Results of a phase 1 dose escalation study of intravesical TMX-101 in patients with nonmuscle invasive bladder cancer.

PURPOSE: Imiquimod, a toll like receptor 7 (TLR-7) agonist, is effective as a topical treatment for skin malignancies. TMX-101 is a liquid formulation of imiquimod. In this study we establish a safety profile of TMX-101 in patients with nonmuscle invasive bladder cancer. MATERIALS AND METHODS: We conducted a multicenter phase 1 dose escalation study in patients with nonmuscle invasive bladder cancer. Patients were included in 1 of 4 dose groups (0.05%, 0.1%, 0.2% or 0.4%) and treated with 6 weekly instillations of TMX-101, starting 2 weeks after transurethral resection of bladder tumor. Patients were evaluated weekly, and pharmacokinetic and pharmacodynamic parameters were measured. RESULTS: A total of 16 patients were included in the study with 4 per dose group. Two patients dropped out after instillation 2 in dose groups 1 and 2. Overall, 88 instillations were administered without serious adverse events. There were 118 adverse events, of which 84 were related to the study drug. All adverse events were mild or moderate and number or severity was not correlated with dose group. Of the related adverse events 70% were confined to the genitourinary tract and resolved without intervention. There was a dose dependent systemic uptake with low plasma levels up to dose group 3 (0.2%, 100 mg). Maximum plasma concentration in dose group 4 (0.4%, 200 mg) was 71.7 ng/ml. This is below plasma concentrations of 123 and 128 ng/ml without significant side effects measured in healthy volunteers after subcutaneous (30 mg) or oral intake (100 mg) of imiquimod, respectively. CONCLUSIONS: Intravesical treatment with TMX-101 is safe. The side effects are common but mild and mostly limited to the genitourinary tract. There is a low systemic uptake.

NOVEL INSIGHTS ON INTAKE OF MEAT AND PREVENTION OF SARCOPENIA: ALL REASONS FOR AN ADEQUATE CONSUMPTION.

INTRODUCION: sarcopenia is defined as a syndrome characterized by progressive and generalized loss of muscle mass and strength. The main cause of sarcopenia is the alteration of protein metabolism, in which the proteolytic processes are not accompanied by an appropriate protein synthesis and muscle cells lose progressively the sensitivity to the anabolic stimulus. The most rational approach to delay the progression of sarcopenia and counteract the anabolic resistance is proper nutrition. Meat contains biologically active compounds, such as creatine, carnitine, Conjugated Linoleic Acid (CLA) which have significant impacts upon human protein metabolism. METHODS: we performed a narrative literature review to evaluate the till-now evidence regarding: 1. adequate intake of meat in elderly as a topic for prevention of sarcopenia; 2. the correct intake of biologically active compounds contain in meat, which have significant impacts upon human protein metabolism and so have beneficial effects on prevention of sarcopenia. This review included 62 eligible studies. RESULTS: the results demonstrated that in elderly the optimum diet therapy for the sarcopenia prevention and treatment, which must aim at achieving specific metabolic goals, must recommend the consumption of 113 g of meat (220 kcal; 30 g protein) five time a week. CONCLUSION: in a varied and balanced diet, for preventing sarcopenia, it is recommended to assume meat 4-5 times a week (white meat 2 times per week, lean red meat less than 2 times per week, processed meat less than 1 time per week), as suggested in the diet pyramid for elderly.

Introducción: la sarcopenia se define como un síndrome caracterizado por la pérdida progresiva y generalizada de la masa muscular y de la fuerza. La principal causa de la sarcopenia es la alteración del metabolismo de las proteínas, en la que los procesos proteolíticos no van acompañados de una síntesis de proteínas y células musculares adecuadas, con lo que se pierde progresivamente la sensibilidad al estímulo anabólico. El enfoque más racional para retrasar la progresión de la sarcopenia y contrarrestar la resistencia anabólica es una nutrición adecuada. La carne contiene compuestos biológicamente activos, tales como creatina, carnitina y ácido linoleico conjugado (CLA) que tienen impactos significativos sobre el metabolismo de la proteína humana. Métodos: se realizó una revisión de la literatura narrativa para evaluar la evidencia hasta ahora, en relación con: 1. ingesta adecuada de carne en ancianos como prevención de la sarcopenia; 2. la ingesta correcta de compuestos biológicamente activos que contiene la carne, que tienen impactos significativos sobre el metabolismo de la proteína humana y para así obtener efectos beneficiosos en la prevención de la sarcopenia. Esta revisión incluyó 62 estudios elegibles. Resultados: los resultados demostraron que en personas de edad avanzada la terapia óptima con dieta para la prevención y tratamiento de la sarcopenia, que debe apuntar al logro de los objetivos metabólicos específicos, debe recomendar el consumo de 113 g de carne (220 kcal; 30 g de proteínas) cinco veces a la semana. Conclusión: en una dieta variada y equilibrada, para prevenir la sarcopenia, se recomienda consumir la carne 4-5 veces a la semana (carne blanca 2 veces por semana, carne roja magra menos de 2 veces por semana, carne procesada menos de 1 vez por semana), como se sugiere en la pirámide de la dieta para personas mayores.

Pharmacokinetic, Pharmacodynamic, and Activity Evaluation of TMX-101 in a Multicenter Phase 1 Study in Patients With Papillary Non-Muscle-Invasive Bladder Cancer.

INTRODUCTION/BACKGROUND: Non-muscle-invasive bladder cancer (NMIBC) has a strong tendency to recur despite adjuvant instillations. TMX-101 is a new liquid form of imiquimod for intravesical instillation and has activity in vitro against urothelial carcinoma. The purpose was to analyze the activity of TMX-101 in low-grade NMIBC. Furthermore, pharmacokinetic and pharmacodynamic characteristics and adverse events were evaluated. PATIENTS AND METHODS: A multicenter, prospective phase 1 trial in 7 patients with low-grade NMIBC was conducted. All patients underwent a marker lesion transurethral resection of the bladder tumor and 6 weekly instillations with TMX-101 0.2% or 0.4%. Cystoscopy 2 to 4 weeks after the last instillation evaluated the effect of TMX-101. RESULTS: The effective biologic dose (EBD = complete response [CR] in > 2 patients) could not be defined because none of the patients experienced CR. Maximum plasma concentration was 75.1 ng/mL in the 0.4% dose group. No drug accumulation was observed. In the pharmacodynamic analysis, urinary interleukin 1 receptor agonist (IL-1ra) represents the most sensitive and uniform response after TMX-101 instillation. A total of 87.0% reported at least 1 adverse event. All events were of grade 2 severity or less (Common Terminology Criteria of Adverse Events version 4.02). No clinically significant changes in laboratory parameters or vital signs were observed during or after treatment. CONCLUSION: Toll-like receptor 7 (TLR-7) agonists are effective in urothelial carcinoma in preclinical research. The EBD in this phase 1 study could not be determined because no patient experienced CR. IL-1ra could be valuable as a urinary biomarker in future developments. The safety of TMX-101 has been reconfirmed. New doses, other schedules, and NMIBC subgroups should be tested to define the EBD. A pilot study in carcinoma-in-situ patients is currently ongoing and results are expected shortly.

Novel insights on intake of meat and prevention of sarcopenia: all reasons for an adequate consumption / Nuevos conocimientos sobre el consumo de carne en la prevención de la sarcopenia: todos los motivos de un consumo adecuado

Introducion: sarcopenia is defined as a syndrome characterized by progressive and generalized loss of muscle mass and strength. The main cause of sarcopenia is the alteration of protein metabolism, in which the proteolytic processes are not accompanied by an appropriate protein synthesis and muscle cells lose progressively the sensitivity to the anabolic stimulus. The most rational approach to delay the progression of sarcopenia and counteract the anabolic resistance is proper nutrition. Meat contains biologically active compounds, such as creatine, carnitine, Conjugated Linoleic Acid (CLA) which have significant impacts upon human protein metabolism. Methods: we performed a narrative literature review to evaluate the till-now evidence regarding: 1. adequate intake of meat in elderly as a topic for prevention of sarcopenia; 2. the correct intake of biologically active compounds contain in meat, which have significant impacts upon human protein metabolism and so have beneficial effects on prevention of sarcopenia. This review included 62 eligible studies. Results: the results demonstrated that in elderly the optimum diet therapy for the sarcopenia prevention and treatment, which must aim at achieving specific metabolic goals, must recommend the consumption of 113 g of meat (220 kcal; 30 g protein) five time a week. Conclusion: in a varied and balanced diet, for preventing sarcopenia, it is recommended to assume meat 4-5 times a week (white meat 2 times per week, lean red meat less than 2 times per week, processed meat less than 1 time per week), as suggested in the diet pyramid for elderly (AU)

Introducción: la sarcopenia se define como un síndrome caracterizado por la pérdida progresiva y generalizada de la masa muscular y de la fuerza. La principal causa de la sarcopenia es la alteración del metabolismo de las proteínas, en la que los procesos proteolíticos no van acompañados de una síntesis de proteínas y células musculares adecuadas, con lo que se pierde progresivamente la sensibilidad al estímulo anabólico. El enfoque más racional para retrasar la progresión de la sarcopenia y contrarrestar la resistencia anabólica es una nutrición adecuada. La carne contiene compuestos biológicamente activos, tales como creatina, carnitina y ácido linoleico conjugado (CLA) que tienen impactos significativos sobre el metabolismo de la proteína humana. Métodos: se realizó una revisión de la literatura narrativa para evaluar la evidencia hasta ahora, en relación con: 1. ingesta adecuada de carne en ancianos como prevención de la sarcopenia; 2. la ingesta correcta de compuestos biológicamente activos que contiene la carne, que tienen impactos significativos sobre el metabolismo de la proteína humana y para así obtener efectos beneficiosos en la prevención de la sarcopenia. Esta revisión incluyó 62 estudios elegibles. Resultados: los resultados demostraron que en personas de edad avanzada la terapia óptima con dieta para la prevención y tratamiento de la sarcopenia, que debe apuntar al logro de los objetivos metabólicos específicos, debe recomendar el consumo de 113 g de carne (220 kcal; 30 g de proteínas) cinco veces a la semana. Conclusión: en una dieta variada y equilibrada, para prevenir la sarcopenia, se recomienda consumir la carne 4-5 veces a la semana (carne blanca 2 veces por semana, carne roja magra menos de 2 veces por semana, carne procesada menos de 1 vez por semana), como se sugiere en la pirámide de la dieta para personas mayores (AU)