lexipafant and Disease-Models--Animal

The clinical diagnostics and therapeutic standards applied in the routine management of human acute pancreatitis are based on the results of animal experiments and human studies performed in the past several decades. During this time period, a number of experimental acute pancreatitis models have been developed, which allowed us to study the etiopathogenesis of acute pancreatitis, analyzing the local and remote complications of the inflammatory processes and also the preclinical testing of potentially effective drugs and agents. Only animal models are suitable to examine the very early phase of the pathogenetic processes in acute pancreatitis. In recent years, the progress in molecular genetic methods allowed us to create genetically engineered animal models to clarify the role of different mediators in the pathogenetic process. There is no doubt that the results gained from experimental animal studies are of limited value concerning human pancreatitis. Nevertheless, experimental studies seem to be indispensable in the progress of management of human pancreatic disorders.

Topics: Animals; Disease Models, Animal; Enteral Nutrition; Gastrointestinal Agents; Humans; Imidazoles; Leucine; Octreotide; Pancreatitis, Acute Necrotizing; Protease Inhibitors; Somatostatin

The incidence of acute pancreatitis per 100,000 population ranges from 10 to 46. The mortality of acute edematous interstitial pancreatitis is < 1%, while patients suffering from hemorrhagic necrotizing pancreatitis die from their disease in 10-24%. 80% of all cases of acute pancreatitis are etiologically correlated to diseases of the biliary tract or an excess alcohol consumption. As of today, no specific and causal treatment for acute pancreatitis has been established. Early prognostic factors for the evaluation of the clinical course of acute eipancreatitis are three or more indicators of organ failure in the Ranson or Imrie score, the development of extrapancreatic complications or the detection of pancreatic necrosis on contrast-enhanced CT scans. Elevated C-reactive protein (CRP) levels > 130 mg/l can predict a severe course of acute pancreatitis with a high sensitivity. The foundation of medical treatment in acute pancreatitis is the substitution of fluids to counteract hypovolemia. Furthermore, the relief of sometimes severe visceral pain has the highest priority. Infusion of procaine has been found to be ineffective for this purpose. The use of antibiotics should be restricted to patients with pancreatic necrosis. Enteral nutrition has no adverse effect compared to parenteral nutrition and is likely to be beneficial to the course of pancreatitis.

Topics: Acute Disease; Adjuvants, Immunologic; Analgesics; Animals; Anti-Bacterial Agents; APACHE; C-Reactive Protein; Cholangiography; Cholangiopancreatography, Endoscopic Retrograde; Clinical Trials as Topic; Disease Models, Animal; Double-Blind Method; Enteral Nutrition; Humans; Imidazoles; Leucine; Multicenter Studies as Topic; Multiple Organ Failure; Pancreatitis; Pancreatitis, Acute Necrotizing; Placebos; Platelet Activating Factor; Prognosis; Protease Inhibitors; Randomized Controlled Trials as Topic; Retrospective Studies; Tomography, X-Ray Computed

The effects of anti-inflammatory drugs on glial immunity and neuropathology were determined in a severe combined immune deficiency (SCID) mouse model of HIV-1 encephalitis. HIV-1-infected human monocyte-derived macrophages (MDM) are stereotactically inoculated into basal ganglia resulting in a multinucleated giant cell encephalitis. A platelet activating factor antagonist and a matrix metalloproteinase inhibitor, which also inhibits tumor necrosis factor alpha release, were administered to animals at the time of the MDM inoculation. The drugs administered in combination markedly reduced brain inflammation, astrogliosis and microglia activation. These findings demonstrate that reduction of brain inflammatory responses, independent of viral replication, can affect HIVE pathology in an animal model system of disease.

Topics: AIDS Dementia Complex; Animals; Benzyl Compounds; Cell Survival; Dexamethasone; Disease Models, Animal; Drug Combinations; Gliosis; HIV-1; Humans; In Vitro Techniques; Interleukin-1; Interleukin-8; Leucine; Macrophages; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Mice; Mice, SCID; Microglia; Neurons; Pentoxifylline; Platelet Activating Factor; Protease Inhibitors; Succinates; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The platelet activating factor (PAF) antagonist, Lexipafant, has been used in experimental models and clinical trials to treat severe acute pancreatitis (AP). The purpose of this study was to determine whether Lexipafant reduces the local and systemic components of AP in a murine model of mild, edematous AP.. Forty-eight female Swiss-Webster mice were divided into four groups. Group 1 received 50 microl of saline ip every hour for 6 h (sham). Group 2 received saline treatment, plus Lexipafant (25 mg/kg dose ip, every 3 h starting 1 h after the first saline injection) (sham/Lex). Group 3 received cerulein (50 microg/kg dose ip, every hour for 6 h) (AP). Group 4 received AP, plus therapeutic treatment with Lexipafant (AP/Lex). Animals were sacrificed 3 h after the last injection. Serum cytokine levels were determined by ELISA. Standard assays were performed for serum amylase activity and lung myeloperoxidase activity (MPO). Histology was scored by two blinded investigators.. Serum cytokines (TNFalpha, IL-1beta), lung MPO, and serum amylase activity were reduced by PAF antagonism. Histology showed a trend toward improvement with Lexipafant, but did not reach statistical significance.. The PAF antagonism reduces the severity of systemic inflammation when given after the induction of mild AP in mice. These results suggest that Lexipafant may be useful in the treatment of mild pancreatitis after its clinical onset.

Topics: Acute Disease; Amylases; Animals; Disease Models, Animal; Female; Imidazoles; Interleukin-1; Leucine; Lung; Mice; Pancreatitis; Peroxidase; Platelet Activating Factor; Tumor Necrosis Factor-alpha

To assess the anti-inflammatory action of lexipafant (BB-882), a platelet activating factor antagonist, in an animal model of acute colitis.. An animal intervention study.. Following the rectal instillation of formalin 0.75% into male New Zealand White (NZW) rabbits, 0.85 ml of aggregated immunoglobulin was administered i.v. Treatment groups (0.8 mg/kg, n = 6; 2.4 mg/kg, n = 13; 3.2 mg/kg, n = 10) were given bolus doses of BB-882 two-hourly i.v. (control group, n = 25). Rectal dialysis was performed before induction of colitis and sacrifice. Dialysate leukotriene B4 (LTB4), prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) levels were determined. Tissue was saved for histology and measurement of myeloperoxidase content.. There was a dose-dependent improvement in macroscopic scores (2.4 and 3.2 mg/kg: P < 0.02, P < 0.001) and myeloperoxidase levels (3.2 mg/kg: P < 0.04). Dialysate LTB4 levels fell (2.4 and 3.2 mg/kg: P < 0.03, P < 0.02) as did PGE2 levels. TXB2 concentrations remained unaffected.. The PAF receptor antagonist BB-882 shows efficacy in treating inflammation in an animal model of acute colitis as evidenced by a dose-dependent fall in macroscopic mucosal damage, neutrophil infiltration and reduced generation of inflammatory mediators.

Topics: Animals; Colitis; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Formaldehyde; Injections, Intravenous; Intestinal Mucosa; Leucine; Leukotriene B4; Male; Platelet Membrane Glycoproteins; Rabbits; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Thromboxane B2