-b estradiol-eluting RStent
TM versus uncoated control stents for the treatment of patients with single de
novo native coronary lesions. Background: Estrogens were reported to inhibit neointimal
proliferation and to accelerate endothelial regeneration after coronary angioplasty
and thus could be an ideal compound to deliver on a stent for the purpose of reducing
in-stent restenosis. Methods: Ninety-five patients were randomized to receive a slowrelease
(n = 32) or the moderate release (n = 31) formulations or the bare metal stent
(n = 32). The primary end point was the 6-month percent in-stent volume obstruction
by intravascular ultrasound (IVUS). Results: Diabetes was present in 29.5% of patients;
the mean reference vessel diameter was 2.90 mm; and the mean lesion length was
13.5 mm. Primary endpoint, 6-month percent in-stent volume obstruction by IVUS, did
not differ significantly between the 3 groups (31% 6 14%, 33% 6 11%, and 31% 6
14%, P = 0.83). Secondary endpoints also did not differ significantly between the
groups including 6-month rates of in-lesion binary angiographic restenosis (13.3%,
14.3%, and 12.5%, P = 0.98), in-stent late loss (0.82 6 0.49 mm, 0.86 6 0.53 mm, and
0.84 6 0.46 mm, P = 0.97), target lesion revascularization (12.5%, 6.9%, and 6.5%, P =
0.64), and major adverse cardiac events (18.8%, 10.3%, and 6.5%, P = 0.31). Conclusions:
In this first-in-man randomized trial, the 17-b estradiol-eluting R-StentTM, in either slowor
moderate-release formulations, was well-tolerated, but showed no benefit for treatment
of coronary lesions when compared to controls.