RESUMEN
Traumatic brain injury (TBI) is a major cause of death and disability worldwide. There are no effective therapies available for TBI patients. Vepoloxamer is an amphiphilic polyethylene-polypropylene-polyethylene tri-block copolymer that seals membranes and restores plasma membrane integrity in damaged cells. We previously demonstrated that treatment of TBI rats with Vepoloxamer improves functional recovery. However, additional studies are needed to potentially translate Vepoloxamer treatment from preclinical studies into clinical applications. We thus conducted a study to investigate dose-response and therapeutic window of Vepoloxamer on functional recovery of adult rats after TBI. To identify the most effective dose of Vepoloxamer, male Wistar adult rats with controlled cortical impact (CCI) injury were randomly treated with 0 (vehicle), 100, 300, or 600 mg/kg of Vepoloxamer, administered intravenously (IV) at 2 h after TBI. We then performed a therapeutic window study in which the rats were treated IV with the most effective single dose of Vepoloxamer at different time points of 2 h, 4 h, 1 day, or 3 days after TBI. A battery of cognitive and neurological tests was performed. Animals were killed 35 days after TBI for histopathological analysis. Dose-response experiments showed that Vepoloxamer at all three tested doses (100, 300, 600 mg/kg) administered 2 h post injury significantly improved cognitive functional recovery, whereas Vepoloxamer at doses of 300 and 600 mg/kg, but not the 100 mg/kg dose, significantly reduced lesion volume compared to saline treatment. However, Vepoloxamer at 300 mg/kg showed significantly improved neurological and cognitive outcomes than treatment with a dose of 600 mg/kg. In addition, our data demonstrated that the dose of 300 mg/kg of Vepoloxamer administered at 2 h, 4 h, 1 day, or 3 days post injury significantly improved neurological function compared with vehicle, whereas Vepoloxamer administered at 2 h or 4 h post injury significantly improved cognitive function compared with the 1-day and 3-day treatments, with the most robust effect administered at 2 h post injury. The present study demonstrated that Vepoloxamer improves functional recovery in a dose-and time-dependent manner, with therapeutic efficacy compared with vehicle evident even when the treatment is initiated 3 days post TBI in the rat.
Asunto(s)
Lesiones Traumáticas del Encéfalo , Humanos , Ratas , Masculino , Animales , Ratas Wistar , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/patología , Polietilenos/farmacología , Polietilenos/uso terapéutico , Recuperación de la Función , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: Red blood cell (RBC)-modifying therapies have provided new opportunities for patients with sickle cell disease, although the absence of validated biomarkers of RBC function is a barrier to FDA approval and clinical adoption. Flow Adhesion (FA) and Mechanical Fragility (MF) biomarkers objectively stratify individuals with SCD into pro-adhesive vs pro-hemolytic phenotypes respectively, which may potentially help predict therapeutic responses. OBJECTIVE: A Phase 3 clinical trial to determine the effectiveness of vepoloxamer, an RBC-modifying therapy in sickle cell disease (SCD), failed to meet its primary clinical outcome. The aim of this study was to determine whether standardized flow adhesion and mechanical fragility bioassays could differentiate cellular level "responders" from "non-responders" to vepoloxamer treatment. METHODS: Standardized biomarkers of RBC function (adhesion and mechanical fragility) were utilized in this study to assess the effect of veploxamer on blood samples collected from SCD subjects and to determine whether our assays could differentiate cellular-level "responders" from "non-responders" to vepoloxamer treatment. A Wilcoxon signed-rank test was used to test for differences in adhesion in response to varying vepoloxamer treatments and a Wilcoxon Mann-Whitney test was used to assess differences in mechanical fragility, pre- and post-vepoloxamer treatment. A p-value<0.05 was considered significant. RESULTS: In this study, we report that in vitro treatment with vepoloxamer reduced adhesion by >75%in 54%of patient samples and induced changes in the membranes of sickle erythrocytes (SSRBCs) making sickle cells behave more like normal erythrocytes (AARBCs) in terms of their resistance to hemolysis. CONCLUSION: This study demonstrates that the standardized flow adhesion and mechanical fragility biomarkers described here may be useful tools to predict clinical responders to RBC-modifying therapies.
Asunto(s)
Anemia de Células Falciformes , Eritrocitos , Biomarcadores/metabolismo , Adhesión Celular , Eritrocitos/metabolismo , Eritrocitos Anormales , Hemólisis , HumanosRESUMEN
Importance: Although effective agents are available to prevent painful vaso-occlusive episodes of sickle cell disease (SCD), there are no disease-modifying therapies for ongoing painful vaso-occlusive episodes; treatment remains supportive. A previous phase 3 trial of poloxamer 188 reported shortened duration of painful vaso-occlusive episodes in SCD, particularly in children and participants treated with hydroxyurea. Objective: To reassess the efficacy of poloxamer 188 for vaso-occlusive episodes. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled, multicenter, international trial conducted from May 2013 to February 2016 that included 66 hospitals in 12 countries and 60 cities; 388 individuals with SCD (hemoglobin SS, SC, S-ß0 thalassemia, or S-ß+ thalassemia disease) aged 4 to 65 years with acute moderate to severe pain typical of painful vaso-occlusive episodes requiring hospitalization were included. Interventions: A 1-hour 100-mg/kg loading dose of poloxamer 188 intravenously followed by a 12-hour to 48-hour 30-mg/kg/h continuous infusion (n = 194) or placebo (n = 194). Main Outcomes and Measures: Time in hours from randomization to the last dose of parenteral opioids among all participants and among those younger than 16 years as a separate subgroup. Results: Of 437 participants assessed for eligibility, 388 were randomized (mean age, 15.2 years; 176 [45.4%] female), the primary outcome was available for 384 (99.0%), 15-day follow-up contacts were available for 357 (92.0%), and 30-day follow-up contacts were available for 368 (94.8%). There was no significant difference between the groups for the mean time to last dose of parenteral opioids (81.8 h for the poloxamer 188 group vs 77.8 h for the placebo group; difference, 4.0 h [95% CI, -7.8 to 15.7]; geometric mean ratio, 1.2 [95% CI, 1.0-1.5]; P = .09). Based on a significant interaction of age and treatment (P = .01), there was a treatment difference in time from randomization to last administration of parenteral opioids for participants younger than 16 years (88.7 h in the poloxamer 188 group vs 71.9 h in the placebo group; difference, 16.8 h [95% CI, 1.7-32.0]; geometric mean ratio, 1.4 [95% CI, 1.1-1.8]; P = .008). Adverse events that were more common in the poloxamer 188 group than the placebo group included hyperbilirubinemia (12.7% vs 5.2%); those more common in the placebo group included hypoxia (12.0% vs 5.3%). Conclusions and Relevance: Among children and adults with SCD, poloxamer 188 did not significantly shorten time to last dose of parenteral opioids during vaso-occlusive episodes. These findings do not support the use of poloxamer 188 for vaso-occlusive episodes. Trial Registration: ClinicalTrials.gov Identifier: NCT01737814.
Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Dolor/tratamiento farmacológico , Poloxámero/uso terapéutico , Vasodilatadores/uso terapéutico , Adolescente , Adulto , Analgésicos Opioides/uso terapéutico , Anemia de Células Falciformes/complicaciones , Niño , Método Doble Ciego , Femenino , Humanos , Masculino , Dolor/etiología , Placebos/efectos adversos , Placebos/uso terapéutico , Poloxámero/efectos adversos , Vasodilatadores/efectos adversos , Adulto JovenRESUMEN
BACKGROUND: Poloxamer-188 (MST-188) is effective in the repair/recovery of damaged cell membranes. MST-188 is a promising agent for protecting blood cell viability. The aim of the study is to test the hypothesis that MST-188 can extend the duration of platelet function. MATERIALS AND METHODS: Blood samples were collected from 20 healthy volunteers. MST-188 (10 or 2 mg/mL) containing platelet-rich plasma (PRP) was prepared with 2 procedures. First, PRP prepared from MST-188 added whole blood (WB); second, MST-188 was added to PRP. These were referred to MST-188-WB preparation (WBP) and MST-188-PRP preparation (PRPP), respectively. For control, saline was used in the same manner. Agonist-induced aggregation (AIA) studies were performed at 30, 180, and 300 minutes using Platelet Aggregation Profiler (PAP-8) aggregometer (Bio/Data Corporation, Horsham, Pennsylvania) and Adenosine diphosphate (ADP), arachidonic acid, collagen, and epinephrine as agonists at final concentration of 20 µM, 500 µg/mL, 0.19 mg/mL, and 100 µM, respectively. RESULTS: There was a protective effect of MST-188 on ADP and collagen AIA. At 300 minutes, ADP AIA was found to be 50.2% higher than saline control in 2-mg WBP, 43% at 10-mg PRPP, and 10.4% at 2-mg PRPP. Protective effect of on collagen AIA was 65.9% in 2-mg WBP, 42.74% at 10-mg PRPP, and 11.42% at 2-mg PRPP. In comparison between 30 and 300 minutes, MST-188 showed significant protection in terms of ADP and collagen receptors and for both types of preparations (WBP and PRPP). CONCLUSION: The protective effects of MST-188 on ADP- and collagen-induced platelet aggregation may contribute to the preservation of platelet functionality upon storage in blood banks.