RESUMEN
PURPOSE: We describe the preparation of injectable polymeric paste (IPP) formulations for local and sustained release of drugs. Furthermore, we include the characterization and possible applications of such pastes. Particular attention is paid to characteristics relevant to the successful clinical formulation development, such as viscosity, injectability, degradation, drug release, sterilization, stability performance and pharmacokinetics. METHODS: Paste injectability was characterized using measured viscosity and the Hagen-Poiseuille equation to determine injection forces. Drug degradation, release and formulation stability experiments were performed in vitro and drug levels were quantified using HPLC-UV methods. Pharmacokinetic evaluation of sustained-release lidocaine IPPs used five groups of six rats receiving increasing doses subcutaneously. An anti-cancer formulation was evaluated in a subcutaneous tumor xenograft mouse model. RESULTS: The viscosity and injectability of IPPs could be controlled by changing the polymeric composition. IPPs demonstrated good long-term stability and tunable drug-release with low systemic exposure in vivo in rats. Preliminary data in a subcutaneous tumor model points to a sustained anticancer effect. CONCLUSIONS: These IPPs are tunable platforms for local and sustained delivery of drugs and have potential for further clinical development to treat a number of diseases.
Asunto(s)
Portadores de Fármacos/química , Composición de Medicamentos/métodos , Pomadas/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Anilidas/química , Anilidas/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Docetaxel/química , Docetaxel/farmacología , Liberación de Fármacos , Estabilidad de Medicamentos , Humanos , Inyecciones , Lidocaína/química , Lidocaína/farmacocinética , Masculino , Ratones , Ratones Desnudos , Neoplasias Experimentales , Nitrilos/química , Nitrilos/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Ratas , Compuestos de Tosilo/química , Compuestos de Tosilo/farmacología , ViscosidadRESUMEN
The role of the calcium channel blocker (verapamil) in kidney transplant is controversial. Verapamil has been hypothesized to mitigate ischemia reperfusion injury (IRI) to the allograft. Herein, we evaluated the effect of intra-operative verapamil administration in a large cohort of kidney transplants. Total 684 transplants were performed during 2007-2017. Of these, 348 (50.9%) transplants received verapamil (2.5 mg) Ver (+), and 336 (49.1%) did not, Ver (-). Based on the donor type, the study was divided into three groups; living donor (LD) (N = 270), neurological determination of death (NDD) (N = 394), and donation after cardiac death (DCD) (N = 20). Ver (-) subgroup had more diabetic recipients as compared to Ver (+) subgroup in LD and NDD groups (P < 0.05). No significant difference was found for delayed graft function in any of the group (P > 0.05). Cold ischemia time and dialysis requirement were significantly higher in Ver (+) LD and NDD groups, respectively. Except for DCD group, there was no significant difference in eGFR (mL/min) immediately and 6 months after kidney transplant in any of the groups. Furthermore, univariate and multivariate logistic regression analysis was performed to account for potential confounders, but verapamil administration did not improve graft function in any of the groups (P > 0.05) after transplant.
Asunto(s)
Funcionamiento Retardado del Injerto/prevención & control , Cuidados Intraoperatorios , Trasplante de Riñón/métodos , Daño por Reperfusión/tratamiento farmacológico , Donantes de Tejidos/provisión & distribución , Obtención de Tejidos y Órganos/métodos , Verapamilo/administración & dosificación , Muerte Encefálica , Bloqueadores de los Canales de Calcio/administración & dosificación , Isquemia Fría , Femenino , Estudios de Seguimiento , Humanos , Donadores Vivos/provisión & distribución , Masculino , Persona de Mediana Edad , Pronóstico , Estudios RetrospectivosRESUMEN
OBJECTIVES: To determine the long-term oncological outcome of organ-confined (Asunto(s)
Cuidados Posteriores/normas
, Carcinoma de Células Renales/cirugía
, Neoplasias Renales/cirugía
, Recurrencia Local de Neoplasia/epidemiología
, Nefrectomía
, Anciano
, Anciano de 80 o más Años
, Neoplasias Óseas/epidemiología
, Neoplasias Óseas/secundario
, Carcinoma de Células Renales/epidemiología
, Carcinoma de Células Renales/secundario
, Progresión de la Enfermedad
, Femenino
, Estudios de Seguimiento
, Humanos
, Incidencia
, Estimación de Kaplan-Meier
, Neoplasias Renales/mortalidad
, Neoplasias Renales/patología
, Esperanza de Vida
, Neoplasias Pulmonares/epidemiología
, Neoplasias Pulmonares/secundario
, Masculino
, Persona de Mediana Edad
, Recurrencia Local de Neoplasia/patología
, Estadificación de Neoplasias
, Guías de Práctica Clínica como Asunto
, Estudios Retrospectivos
, Factores de Tiempo
RESUMEN
PURPOSE: Time to metastasis is often used as a surrogate parameter of treatment success in clinical trials for prostate cancer. However, it has not been shown that there is a clear correlation between time to metastasis and overall survival. Our objective was to evaluate the impact of time to metastasis on OS in patients with prostate cancer. METHODS: Between 2008 and 2015, 269 patients with mPCa were included in this retrospective study with a median follow-up of 7.1 years. Patients were divided into three groups: (1) Presentation with metastasis within three months of initial diagnosis (de-novo-M); (2) patients free of metastasis initially but developed metastasis more than 6 months prior to castration resistance (CSPC-M); (3) patients who developed metastasis within 6 months of becoming castration resistant or after (CRPC-M). RESULTS: There was a significant decrease in OS when metastases were present at diagnosis (median 6.39 years) compared to CRPC-M (19.07) and CSPC-M (18.19 years). De-novo-M and CSPC-M showed a longer OS from occurrence of metastasis to death when compared to CRPC-M, although reaching CRPC earlier. There was no difference in OS between the groups once castration resistance was reached. Time from initial diagnosis to metastasis and to CRPC was correlated with OS and remained important prognosticators in multivariate Cox-regression (p < 0.01 for both). CONCLUSIONS: Time from diagnosis to CRPC (all patients) and time to metastasis (for CRPC-M and CSPC-M patients) are significant prognosticators of overall survival and are therefore valid surrogates in a study setting. Therefore, time to CRPC should be prolonged as long as possible.
Asunto(s)
Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Orquiectomía , Pronóstico , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata Resistentes a la Castración/sangre , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Neoplasias de la Próstata Resistentes a la Castración/patología , Estudios Retrospectivos , Análisis de Supervivencia , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Ureteral contractility is a poorly understood process. Contractions have been demonstrated to occur in the smooth muscle layers of the ureter. Previous work suggests the involvement of Gli family proteins and erythropoietin (EPO) in regulating mammalian ureteral smooth muscle contraction. We sought to devise a method by which the effects of these proteins and tamsulosin on distal human ureteral tissue contractility could be investigated to better understand mechanisms regulating human ureteral function. METHODS: IRB approval was obtained to procure portions of extraneous distal ureteral tissue from living donor renal transplants. Contractility was measured by placing the tissue in Krebs buffer and stimulating via a uniform electric current. Contractile force was recorded with each stimulation with and without the presence of a Gli inhibitor (GANT61) or EPO. Each ureteral specimen was subsequently fixed and tested by immunohistochemistry to determine Gli, EPO and alpha-adrenergic receptor activity. RESULTS: Electrical field stimulation successfully elicited contractions in the ureteral tissue. Administering tamsulosin decreased force and duration of ureteral contractions. Inhibiting Gli signaling decreased contractility and EPO decreased ureteral contractile forces within 5 minutes of administration versus untreated controls. Staining confirmed Gli1 protein and α-adrenergic receptor expression in ureteral smooth muscle and epithelial tissue with EPO receptor expression confined to the epithelial layer. CONCLUSIONS: Distal ureteral contractile forces are decreased by inhibition of Gli family proteins and the α-adrenergic receptor. EPO acts within five minutes, suggesting ion channel involvement instead of changes in gene expression. Continuing work will elucidate the role of these proteins in coordinating ureteral contractions. This has implications for the use of pharmacologic methods to address ureteral contractility and dysfunctional peristalsis during stone passage, ureteroscopy, in transplant patients and potentially to reduce symptoms from ureteral stents.
RESUMEN
BACKGROUND: Intravesical instillation of chemo- or immunotherapy is commonly used in bladder cancer. Upper tract urothelial carcinoma (UTUC) shares similar pathological features, but current formulations are not suitable for direct instillation to the upper urinary tract. OBJECTIVE: To evaluate in vivo applicability, characteristics and toxicity of ST-UC, a mucoadhesive polymeric paste formulation of gemcitabine, for upper urinary tract instillation. MATERIAL AND METHODS: Three pigs received 10 ml of ST-UC (100 mg/ml gemcitabine) retrogradely into 1 renal pelvis for pharmacokinetic studies. Four days later, a second injection into the contralateral renal pelvis was followed by serial euthanasia of the pigs and nephroureterectomy after 1, 3, and 6 hours. Adverse effects were monitored. Urine, serum, and tissue gemcitabine concentrations were measured, along with histologic examination of the upper urinary tract. RESULTS: Retrograde instillation of ST-UC was well tolerated with mild, completely receding hydronephrosis. Urine gemcitabine concentrations were highest in the first 3-hour collection interval. Hundred percent of gemcitabine was recovered in the urine within 24 hours. Serum peak concentrations (cmax) of gemcitabine were low at 5.5 µg/ml compared to the 10 to 30 µg/ml levels observed after a single intravenous dose of 1,000 mg/m2 gemcitabine. The formulation was still traceable after one hour and gemcitabine tissue concentrations are supportive of this extended drug exposure. No major histopathological changes were observed. The main limitation of this study is the lack of antitumor activity data. CONCLUSION: This preclinical evaluation of ST-UC demonstrated feasible instillation in the renal pelvis, no significant safety concerns, and sustained release of gemcitabine.
Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Carcinoma de Células Transicionales/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Composición de Medicamentos , Neoplasias Renales/tratamiento farmacológico , Pelvis Renal , Neoplasias Ureterales/tratamiento farmacológico , Administración Tópica , Animales , Desoxicitidina/administración & dosificación , Femenino , Humanos , Polímeros , Porcinos , GemcitabinaRESUMEN
OBJECTIVE: Focal therapy has emerged as a treatment option for low- to intermediate-risk localized prostate cancer (PCa) patients, to balance the risks for urinary and sexual morbidity of radical treatment with the psychological burden of active surveillance. In this context, we developed ST-4PC, an injectable, polymeric paste formulation containing docetaxel (dtx) and bicalutamide (bic) for image-guided focal therapy of PCa. The objective of this work was to evaluate the in vitro characteristics and in vivo toxicity and efficacy of ST-4PC. MATERIAL AND METHODS: In vitro drug release was evaluated using high-performance liquid chromatography. In vivo toxicity of blank- and drug-loaded ST-4PC was assessed in mice and rats. Tumor growth inhibition was evaluated in LNCaP subcutaneous (s.c.) and LNCaP-luc orthotopic xenograft models. Using the s.c. model, mice were monitored weekly for weight loss, tumor volume (TV) and serum PSA. For the orthotopic model, mice were additionally monitored for bioluminescence as measure of tumor growth. RESULTS: ST-4PC demonstrated a sustained and steady release of incorporated drugs with 50% dtx and 20% bic being released after 14 days. While no systemic toxicity was observed, dose-dependent local side effects from dtx developed in the s.c. but not in the orthotopic model, illustrating the limitations of s.c. models for evaluating local cytotoxic therapy. In the s.c. model, 0.1%/4% and 0.25%/4% dtx/bic ST-4PC paste significantly reduced PSA progression, but did not have a significant inhibitory effect on TV. ST-4PC loaded with 1%/4% dtx/bic significantly reduced TV, serum PSA, and bioluminescence in the orthotopic xenograft model. Compared with drugs dissolved in DMSO, ST-4PC significantly delayed tumor growth. CONCLUSION: Image-guided focal therapy using ST-4PC demonstrated promising inhibition of PSA progression and orthotopic tumor growth in vivo without significant toxicity, and warrants further clinical evaluation.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Composición de Medicamentos/métodos , Polímeros/química , Neoplasias de la Próstata/tratamiento farmacológico , Anilidas/administración & dosificación , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/química , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Apoptosis , Proliferación Celular , Docetaxel/administración & dosificación , Humanos , Masculino , Ratones , Nitrilos/administración & dosificación , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Ratas , Distribución Tisular , Compuestos de Tosilo/administración & dosificación , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Neuroendocrine (NE) differentiation of advanced prostate adenocarcinoma following androgen receptor (AR) axis-directed therapy is becoming increasingly recognized. Several models of this transdifferentiation provide insight into its molecular pathogenesis and have highlighted the placental gene PEG10 for further study. Using our unique model of enzalutamide resistance (ENZR) and NE differentiation, we studied PEG10/AR interplay in enzalutamide treatment-resistant cell lines 42DENZR and 42FENZR compared to LNCaP and castration-resistant 16DCRPC cells. ENZR cell lines with positive terminal NE marker status also displayed higher baseline expression of PEG10 compared to LNCaP and 16DCRPC. Antagonism of AR activity increased PEG10 expression followed by an increase in terminal NE markers. Conversely, stimulating AR activity via androgen supplementation reversed PEG10 and NE marker expression in a time and dose-dependent manner. These results were supported by human data showing that PEG10 expression is highest in NEPC and that AR-dependent gene, PSA, is negatively correlated with PEG10 in adenocarcinoma. Further, ChIP assay confirmed binding of activated AR to the PEG10 enhancer, decreasing PEG10 expression. While PEG10 did not drive NEPC, its knockdown reduced NE markers in our cell lines. Moreover, PEG10 knockdown in vitro- and in vivo-attenuated tumor growth. Overall, these observations indicate that PEG10 is an AR-repressed gene which modulates NE markers in ENZR cells and targeting PEG10 in advanced prostate cancer with NE features is a rational and viable option.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas de Unión al ADN/metabolismo , Neoplasias de la Próstata/inducido químicamente , Neoplasias de la Próstata/metabolismo , Proteínas de Unión al ARN/metabolismo , Animales , Antineoplásicos/uso terapéutico , Proteínas Reguladoras de la Apoptosis/genética , Benzamidas , Western Blotting , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inmunoprecipitación de Cromatina , Proteínas de Unión al ADN/genética , Resistencia a Antineoplásicos/genética , Humanos , Masculino , Ratones , Ratones Desnudos , Sistemas Neurosecretores/metabolismo , Nitrilos , Feniltiohidantoína/análogos & derivados , Feniltiohidantoína/uso terapéutico , Neoplasias de la Próstata/genética , Proteínas de Unión al ARN/genética , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/genética , Transducción de Señal/fisiologíaRESUMEN
INTRODUCTION: Anastomotic pseudoaneurysm is one of the rarest vascular complications after renal transplant surgery. Therapeutic options include open surgical repair or endovascular stenting. CASE PRESENTATION: Case 1 had pseudoaneurysm involving external iliac artery and was managed by jump graft to allograft using cadaveric donor iliac arteries and patch angioplasty repair of external iliac artery after excising pseudoaneurysm. Case 2 had undergone orthotopic renal transplant with spleno-renal arterial anastomosis and developed a massive pseudoaneurysm proximal to spleno-renal arterial anastomosis. This patient underwent endovascular stenting preserving allograft vascularity and graft function. Outcome in both patients was successful with normalization of renal function to baseline levels. CONCLUSION: Treatment of renal transplant anastomotic pseudoaneurysms is difficult and associated with high rates of graft loss. Open surgery is the gold standard providing several possibilities for arterial reconstruction preserving graft and limb circulation. Endovascular treatment should be considered in high-risk surgical patients with favorable anatomy.
RESUMEN
Orthotopic mouse models of urothelial cancer are essential for testing novel therapies and molecular manipulations of cell lines in vivo. These models are either established by orthotopic inoculation of human (xenograft models) or murine tumor cells (syngeneic models) in immunocompromised or immune competent mice. Current techniques rely on inoculation by intravesical instillation or direct injection into the bladder wall. Alternative models include the induction of murine bladder tumors by chemical carcinogens (BBN) or genetic engineering (GEM).
Asunto(s)
Modelos Animales de Enfermedad , Neoplasias Urológicas/patología , Animales , Línea Celular Tumoral , Transformación Celular Neoplásica/inducido químicamente , Xenoinjertos , Humanos , Ratones , Ratones Transgénicos , Neoplasias Urológicas/etiologíaRESUMEN
Ureteral stents are one of the most commonly used urologic devices with the purpose of establishing and maintaining ureteral patency. They are also associated with a number of complications including infection, migration, stent-related symptoms, and encrustation, leading to lithiasis. Prolonged stent dwell time is associated with a greater degree of these complications. We present the case of a 36-year-old man who presented with a severely encrusted ureteral stent that had been placed 12.5 years prior for an obstructive left-sided ureteral stone and was lost to follow-up. The patient underwent a combination of percutaneous nephrolithomy, cystolitholapaxy, and ureteroscopy to remove the stent and associated 1.7 cm renal pelvic stone and 4.1 cm bladder stone, necessitating two operative sittings to render him stone free.
RESUMEN
INTRODUCTION: Urological dogma dictates that washings collected from the urinary tract for cytological assessment must be performed without interference from contrast agents that may alter cellular integrity and diagnostic interpretation. In practice, the initial contrast used to outline the upper tracts is commonly discarded with subsequent saline washings sent for cytology. We hypothesize that contrast washings do not affect the morphology of urothelial carcinoma cells or the integrity of cytology interpretation. METHODS: Samples obtained from (1) human bladder cell lines; (2) urine from a human xenograft bladder cancer model using UC-3 cells; and (3) patients with urothelial carcinoma were subjected to various experimental solutions (water, saline, urine, and dilutions of contrast media) for different exposure times. After exposure to various different solutions, samples underwent cytological analysis to assess morphologic and degenerative changes. RESULTS: No cytological differences were seen when cells were exposed to ionic, hyperosmolar, or non-ionic low-osmolar contrast agents for any exposures up to five minutes. Cells exposed to mixtures of contrast agents and urine also demonstrated no evidence of degenerative change. Cells exposed to water for greater than one minute demonstrated significant hydropic degeneration impacting cytological interpretation. At 40 minutes or later, all reagents caused severe degeneration when evaluating urine samples from the mouse bladder cancer model and from patients undergoing urothelial carcinoma. CONCLUSIONS: Commonly used contrast agents have no effect on urinary cytology up to five minutes. Contrast washings of the urinary tract should not be discarded and can be sent for cytological diagnosis if fixed within this time period.
RESUMEN
Ureteral stents are one of the most commonly used devices in the treatment of benign and malignant urological diseases. However, they are associated with common complications including encrustation, infection, pain and discomfort caused by ureteral tissue irritation and possibly irregular peristalsis. In addition, stent migration and failure due to external compression by malignancies or restenosis occur, albeit less frequently. As these complications restrict optimal stent function, including maintenance of adequate urine drainage and alleviation of hydronephrosis, novel stent materials and designs are required. In recent years, progress has been made in the development of drug-eluting expandable metal stents and biodegradable stents. New engineering technologies are being investigated to provide stents with increased biocompatibility, decreased susceptibility to encrustation and improved drug-elution characteristics. These novel stent characteristics might help eliminate some of the common complications associated with ureteral stenting and will be an important step towards understanding the behaviour of stents within the urinary tract.
Asunto(s)
Diseño de Prótesis , Falla de Prótesis/efectos adversos , Stents/efectos adversos , Uréter , Implantes Absorbibles , Materiales Biocompatibles , Migración de Cuerpo Extraño , Humanos , Diseño de Prótesis/efectos adversos , Diseño de Prótesis/instrumentación , Diseño de Prótesis/métodos , Falla de Prótesis/etiologíaRESUMEN
Renal vein aneurysms are rare; there are less than 10 reported cases. As of yet there have been no reported cases of renal vein aneurysm following renal transplantation. We present a case of an incidentally discovered renal vein aneurysm following uncomplicated living related renal transplant. The lesion was discovered 4 years after the transplant through abdominal ultrasound investigation of new right lower quadrant discomfort. Magnetic resonance imaging confirmed the presence of a 2.3-cm thrombosed renal vein aneurysm of the main renal vein. This case report highlights the rare nature of these events, the diagnostic challenges and the lack of satisfactory management guidelines in these cases.