A new model of interactive effects of alcohol and high-fat diet on hepatic fibrosis

Alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) are the most frequent conditions leading to elevated liver enzymes and liver cirrhosis, respectively, in the Western world. However, despite strong epidemiological evidence for combined effects on the progression of liver injury, the mutual interaction of the pathophysiological mechanisms is incompletely understood. The aim of this study was to establish and analyze an experimental murine model, where we combined chronic alcohol administration with a NASH-inducing high-fat (HF) diet.

Pharmacokinetics and pharmacodynamic effects of meloxicam in piglets subjected to a kaolin inflammation model

The pharmacokinetics and the analgesic, anti-inflammatory and antipyretic effects of meloxicam were investigated in a placebo controlled study in 2-week-old piglets. Inflammation was induced by a subcutaneous injection of kaolin in the left metacarpus, and 16 h later, meloxicam (0.6 mg/kg) or saline was administered intramuscularly. The absorption half-life was relatively short (0.19 h) and the elimination half-life was 2.6 h. Mechanical nociceptive threshold testing was used to evaluate the analgesic effect, but no significant effect of the meloxicam treatment was found. The skin temperature of the inflamed area increased after the kaolin injection, but no significant decrease in temperature was found after administration of meloxicam. Only limited pyresis was observed after the kaolin injection, and no significant antipyretic effect of meloxicam was found. The results indicated that this dose of meloxicam had very limited anti-inflammatory and analgesic effects in piglets.

The well-being model: a new drug interaction model for positive and negative effects

BACKGROUND: Drugs are routinely combined in anesthesia and pain management to obtain an enhancement of the desired effects. However, a parallel enhancement of the undesired effects might take place as well, resulting in a limited therapeutic usefulness. Therefore, when addressing the question of optimal drug combinations, side effects must be taken into account. METHODS: By extension of a previously published interaction model, the authors propose a method to study drug interactions considering also their side effects. A general outcome parameter identified as patient's well-being is defined by superposition of positive and negative effects. Well-being response surfaces are computed and analyzed for varying drugs pharmacodynamics and interaction types. In particular, the existence of multiple maxima and of optimal drug combinations is investigated for the combination of two drugs. RESULTS: Both drug pharmacodynamics and interaction type affect the well-being surface and the deriving optimal combinations. The effect of the interaction parameters can be explained in terms of synergy and antagonism and remains unchanged for varying pharmacodynamics. For all simulations performed for the combination of two drugs, the presence of more than one maximum was never observed. CONCLUSIONS: The model is consistent with clinical knowledge and supports previously published experimental results on optimal drug combinations. This new framework improves understanding of the characteristics of drug combinations used in clinical practice and can be used in clinical research to identify optimal drug dosing.

Effects of local continuous release of brain derived neurotrophic factor (BDNF) on peripheral nerve regeneration in a rat model

The purpose of this study was to evaluate the effect of continuously released BDNF on peripheral nerve regeneration in a rat model. Initial in vitro evaluation of calcium alginate prolonged-release-capsules (PRC) proved a consistent release of BDNF for a minimum of 8 weeks. In vivo, a worst case scenario was created by surgical removal of a 20-mm section of the sciatic nerve of the rat. Twenty-four autologous fascia tubes were filled with calcium alginate spheres and sutured to the epineurium of both nerve ends. The animals were divided into 3 groups. In group 1, the fascial tube contained plain calcium alginate spheres. In groups 2 and 3, the fascial tube contained calcium alginate spheres with BDNF alone or BDNF stabilized with bovine serum albumin, respectively. The autocannibalization of the operated extremity was clinically assessed and documented in 12 additional rats. The regeneration was evaluated histologically at 4 weeks and 10 weeks in a blinded manner. The length of nerve fibers and the numbers of axons formed in the tube was measured. Over a 10-week period, axons have grown significantly faster in groups 2 and 3 with continuously released BDNF compared to the control. The rats treated with BDNF (groups 2 and 3) demonstrated significantly less autocannibalization than the control group (group 1). These results suggest that BDNF may not only stimulate faster peripheral nerve regeneration provided there is an ideal, biodegradable continuous delivery system but that it significantly reduces the neuropathic pain in the rat model.

Vascular remodeling and antitumoral effects of mTOR inhibition in a rat model of hepatocellular carcinoma

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is amenable to only few treatments. Inhibitors of the kinase mTOR are a new class of immunosuppressors already in use after liver transplantation. Their antiproliferative and antiangiogenic properties suggest that these drugs could be considered to treat HCC. We investigated the antitumoral effects of mTOR inhibition in a HCC model. METHODS: Hepatoma cells were implanted into livers of syngeneic rats. Animals were treated with the mTOR inhibitor sirolimus for 4 weeks. Tumor growth was monitored by MR imaging. Antiangiogenic effects were assessed in vivo by microvessel density and corrosion casts and in vitro by cell proliferation, tube formation and aortic ring assays. RESULTS: Treated rats had significantly longer survival and developed smaller tumors, fewer extrahepatic metastases and less ascites than controls. Sirolimus decreased intratumoral microvessel density resulting in extensive necrosis. Endothelial cell proliferation was inhibited at lower drug concentrations than hepatoma cells. Tube formation and vascular sprouting of aortic rings were significantly impaired by mTOR inhibition. Casts revealed that in tumors treated with sirolimus vascular sprouting was absent, whereas intussusception was observed. CONCLUSIONS: mTOR inhibition significantly reduces HCC growth and improves survival primarily via antiangiogenic effects. Inhibitors of mTOR may have a role in HCC treatment.

Effects of an aging vascular model on healthy and diseased hearts

The vitamin D(3) and nicotine (VDN) model is a model of isolated systolic hypertension (ISH) due to arterial calcification raising arterial stiffness and vascular impedance similar to an aged and stiffened arterial tree. We therefore analyzed the impact of this aging model on normal and diseased hearts with myocardial infarction (MI). Wistar rats were treated with VDN (n = 9), subjected to MI by coronary ligation (n = 10), or subjected to a combination of both MI and VDN treatment (VDN/MI, n = 14). A sham-treated group served as control (Ctrl, n = 10). Transthoracic echocardiography was performed every 2 wk, whereas invasive indexes were obtained at week 8 before death. Calcium, collagen, and protein contents were measured in the heart and the aorta. Systolic blood pressure, pulse pressure, thoracic aortic calcium, and end-systolic elastance as an index of myocardial contractility were highest in the aging model group compared with MI and Ctrl groups (P(VDN) < 0.05, 2-way ANOVA). Left ventricular wall stress and brain natriuretic peptide (P(VDNxMI) = not significant) were highest, while ejection fraction, stroke volume, and cardiac output were lowest in the combined group versus all other groups (P(VDNxMI) < 0.05). The combination of ISH due to this aging model and MI demonstrates significant alterations in cardiac function. This model mimics several clinical phenomena of cardiovascular aging and may thus serve to further study novel therapies.

Drug-induced respiratory depression: an integrated model of drug effects on the hypercapnic and hypoxic drive

Drug-induced respiratory depression is a common side effect of the agents used in anesthesia practice to provide analgesia and sedation. Depression of the ventilatory drive in the spontaneously breathing patient can lead to severe cardiorespiratory events and it is considered a primary cause of morbidity. Reliable predictions of respiratory inhibition in the clinical setting would therefore provide a valuable means to improve the safety of drug delivery. Although multiple studies investigated the regulation of breathing in man both in the presence and absence of ventilatory depressant drugs, a unified description of respiratory pharmacodynamics is not available. This study proposes a mathematical model of human metabolism and cardiorespiratory regulation integrating several isolated physiological and pharmacological aspects of acute drug-induced ventilatory depression into a single theoretical framework. The description of respiratory regulation has a parsimonious yet comprehensive structure with substantial predictive capability. Simulations relative to the synergistic interaction of the hypercarbic and hypoxic respiratory drive and the global effect of drugs on the control of breathing are in good agreement with published experimental data. Besides providing clinically relevant predictions of respiratory depression, the model can also serve as a test bed to investigate issues of drug tolerability and dose finding/control under non-steady-state conditions.

Exogenous surfactant application in a rat lung ischemia reperfusion injury model: effects on edema formation and alveolar type II cells

BACKGROUND: Prophylactic exogenous surfactant therapy is a promising way to attenuate the ischemia and reperfusion (I/R) injury associated with lung transplantation and thereby to decrease the clinical occurrence of acute lung injury and acute respiratory distress syndrome. However, there is little information on the mode by which exogenous surfactant attenuates I/R injury of the lung. We hypothesized that exogenous surfactant may act by limiting pulmonary edema formation and by enhancing alveolar type II cell and lamellar body preservation. Therefore, we investigated the effect of exogenous surfactant therapy on the formation of pulmonary edema in different lung compartments and on the ultrastructure of the surfactant producing alveolar epithelial type II cells. METHODS: Rats were randomly assigned to a control, Celsior (CE) or Celsior + surfactant (CE+S) group (n = 5 each). In both Celsior groups, the lungs were flush-perfused with Celsior and subsequently exposed to 4 h of extracorporeal ischemia at 4 degrees C and 50 min of reperfusion at 37 degrees C. The CE+S group received an intratracheal bolus of a modified natural bovine surfactant at a dosage of 50 mg/kg body weight before flush perfusion. After reperfusion (Celsior groups) or immediately after sacrifice (Control), the lungs were fixed by vascular perfusion and processed for light and electron microscopy. Stereology was used to quantify edematous changes as well as alterations of the alveolar epithelial type II cells. RESULTS: Surfactant treatment decreased the intraalveolar edema formation (mean (coefficient of variation): CE: 160 mm3 (0.61) vs. CE+S: 4 mm3 (0.75); p < 0.05) and the development of atelectases (CE: 342 mm3 (0.90) vs. CE+S: 0 mm3; p < 0.05) but led to a higher degree of peribronchovascular edema (CE: 89 mm3 (0.39) vs. CE+S: 268 mm3 (0.43); p < 0.05). Alveolar type II cells were similarly swollen in CE (423 microm3(0.10)) and CE+S (481 microm3(0.10)) compared with controls (323 microm3(0.07); p < 0.05 vs. CE and CE+S). The number of lamellar bodies was increased and the mean lamellar body volume was decreased in both CE groups compared with the control group (p < 0.05). CONCLUSION: Intratracheal surfactant application before I/R significantly reduces the intraalveolar edema formation and development of atelectases but leads to an increased development of peribronchovascular edema. Morphological changes of alveolar type II cells due to I/R are not affected by surfactant treatment. The beneficial effects of exogenous surfactant therapy are related to the intraalveolar activity of the exogenous surfactant.

Effects of EDP-420 on penicillin-resistant and quinolone- and penicillin-resistant pneumococci in the rabbit meningitis model

OBJECTIVES: To test the efficacy of EDP-420, a new ketolide, in experimental pneumococcal meningitis and to determine its penetration into the CSF. METHODS: The experimental rabbit model was used in this study and EDP-420 was tested against a penicillin-resistant and a penicillin- and quinolone-resistant mutant. EDP-420 was also tested against both strains in time-killing assays over 8 h in vitro. RESULTS: In experimental meningitis, EDP-420 produced a bactericidal activity comparable to the standard regimen based on a combination of vancomycin with ceftriaxone against a penicillin-resistant Streptococcus pneumoniae and a penicillin- and quinolone-resistant S. pneumoniae isolate. The penetration of EDP-420 into inflamed meninges was 38% after an i.v. injection of 10 mg/kg. The bactericidal activity of EDP-420 was also confirmed in in vitro time-killing assays. CONCLUSIONS: EDP-420 is an efficacious alternative treatment in pneumococcal meningitis, especially when resistant strains are suspected.

Cytotoxic effects of camptothecin and cisplatin combined with tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) in a model of primary culture of non-small cell lung cancer

The cytokine tumor-necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) has been shown to preferentially induce apoptosis in cancer cells. A previous study of our group demonstrated that non-small cell lung cancer cell lines can be sensitized to Apo2L/TRAIL-induced apoptosis by chemotherapeutic agents. The aim of the present study was the evaluation of these results in a model of primary culture of non-small cell lung cancer.