RESUMO
AIMS: To address the need for noninvasive alternatives to metabolic surgery or duodenal exclusion devices for the management of type 2 diabetes (T2D) and obesity by developing an orally administered therapeutic polymer, GLY-200, designed to bind to and enhance the barrier function of mucus in the gastrointestinal tract to establish duodenal exclusion noninvasively. MATERIALS AND METHODS: A Phase 1, randomized, double-blind, placebo-controlled, single- (SAD) and multiple-ascending-dose (MAD) healthy volunteer study was conducted. In the SAD arm, four cohorts received a single dose of 0.5 g up to 6.0 g GLY-200 or placebo, while in the MAD arm, four cohorts received 5 days of twice-daily or three-times-daily dosing (total daily dose 2.0 g up to 6.0 g GLY-200 or placebo). Assessments included safety and tolerability (primary) and exploratory pharmacodynamics, including serum glucose, insulin, bile acids and gut hormones. RESULTS: No safety signals were observed; tolerability signals were limited to mild to moderate dose-dependent gastrointestinal events. In the MAD arm (Day 5), reductions in glucose and insulin and increases in bile acids, glucagon-like peptide-1, peptide YY and glicentin, were observed following a nonstandardized meal in subjects receiving twice-daily dosing of 2.0 g GLY-200 (N = 9) versus those receiving placebo (N = 8). CONCLUSIONS: GLY-200 is safe and generally well tolerated at doses of ≤2.0 g twice daily. Pharmacodynamic results mimic the biomarker signature observed after Roux-en-Y gastric bypass and duodenal exclusion devices, indicating a pharmacological effect in the proximal small intestine. This study represents the first clinical demonstration that duodenal exclusion can be achieved with an oral drug and supports further development of GLY-200 for the treatment of obesity and/or T2D.
Assuntos
Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Insulina/uso terapêutico , Ácidos e Sais Biliares , Glicemia/metabolismo , Insulina Regular Humana/uso terapêutico , Glucose/uso terapêutico , Obesidade/tratamento farmacológico , Método Duplo-CegoRESUMO
More than 90% of surgical patients develop postoperative adhesions, and the incidence of hospital re-admissions can be as high as 20%. Current adhesion barriers present limited efficacy due to difficulties in application and incompatibility with minimally invasive interventions. To solve this clinical limitation, we developed an injectable and sprayable shear-thinning hydrogel barrier (STHB) composed of silicate nanoplatelets and poly(ethylene oxide). We optimized this technology to recover mechanical integrity after stress, enabling its delivery though injectable and sprayable methods. We also demonstrated limited cell adhesion and cytotoxicity to STHB compositions in vitro. The STHB was then tested in a rodent model of peritoneal injury to determine its efficacy preventing the formation of postoperative adhesions. After two weeks, the peritoneal adhesion index was used as a scoring method to determine the formation of postoperative adhesions, and STHB formulations presented superior efficacy compared to a commercially available adhesion barrier. Histological and immunohistochemical examination showed reduced adhesion formation and minimal immune infiltration in STHB formulations. Our technology demonstrated increased efficacy, ease of use in complex anatomies, and compatibility with different delivery methods, providing a robust universal platform to prevent postoperative adhesions in a wide range of surgical interventions.
RESUMO
Few therapeutic options exist for treatment of IC/BPS. A novel high MW GAG biopolymer ("SuperGAG") was synthesized by controlled oligomerization of CS, purified by TFF and characterized by SEC-MALLS and 1H-NMR spectroscopy. The modified GAG biopolymer was tested in an OVX female rat model in which bladder permeability was induced by a 10-minute intravesicular treatment with dilute (1 mg/ml) protamine sulfate and measured by classical Ussing Chamber TEER measurements following treatment with SuperGAG, chondroitin sulfate, or saline. The effect on abrogating the abdominal pain response was assessed using von Frey filaments. The SuperGAG biopolymer was then investigated in a second, genetically modified mouse model (URO-MCP1) that increasingly is accepted as a model for IC/BPS. Permeability was induced with a brief exposure to a sub-noxious dose of LPS and was quantified using contrast-enhanced MRI (CE-MRI). The SuperGAG biopolymer restored impermeability to normal levels in the OVX rat model as measured by TEER in the Ussing chamber and reduced the abdominal pain response arising from induced permeability. Evaluation in the URO-MCP1 mouse model also showed restoration of bladder impermeability and showed the utility of CE-MRI imaging for evaluating the efficacy of agents to restore bladder impermeability. We conclude novel high MW SuperGAG biopolymers are effective in restoring urothelial impermeability and reducing pain produced by loss of the GAG layer on the urothelium. SuperGAG biopolymers could offer a novel and effective new therapy for IC/BPS, particularly if combined with MRI to assess the efficacy of the therapy.
Assuntos
Biopolímeros/uso terapêutico , Cistite Intersticial/tratamento farmacológico , Glicosaminoglicanos/uso terapêutico , Animais , Cistite Intersticial/diagnóstico por imagem , Cistite Intersticial/metabolismo , Feminino , Imageamento por Ressonância Magnética , Camundongos Transgênicos , Ovariectomia , Permeabilidade/efeitos dos fármacos , Protaminas , Ratos Sprague-Dawley , Bexiga Urinária/diagnóstico por imagem , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismoRESUMO
BACKGROUND: Chemically modified sodium hyaluronate and carboxymethylcellulose (HA/CMC) membrane clinically reduces adhesion formation following surgery but was not designed for laparoscopic use. HA/CMC powder of identical chemical composition has been developed to allow for application laparoscopically. We compared the adhesion reduction efficacy of HA/CMC powder and film when applied directly to or remote from sites of surgical trauma. We also investigated the effect of the powder on wound healing. MATERIALS AND METHODS: Two animal models of adhesion formation were used to evaluate efficacy: a rat peritoneal sidewall defect model and a rabbit cecal abrasion/sidewall defect model. The products were applied directly to the defect or the contralateral sidewall. Adhesions were examined seven days after surgery. In a separate study, the effect of the powder on healing was evaluated at 5, 7, and 28 days using a rat incisional wound strength model. RESULTS: HA/CMC powder and film, when applied directly to the peritoneal defect, significantly reduced adhesions relative to the untreated control in both models. Remote applications of HA/CMC powder also reduced adhesions. In contrast, remote applications of HA/CMC film had no effect. HA/CMC powder did not significantly alter incisional wound strength at any of the timepoints tested. CONCLUSION: In our preclinical models, HA/CMC powder had similar adhesion reduction efficacy to HA/CMC film when applied directly to sites of trauma. In addition, HA/CMC powder reduced adhesions remote from the application site. Importantly, HA/CMC powder did not impair incisional wound healing. On the basis of these results, future investigation of HA/CMC powder is warranted.
Assuntos
Carboximetilcelulose Sódica/administração & dosagem , Ácido Hialurônico/administração & dosagem , Aderências Teciduais/prevenção & controle , Animais , Materiais Biocompatíveis/administração & dosagem , Feminino , Laparoscopia/efeitos adversos , Laparoscopia/métodos , Teste de Materiais , Membranas Artificiais , Modelos Animais , Pós , Coelhos , Ratos , Ratos Sprague-Dawley , CicatrizaçãoRESUMO
A series of poly(ethylene glycol)-co-poly(lactide) diacrylate macromers was synthesized with variable PEG molecular weights (10 or 20 kDa) and lactate contents (0 or 6 lactates per end group). These macromers were polymerized to form hydrogels by free radical polymerization using either redox or photochemical initiators. The extent of polymerization was determined by monitoring the compressive modulus of the resulting hydrogels and by quantitative determination of unreacted acrylate after exhaustive hydrolysis of the gel. Polymerization efficiency was found to depend on the lactate content of the macromer, with higher lactate macromers giving more efficient polymerization. For redox-initiated polymerization using ferrous gluconate/t-butyl hydroperoxide initiator, macromers containing approximately six lactate repeats per end group required lower concentrations of initiator to reach high conversion than lactate-free macromers. Photochemical polymerization with α,α-dimethoxy-α-phenylacetophenone (Irgacure 651(®)) was found to be less efficient than redox polymerization, requiring the addition of N-vinyl-2- pyrrolidone (NVP) as a co-monomer to achieve conversions comparable with redox polymerization. When conditions were optimized to provide near complete conversion for all gels, the presence of lactate repeat units in the hydrogel was generally found to reduce swelling and increase the compressive modulus. Calculated values of molecular weight between cross-links (M(c)) and mesh size using Flory-Rehner theory showed that macromer molecular weight had the greatest impact on the network structure of the gel.