Craig Wegner

AstraZeneca | AZ · New Opportunities Group

A new model for translational research and drug repositioning has recently been established based on three-way partnerships between public funders, the pharmaceutical industry and academic investigators. Through two pioneering initiatives - one involving the Medical Research Council in the United Kingdom and one involving the National Center for Ad...

In an effort to uncover systematic learnings that can be applied to improve compound survival, an analysis was performed on data from Phase II decisions for 44 programs at Pfizer. It was found that not only were the majority of failures caused by lack of efficacy but also that, in a large number of cases (43%), it was not possible to conclude wheth...

The design and synthesis of a series of 11,12-cyclic carbamate derivatives of 6-O-methylerythromycin A that are novel, nonpeptide LHRH antagonists, is described. The macrolide antagonist 1, discovered during a screen of our chemical repository, was compared to a macrocyclic peptide antagonist 2 using molecular modeling, thus providing a model for t...

Many therapeutic agents stimulate histamine release from mast cells, which results in a decrease in blood pressure. The purpose of this study is to establish a method to determine if the mechanism of action, or one of the mechanisms, of hypotensive compounds is related to the release of histamine. The method was developed using a novel hypotensive...

Reactive oxygen species (ROS) have been implicated as important mediators of cellular damage during ischemia/reperfusion. AEOL10113 is a low-molecular-weight superoxide dismutase mimetic that has dismutase activity against ROS. The objective of this study was to test the cardioprotective efficacy of postischemic administration of AEOL10113 in a rat...

The role of endothelin-B (ET(B)) receptors in circulatory homeostasis is ambiguous, reflecting vasodilator and constrictor effects ascribed to the receptor and diuretic and natriuretic responses that could oppose the hypertensive effects of ET excess. With the use of conscious, telemetry-instrumented cynomolgus monkeys, we characterized the hyperte...

Transforming growth factor beta (TGF-beta) is a multifunctional protein that has been shown to possess potent growth-inhibitory activity. To identify small molecular weight compounds with TGF-beta-like activities, high throughput screening was performed using mink lung epithelial cells stably transfected with a TGF-beta-responsive plasminogen activ...

To evaluate the feasibility of using dynamic contrast-enhanced magnetic resonance imaging (MRI) for assessment of muscle perfusion in a rat model of hind-limb ischemia. The acute alteration and chronic recovery in muscle perfusion and perfusion reserve after femoral artery ligation were quantified using the maximum Gd-DTPA uptake rate obtained by a...

Bimoclomol is a new compound that improves cell survival under experimental stress conditions partly by increasing intracellular heat shock proteins (HSPs). HSPs, especially HSP70, play a cytoprotective role in the rat heart. Rat neonatal cardiomyocytes were used to determine the ability of bimoclomol to induce HSP70 and affect cell survival across...

Bimoclomol has been shown to increase an inducible member of the heat shock protein 70 family (HSP70) and cytoprotect in vitro. Here, we addressed whether oral pretreatment of rats with bimoclomol could elevate myocardial HSP70 and reduce infarct size in a rat model of ischemia and reperfusion. Rats were pretreated with bimoclomol at 3, 6 or 18 h o...

Torsade de pointes is a rare but potentially fatal ventricular arrhythmia associated with drug-induced delayed repolarization and prolongation of the QT interval. To determine if the arrhythmogenic potential of noncardiac drugs can be assessed in vitro, we evaluated the effects of 12 drugs on the action potential duration (APD) of cardiac Purkinje...

Three models/protocols designed to mimic an inflammation process characteristic of a specific lung disease are described in this unit. Included are a single allergen inhalation in monkeys to model acute asthmatic episodes, repeated allergen inhalations in monkeys to model chronic asthma, and a lower-respiratory viral infection in mice to model acut...

Gonadotropin-releasing hormone (GnRH) stimulates the synthesis and secretion of the gonadotropins that maintain the reproductive axis in mammals. Efforts have focused on the characterization of novel, nonpeptidic orally active antagonists of the GnRH receptor. An erythromycin A derivative, A-198401 (11-deoxy-11-[carboxy (3,4-dichlorophenethyl) amin...

This study was designed to quantify the long-term contribution of endogenous endothelin-1 (ET-1) and ET(A) receptors to the regulation of arterial pressure under normal conditions in nonhuman primates. Therefore, mean arterial pressure (MAP) and heart rate were measured 24 h/day with the use of telemetry techniques in conscious cynomolgus monkeys u...

A series of bis(trifluoromethyl)pyrazoles (BTPs) has been found to be a novel inhibitor of cytokine production. Identified initially as inhibitors of IL-2 synthesis, the BTPs have been optimized in this regard and even inhibit IL-2 production with a 10-fold enhancement over cyclosporine in an ex vivo assay. Additionally, the BTPs show inhibition of...

ABT-229 (8,9-anhydro-4"-deoxy-3'-N-desmethyl-3'-N-ethylerythromycin B-6,9-hemiacetal), a synthetic derivative of erythromycin (ERY) with no antibiotic activity, has been shown to bind to motilin receptors and stimulate contractile activity of the antrum and small intestine. The objective of this study was to determine the effect of ABT-229 on canin...

Endothelin-1 (ET-1), a potent vasoactive and mitogenic peptide, has been implicated in a number of cardiovascular diseases, including congestive heart failure, neointimal hyperplasia associated with restenosis, and hypertension. The vasoconstriction induced by ET-1 is thought to be mediated mainly by its action on ET(A) receptors on vascular smooth...

To test the hypothesis that neutrophil influx is important for the removal of necrotic airway epithelial cells, rhesus monkeys were treated with a function-blocking monoclonal antibody (MAb) against CD18 followed by exposure to ozone or filtered air. CD18 MAb-treated, ozone-exposed monkeys showed a significant inhibition of neutrophil emigration an...

Rapamycin, a macrolide antibiotic known to prevent allograft rejection, is a potent inhibitor of cell proliferation. Therefore we studied the effects of orally administered rapamycin in a pig model of balloon injury in an attempt to reduce the cellular proliferation and neointimal formation thought to play a role in restenosis. Twenty Yucatan minip...

Catheter-directed thrombolysis has gained increasing acceptance for the treatment of patients who present with vascular occlusion; however, intravenous injection may be preferable in selected patients. Recombinant prourokinase (r-proUK) is a recently-developed fibrin-selective thrombolytic agent with specificity for clot-bound plasminogen. To compa...

Platelet-activating factor (PAF) may be an important mediator of allergic rhinitis. In the present study we evaluated the effectiveness of a recently described PAF antagonist (ABT-491) in rat and guinea pig models of allergic rhinitis. PAF, when perfused through the nasal passages of anesthetized Brown Norway rats, provoked an acute increase, measu...

Endothelin has been implicated in the pathogenesis of acute renal failure associated with radiocontrast media. The current study was designed to determine the effect of endothelin receptor blockade in a model of radiocontrast-induced nephropathy. Inhibition of prostanoids and nitric oxide with indomethacin and L-nitroarginine methyl ester (L-NAME)...

To investigate the cellular immune events contributing to airway hyperreactivity (AHR), we studied an in vivo mouse model induced by the hapten picryl (trinitrophenyl) chloride (PCl). Mice were immunized by cutaneous contact sensitization with PCl and airway challenged subsequently with picryl sulfonic acid (PSA) antigen (Ag). Increased airway resi...

Balloon angioplasty has become an important intervention in clinical cardiology; however, the technique is associated with a high incidence of restenosis, requiring repeated procedures. Endothelin-1 (ET-1), specifically through its action on ET(A) receptors, has been implicated in the cell proliferation and subsequent neointimal formation that lead...

Endothelin-1 (ET-1), a potent vasoactive and mitogenic peptide produced by endothelial cells, has been implicated in a number of cardiovascular diseases, including congestive heart failure and neointimal hyperplasia associated with restenosis. The vasoconstriction induced by ET-1 is thought to be mediated mainly by its action on ET-A receptors on v...

Proinflammatory mediators such as histamine promote expression of Pselectin and PAF on endothelium of post-capillary venules, events which can lead to rolling and adhesion of leukocytes to the vessel wall. Although these interactions have been modified by PAF antagonists at single dose levels, dose-response data for this phenomenon has not been rep...

Oxygen-derived radicals play critical roles in many types of lung injuries involving environmental pollutants. Recently, intranasal insufflation of recombinant human manganese superoxide dismutase (rh-MnSOD) was reported to be efficacious against a hyperoxia model of oxidant lung injury in mice. We employed immunocytochemistry to examine the distri...

Using various animal models of toxic or antigenic-induced airway inflammation, we have demonstrated that adhesion molecules play an important role in the recruitment, retention, and site-specific activation of inflammatory cells within the airways. Furthermore, we have shown that cytokines may contribute to inflammatory responses in the airways by...

The distribution of intercellular adhesion molecule-1 (ICAM-1) on alveolar epithelial cells and the effects of exposure to 100% O2 on ICAM-1 expression in mouse lungs were studied by EM immunocytochemistry and immunoblot analysis. Cryoultrathin sections from mouse lungs exposed to air or 100% O2 for 84 h were labeled with a monoclonal rat anti-mous...

BI-L-226, a 2,6-disubstituted 4-(2-arylethenyl)phenol, is a potent and selective 5-lipoxygenase inhibitor which shows excellent inhibition of antigen-induced leukotriene generation in the lung of cynomolgus monkeys by aerosol administration, although little activity has been observed by the p.o. route. The facile synthesis of the succinate ester BI...

Background: The action of 5-lipoxygenase on arachidonic acid generates potent inflammatory mediators that may contribute to the pathophysiology of asthma. Methods: Using the potent and selective 5-lipoxygenase inhibitor BI-L-239, we have examined the role of 5-lipoxygenase products in three animal models of asthma. Results: In vitro BI-L-239 i...

Cell surface adhesive glycoproteins are principal regulators of nearly all aspects of immune/inflammatory responses. Using monoclonal antibodies to individual adhesion molecules, the expression and contribution of specific molecules in the pathogenesis of allergen-induced airway hyperresponsiveness in monkeys has been deciphered. Results confirm th...

Prompted by the realization of the importance of chronic airway inflammation in allergic asthma, recent interest has focused on defining the role of adhesion glycoproteins in the development of airway inflammation and subsequent changes in airway function. Many studies in vitro and in vivo have demonstrated an increased expression of certain adhesi...

Cell surface adhesive glycoproteins are principal regulators of nearly all aspects of immune/inflammatory responses. Using monoclonal antibodies to individual adhesion molecules, the expression and contribution of specific molecules in the pathogenesis of allergen-induced airway hyperresponsiveness in monkeys has been studied. Results confirm the i...

In the quest to understand the events involved with an inflammatory response, research has focused on understanding the role of single mediators such as leukotrienes, thromboxane, platelet activating factor, histamine, etc. Whereas each of these single mediators undoubtedly contributes to the complexity of disease, illustrating individual pathophys...

The role of pro-inflammatory cells and inflammatory mediators in the pathogenesis of asthma has become a subject of profound investigation. The inflammatory process involves a highly complex series of events occurring at both the tissue and cellular levels in response to a diverse number of stimuli. Of particular interest in recent years has been t...

We have examined the proinflammatory cell influx as well as the levels of eosinophil and neutrophil-derived granule proteins in BAL fluid obtained from monkeys undergoing acute and late-phase (dual) or single acute bronchoconstriction following antigen inhalation. Prior to antigen inhalation, there was a significantly higher number (and percentage)...

We have examined the role of intercellular adhesion molecule-1 (ICAM-1) in chronic airway inflammation and airway hyperresponsiveness in a primate model of asthma. Airway cellular composition was assessed by bronchoalveolar lavage (BAL) and airway responsiveness was measured as the bronchoconstrictor response to inhaled methacholine. In animals wit...

The purpose of this study was to develop a primate model of chronic bronchial neutrophilia to investigate the role of neutrophils in the pathogenesis of airway hyperresponsiveness. Ten adult male cynomolgus monkeys (Macaca fascicularis) were anaesthetized and intubated for each study. Six animals each received a total of seven inhalation treatments...

Using animal models of granulocyte-mediated inflammatory lung disease/dysfunction, we have demonstrated that a single cell adhesion glycoprotein, ICAM-1, contributes substantially to the pathogenesis of antigen-induced airway hyperresponsiveness and pulmonary oxygen toxicity. ICAM-1 confers these effects through its upregulated expression on vascul...

The inflammatory response requires the adhesion of multiple leukocyte types with other leukocytes, extracellular matrices and with other cell types. Leukocytes must adhere to vascular endothelial cells and to extracellular matrices in order to migrate from peripheral circulation to sites of inflammation. T lymphocytes must adhere to class II-positi...

Previous studies from our laboratory have demonstrated a temporal relationship between eosinophil influx into the airways and the onset of airway hyperresponsiveness to inhaled methacholine. The purpose of the present study was to extend this observation by evaluating changes in airway cellular composition and measuring the levels of granulocyte-de...

Platelet-activating factor (PAF) is a potent pro-inflammatory mediator that may play a role in the pathogenesis of airway hyper-responsiveness and asthma. In man, a single inhalation of PAF induces a small but prolonged increase in airway responsiveness in some individuals. The purpose of this study was to determine the effects of single and multip...

In immature or injured lungs, impaired alveolar gas exchange forces the use of elevated levels of inhaled oxygen to maintain life. But, at high concentrations oxygen induces lung injury, edema, and bronchopulmonary dysplasia, probably by stimulating the generation of reactive oxygen radicals and subsequent neutrophil infiltration. In addition to re...

We have examined the effects of a PAF receptor antagonist, WEB 2170, on several indices of acute and chronic airway inflammation and associated changes in lung function in a primate model of allergic asthma. A single oral administration WEB 2170 provided dose related inhibition of the release of leukotriene C(4) (LTC(4)) and prostaglandin D(2) (PGD...

This study examines the role of endothelial leukocyte adhesion molecule-1 (ELAM-1) in the development of the acute airway inflammation (cell influx) and late-phase airway obstruction in a primate model of extrinsic asthma. In animals sensitive to antigen, a single inhalation exposure induced the rapid expression of ELAM-1 (6 h) exclusively on vascu...

Male Hartley guinea pigs were actively sensitized to ovalbumin (OA). Respiratory system resistance (Rrs) was measured by forced oscillations superimposed on tidal breathing. Airway responsiveness (inhaled methacholine PC100) was determined three days prior and three days after (day 10) three alternate day inhalations of OA. Airway cell composition...

We examined the release of bronchoactive mediators into the airways of allergic primates during the acute response to specific antigen inhalation. Twelve adult male cynomolgus monkeys (Macaca fascicularis) with a naturally occurring respiratory sensitivity to inhaled Ascaris suum extract were anesthetized and intubated for each study. Respiratory s...

Airway hyperresponsiveness is an important and characteristic feature of asthma. In monkeys, we have reported that antigen (Ag) inhalation induces a prolonged airway eosinophilia, that chronic airway eosinophilia is associated with marked airway hyperresponsiveness, and that chronic Ag inhalations induce airway eosinophilia and hyperresponsiveness....

Inhaled BI-L-239 significantly inhibited i-LTC4 generation, late-phase bronchoconstriction and the influx of neutrophils into the lungs. We conclude that leukotriene generation and release within the lungs, following allergen exposure, in part mediate altered lung function and contribute to the development of airway inflammation. As such, treatment...

Using a primate antigen inhalation model the mechanisms involved in the induction of airway hyperresponsiveness were studied. Antigen inhalation induced a prolonged airway eosinophilia. Chronic airway eosinophilia, intratracheal instillation of eosinophil major basic protein, repeated antigen inhalation, and airway epithelial desquamation induced,...

A series of 2,6-disubstituted 4-(2-arylethenyl)phenols with potent human neutrophil 5-lipoxygenase (5-LO) inhibiting activity (IC50S in the 10(-7) M range) and weaker human platelet cyclooxygenase (CO) inhibiting activity (IC50S in the 10(-6) M range) is described. This series evolved from the chemical modification of an antiinflammatory dual CO/5-...

The effects of repeated antigen inhalation on airway cellular composition and airway responsiveness were examined in primates. Airway cellular composition was assessed by bronchoalveolar lavage (BAL), and airway responsiveness was measured as the bronchoconstrictor response to cumulative methacholine dose-response determinations over the course of...

Airway eosinophilia, epithelial desquamation, and hyperresponsiveness are characteristics of the airway inflammation underlying bronchial asthma. The contribution of intercellular adhesion molecule-1 (ICAM-1) to eosinophil migration and airway responsiveness was studied. ICAM-1 partially mediated eosinophil adhesion to to endothelium in vitro and w...

Evidence from several laboratories suggest that eosinophil migration into the lung interstitium and airway lumen plays a major role in the pathogenesis of airway hyperresponsiveness and asthma. In asthmatics, eosinophils in the airway lumen have been found to increase following allergen inhalation. This increase is correlated with the magnitude of...

A method of inducing sustained airway eosinophilia and airway hyperresponsiveness in primates has been developed. Our method utilizes a series of intratracheal instillations of Ascaris suum-coated sepharose 4B beads (3 x 10(5] administered once a week for four weeks. Five cynomolgus monkeys (Macaca fascicularis) demonstrating a naturally occurring...

It is well established that cotton dust inhalation can compromise lung function in textile workers. Challenges with a water-soluble extract of cotton bract (CBE) can also induce reversible airway obstruction in healthy volunteers. We have examined the effect of inhaled CBE in nonhuman primates and have attempted to inhibit the bronchoconstrictive r...

Pulmonary impedance, ZL, measured from 2 to 32 Hz in anesthetized, intubated and paralyzed bonnet monkeys (Macaca radiata) was fitted to a variety of linearlumped parameter mechanical networks. Parameter values for each network were obtained by minimizing the average of the percent distance, Dr, between the computed network impedance and measured Z...

We measured impedances of the lungs (ZL) and respiratory system (Zrs) by discrete frequency (f) forced oscillations in adult bonnet monkeys at two lung volumes, FRC and at transrespiratory system pressure (Prs) of -5 cm H2O. Measurements were made from 2 to 32 Hz to study f dependence of effective resistances (Reff) and reactances, and from 1 to 8...