ABSTRACT
Celiac disease (CD) is an autoimmune disorder in individuals that carry DQ2 or DQ8 MHC class II haplotypes, triggered by the ingestion of gluten. There is no current treatment other than a gluten-free diet (GFD). We have previously shown that the BL-7010 copolymer poly(hydroxyethyl methacrylate-co-styrene sulfonate) (P(HEMA-co-SS)) binds with higher efficiency to gliadin than to other proteins present in the small intestine, ameliorating gliadin-induced pathology in the HLA-HCD4/DQ8 model of gluten sensitivity. The aim of this study was to investigate the efficiency of two batches of BL-7010 to interact with gliadin, essential vitamins and digestive enzymes not previously tested, and to assess the ability of the copolymer to reduce gluten-associated pathology using the NOD-DQ8 mouse model, which exhibits more significant small intestinal damage when challenged with gluten than HCD4/DQ8 mice. In addition, the safety and systemic exposure of BL-7010 was evaluated in vivo (in rats) and in vitro (genetic toxicity studies). In vitro binding data showed that BL-7010 interacted with high affinity with gliadin and that BL-7010 had no interaction with the tested vitamins and digestive enzymes. BL-7010 was effective at preventing gluten-induced decreases in villus-to-crypt ratios, intraepithelial lymphocytosis and alterations in paracellular permeability and putative anion transporter-1 mRNA expression in the small intestine. In rats, BL-7010 was well-tolerated and safe following 14 days of daily repeated administration of 3000 mg/kg. BL-7010 did not exhibit any mutagenic effect in the genetic toxicity studies. Using complementary animal models and chronic gluten exposure the results demonstrate that administration of BL-7010 is effective and safe and that it is able to decrease pathology associated with gliadin sensitization warranting the progression to Phase I trials in humans.
Subject(s)
Celiac Disease/immunology , Gliadin/immunology , Polyhydroxyethyl Methacrylate/analogs & derivatives , Polystyrenes/pharmacology , Animals , Celiac Disease/drug therapy , Celiac Disease/pathology , Disease Models, Animal , Female , Gliadin/metabolism , Humans , Intestinal Mucosa/drug effects , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Male , Mice , Mice, Transgenic , Permeability , Polyhydroxyethyl Methacrylate/chemical synthesis , Polyhydroxyethyl Methacrylate/metabolism , Polyhydroxyethyl Methacrylate/pharmacology , Polystyrenes/chemical synthesis , Polystyrenes/metabolism , Protein Binding , Rats , Toxicity TestsABSTRACT
The GABA amides of the antidepressants nortriptyline and fluoxetine, 1 and 2, were compared to their respective parent compounds in rodent models of pain. The amides significantly reduced early nociceptive and late inflammatory responses compared to nortriptyline or fluoxetine, where 1 exhibited overall better efficacy than 2. Amide 1 was most efficacious in lowering cytokine secretion, edema and hyperalgesia induced by formalin and lambda-carrageenan, respectively. Thus, 1 is a promising candidate for the treatment of pain.
Subject(s)
Fluoxetine/chemistry , Fluoxetine/pharmacology , Nortriptyline/chemistry , Nortriptyline/pharmacology , Pain/drug therapy , gamma-Aminobutyric Acid/chemistry , Analgesics/chemical synthesis , Analgesics/chemistry , Analgesics/pharmacology , Analgesics/therapeutic use , Animals , Antidepressive Agents/chemical synthesis , Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Anxiety/chemically induced , Anxiety/drug therapy , Behavior, Animal/drug effects , Fluoxetine/chemical synthesis , Fluoxetine/therapeutic use , Formaldehyde/toxicity , Inflammation/chemically induced , Inflammation/drug therapy , Male , Mice , Nortriptyline/chemical synthesis , Nortriptyline/therapeutic use , Pain/chemically induced , RatsABSTRACT
We presently investigated the pathological effects of prolonged inhibition of brain beta-amyloid (Abeta) degradation in vivo. The results obtained revealed that intracerebroventricular injection of the protease inhibitor phosphoramidon into wild-type mice for up to a month elevated the soluble and deposited brain Abeta levels and concomitantly induced the neurodegeneration of distinct hippocampal neurons as well as neuroinflammation. These findings reproduce pathological effects associated with the initial stages of the amyloid cascade and provide a novel model system for studying their underlying mechanisms.
