RESUMEN
Priapism is a persistent penile erection lasting more than four hours without sexual arousal or stimulation. We report on a high-flow priapism, an uncommon arteriovenous fistula of the corpus cavernosum after a straddle trauma which was successfully embolized. At follow up no recurrent episodes of priapism occurred without symptoms of erectile dysfunction or other complications.
RESUMEN
The present study describes the development of a good manufacturing practice (GMP)-grade liposomal nanotherapy containing prednisolone phosphate for the treatment of inflammatory diseases. After formulation design, GMP production was commenced which yielded consistent, stable liposomes sized 100nm±10nm, with a prednisolone phosphate (PLP) incorporation efficiency of 3%-5%. Pharmacokinetics and toxicokinetics of GMP-grade liposomal nanoparticles were evaluated in healthy rats, which were compared to daily and weekly administration of free prednisolone phosphate, revealing a long circulatory half-life with minimal side effects. Subsequently, non-invasive multimodal clinical imaging after liposomal nanotherapy's intravenous administration revealed anti-inflammatory effects on the vessel wall of atherosclerotic rabbits. The present program led to institutional review board approval for two clinical trials with patients with atherosclerosis. FROM THE CLINICAL EDITOR: In drug discovery, bringing production to industrial scale is an essential process. In this article the authors describe the development of an anti-inflammatory nanoparticle according to good manufacturing practice. As a result, this paves the way for translating laboratory studies to clinical trials in humans.
Asunto(s)
Antiinflamatorios/administración & dosificación , Aterosclerosis/tratamiento farmacológico , Química Farmacéutica/métodos , Glucocorticoides/administración & dosificación , Prednisolona/análogos & derivados , Animales , Antiinflamatorios/farmacocinética , Antiinflamatorios/uso terapéutico , Antiinflamatorios/toxicidad , Aorta/efectos de los fármacos , Aorta/patología , Aterosclerosis/patología , Glucocorticoides/farmacocinética , Glucocorticoides/uso terapéutico , Glucocorticoides/toxicidad , Semivida , Humanos , Liposomas , Masculino , Prednisolona/administración & dosificación , Prednisolona/farmacocinética , Prednisolona/uso terapéutico , Prednisolona/toxicidad , Conejos , Ratas , Ratas Sprague-Dawley , Ratas WistarRESUMEN
Drug delivery to atherosclerotic plaques via liposomal nanoparticles may improve therapeutic agents' risk-benefit ratios. Our paper details the first clinical studies of a liposomal nanoparticle encapsulating prednisolone (LN-PLP) in atherosclerosis. First, PLP's liposomal encapsulation improved its pharmacokinetic profile in humans (n=13) as attested by an increased plasma half-life of 63h (LN-PLP 1.5mg/kg). Second, intravenously infused LN-PLP appeared in 75% of the macrophages isolated from iliofemoral plaques of patients (n=14) referred for vascular surgery in a randomized, placebo-controlled trial. LN-PLP treatment did however not reduce arterial wall permeability or inflammation in patients with atherosclerotic disease (n=30), as assessed by multimodal imaging in a subsequent randomized, placebo-controlled study. In conclusion, we successfully delivered a long-circulating nanoparticle to atherosclerotic plaque macrophages in patients, whereas prednisolone accumulation in atherosclerotic lesions had no anti-inflammatory effect. Nonetheless, the present study provides guidance for development and imaging-assisted evaluation of future nanomedicine in atherosclerosis. FROM THE CLINICAL EDITOR: In this study, the authors undertook the first clinical trial using long-circulating liposomal nanoparticle encapsulating prednisolone in patients with atherosclerosis, based on previous animal studies. Despite little evidence of anti-inflammatory effect, the results have provided a starting point for future development of nanomedicine in cardiovascular diseases.
Asunto(s)
Antiinflamatorios/administración & dosificación , Aterosclerosis/tratamiento farmacológico , Glucocorticoides/administración & dosificación , Macrófagos/efectos de los fármacos , Placa Aterosclerótica/tratamiento farmacológico , Prednisolona/administración & dosificación , Administración Intravenosa , Adulto , Anciano , Antiinflamatorios/farmacocinética , Antiinflamatorios/uso terapéutico , Arterias/efectos de los fármacos , Arterias/patología , Aterosclerosis/patología , Femenino , Glucocorticoides/farmacocinética , Glucocorticoides/uso terapéutico , Humanos , Liposomas , Macrófagos/patología , Masculino , Persona de Mediana Edad , Placa Aterosclerótica/patología , Prednisolona/farmacocinética , Prednisolona/uso terapéuticoRESUMEN
Inflammation is a key feature of atherosclerosis and a target for therapy. Statins have potent anti-inflammatory properties but these cannot be fully exploited with oral statin therapy due to low systemic bioavailability. Here we present an injectable reconstituted high-density lipoprotein (rHDL) nanoparticle carrier vehicle that delivers statins to atherosclerotic plaques. We demonstrate the anti-inflammatory effect of statin-rHDL in vitro and show that this effect is mediated through the inhibition of the mevalonate pathway. We also apply statin-rHDL nanoparticles in vivo in an apolipoprotein E-knockout mouse model of atherosclerosis and show that they accumulate in atherosclerotic lesions in which they directly affect plaque macrophages. Finally, we demonstrate that a 3-month low-dose statin-rHDL treatment regimen inhibits plaque inflammation progression, while a 1-week high-dose regimen markedly decreases inflammation in advanced atherosclerotic plaques. Statin-rHDL represents a novel potent atherosclerosis nanotherapy that directly affects plaque inflammation.