[Show abstract][Hide abstract] ABSTRACT: Brevenal is a ladder frame polyether produced by the dinoflagellate Karenia brevis. This organism is also responsible for the production of the neurotoxic compounds known as brevetoxins. Ingestion or inhalation of the brevetoxins leads to adverse effects such as gastrointestinal maladies and bronchoconstriction. Brevenal shows antagonistic behavior to the brevetoxins and shows beneficial attributes when administered alone. For example, in an asthmatic sheep model, brevenal has been shown to increase tracheal mucosal velocity, an attribute which has led to its development as a potential treatment for Cystic Fibrosis. The mechanism of action of brevenal is poorly understood and the exact binding site has not been elucidated. In an attempt to further understand the mechanism of action of brevenal and potentially develop a second generation drug candidate, a series of brevenal derivatives were prepared through modification of the aldehyde moiety. These derivatives include aliphatic, aromatic and heteroaromatic hydrazide derivatives. The brevenal derivatives were tested using in vitro synaptosome binding assays to determine the ability of the compounds to displace brevetoxin and brevenal from their native receptors. A sheep inhalation model was used to determine if instillation of the brevenal derivatives resulted in bronchoconstriction. Only small modifications were tolerated, with larger moieties leading to loss of affinity for the brevenal receptor and bronchoconstriction in the sheep model.
[Show abstract][Hide abstract] ABSTRACT: The tetrasaccharide sequence of heparin oligosaccharides is the minimum chain length possessing anti-allergic activity, as the disaccharide fraction is inactive. Since sulfation pattern can modify the biological actions of heparin, we hypothesized that "supersulfation" of the inactive heparin disaccharide could confer anti-allergic activity to this molecule. To test this, we produced a supersulfated heparin disaccharide (Hep-SSD) and evaluated its anti-allergic activity in sheep with documented antigen-induced early and late airway responses (EAR and LAR) and airway hyperresponsiveness (AHR). Porcine intestinal heparin was depolymerized with nitrous acid, the disaccharide fraction separated by size exclusion chromatography, and then treated with pyridine-sulfur trioxide complex to yield Hep-SSD. Its chemical structure [IdoU2´,3´,4´S (1→4) AMan1,3,6S] was confirmed by HPLC, Mass Spectrometry and NMR analysis. Inhaled doses of 5 mg, 10 mg and 20 mg Hep-SSD produced inhibition of EAR (8%, 35% and 35%), LAR (50%, 80%, and 77%) and AHR (67%, 100% and 75%), respectively. A single oral dose of 2 mg/kg Hep-SSD given 90 min before challenge significantly inhibited EAR, LAR and AHR, but 1 mg/kg was ineffective. Multidose oral treatment with Hep-SSD had a cumulative effect, as a once daily dose of 2 mg/kg for 3 days (last dose, 16 hours before antigen) inhibited EAR, LAR and AHR by 30%, 75% and 74%, respectively. Finally, the oral activity of Hep-SSD could be enhanced 4 fold by formulating it with Carbopol®934P, in an enteric coated capsule. These data demonstrate that "supersulfation" can confer biological activity to the inactive heparin disaccharide. Both inhaled and oral Hep-SSD demonstrate significant anti-allergic activity and, therefore, may have therapeutic potential.
[Show abstract][Hide abstract] ABSTRACT: Mucus clearance is an important component of the lung's innate defense system. A failure of this system brought on by mucus dehydration is common to both cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Mucus clearance rates are regulated by the volume of airway surface liquid (ASL) and by ciliary beat frequency (CBF). Chronic treatment with macrolide antibiotics is known to be beneficial to both CF and COPD patients. However, chronic macrolide usage may induce bacterial resistance. We have developed a novel macrolide, 2'-desoxy-9-(S)-erythromycylamine (GS-459755), which has significantly diminished antibiotic activity against Staphlococcus aureus, Streptococcus pneumonia, Moraxella catarrhalis and Haemophilus influenzae. Since neutrophilia frequently occurs in chronic lung disease and human neutrophil elastase (HNE) induces mucus stasis by activating the epithelial sodium channel (ENaC), we tested the ability of GS-459755 to protect against HNE-induced mucus stasis. GS-459755 had no effect on HNE activity. However, GS-459755 pretreatment protected against HNE-induced ASL volume depletion in human bronchial epithelial cells (HBECs). The effect of GS-459755 on ASL volume was dose-dependent (IC50 ~3.9 μM) and comparable to the antibacterial macrolide azithromycin (IC50 ~2.4 μM). Macrolides had no significant effect on CBF, or the transepithelial water permeability. However, the amiloride-sensitive transepithelial voltage, a marker of ENaC activity, was diminished by macrolide pretreatment. We conclude that GS-459755 may limit HNE-induced activation of ENaC and may be useful for the treatment of mucus dehydration in CF and COPD without inducing bacterial resistance.
[Show abstract][Hide abstract] ABSTRACT: Acute metabolic acidosis impairs cardiovascular function and increases the mortality of critically ill patients. However, the precise mechanism(s) underlying these effects remain unclear. We hypothesized that targeting pH-regulatory protein, Na(+)/H(+) exchanger (NHE1) could be a novel approach for the treatment of acute metabolic acidosis. The aim of the present study was to examine the impact of a novel NHE1 inhibitor, sabiporide, on cardiovascular function, blood oxygen transportation, and inflammatory response in an experimental model of metabolic acidosis produced by hemorrhage-induced hypovolemia followed by an infusion of lactic acid.
Anesthetized pigs were subjected to hypovolemia for 30 minutes. The animals then received a bolus infusion of sabiporide (3 mg/kg) or vehicle, followed by an infusion of lactic acid for 2 hours. The animals were continuously monitored for additional 3 hours. Hypovolemia followed by a lactic acid infusion resulted in a severe metabolic acidosis with blood pH falling to 6.8. In association with production of the acidemia, there was an excessive increase in pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR). Treatment with sabiporide significantly attenuated the increase in PAP by 38% and PVR by 67%, as well as significantly improved cardiac output by 51%. Sabiporide treatment also improved mixed venous blood oxygen saturation (55% in sabiporide group vs. 28% in control group), and improved systemic blood oxygen delivery by 36%. In addition, sabiporide treatment reduced plasma levels of TNF-α (by 33%), IL-6 (by 63%), troponin-I (by 54%), ALT (by 34%), AST (by 35%), and urea (by 40%).
These findings support the possible beneficial effects of sabiporide in the treatment of acute metabolic acidosis and could have implications for the treatment of metabolic acidosis in man.
PLoS ONE 01/2013; 8(1):e53932. · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We have shown that inhaled heparin (hep) oligosaccharides attenuate allergic airway responses in sheep and that this anti-allergic activity resides in a tetrasaccharide sequence. Here we determined: (a) the anti-allergic activity of oral and intravenous hep-tetrasaccharide on allergic airway responses in the sheep model of asthma; and (b) the role of N-sulfation in mediating this anti-allergic activity. Ascaris suum-induced early (EAR) and Late (LAR) airway responses and airway hyperresponsiveness (AHR) to carbachol were measured in allergic sheep without and after treatment with different doses of oral or intravenous hep-tetrasaccharide. At doses of 0.06 mg/kg, 0.125 mg/kg, and 0.25 mg/kg, oral hep-tetrasaccharide caused a dose-dependent inhibition of EAR and LAR. Post-antigen AHR was also inhibited dose dependently. The same doses of intravenous hep-tetrasaccharide yielded comparable inhibition of EAR, LAR and AHR, confirming that orally delivered hep-tetrasaccharide has good bioavailability. The protection by hep-tetrasaccharide on EAR and LAR was dependent on N-sulfation, as N-desulfated /N-acetylated tetrasaccharide had a markedly reduced effect. However, inhibition of the post-antigen AHR was independent of N-sulfation. These results demonstrate that orally administered hep-tetrasaccharide inhibits allergic airway responses in the sheep model of asthma. Hep-tetrasaccharide has good oral bioavailability and its anti-allergic activity is critically dependent on N-sulfation of the glucosamine ring.
[Show abstract][Hide abstract] ABSTRACT: INTRODUCTION: This study tested the hypothesis that blockade of the pH-regulatory protein, Na(+)/H(+) exchanger (NHE1) during prolonged hemorrhagic shock can protect against whole-body ischemia-reperfusion injury, resulting in improved neurological outcomes. METHODS: We used a total of 24 male pigs in this study. We excluded two animals: one because of cardiac arrest after the initial hemorrhage, and the second because of a catheter malfunction for color microspheres. In Series 1, anesthetized pigs underwent an initial hemorrhage of 40 mL/kg for 30 min, and then were given either 3 mg/kg of NHE1 selective inhibitor BIIB513 (n = 6) or vehicle (n = 6). At 1 h after treatment, all animals received fluid resuscitation. We assessed survival and neurologic outcomes 72 h postresuscitation. In Series 2, we measured organ blood flow in a separate group of control (n = 5) and BIIB513-treated pigs (n = 5) undergoing the same experimental paradigm. RESULTS: Five of six control animals failed to be weaned from mechanical ventilation. We killed another control animal the next day because of severe complications. In contrast, all six animals treated with BIIB513 were weaned off the ventilator, and all but one survived the 72-h experimental period with normal neurological outcome. Results showed that NHE1 inhibition with BIIB513 improved blood flow to the brain, heart, and kidney, and prevented the development of metabolic acidosis in the 1-h hypovolemic period. In addition, BIIB513 facilitated the hemodynamic response to fluid resuscitation, increased mixed venous blood oxygen saturation and oxygen delivery, and reduced proinflammatory cytokine release and multiorgan injury compared with vehicle controls. CONCLUSIONS: In this study, NHE1 inhibition with BIIB513 improved vital organ blood flow, prevented the development of metabolic acidosis during prolonged hypovolemia, and facilitated the hemodynamic response to fluid resuscitation, resulting in increased survival and normal neurological outcomes.
Journal of Surgical Research 07/2012; · 2.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Previous studies showed that heparin's anti-allergic activity is molecular weight dependent and resides in oligosaccharide fractions of <2500 daltons.
To investigate the structural sequence of heparin's anti-allergic domain, we used nitrous acid depolymerization of porcine heparin to prepare an oligosaccharide, and then fractionated it into disaccharide, tetrasaccharide, hexasaccharide, and octasaccharide fractions. The anti-allergic activity of each oligosaccharide fraction was tested in allergic sheep.
Allergic sheep without (acute responder) and with late airway responses (LAR; dual responder) were challenged with Ascaris suum antigen with and without inhaled oligosaccharide pretreatment and the effects on specific lung resistance and airway hyperresponsiveness (AHR) to carbachol determined. Additional inflammatory cell recruitment studies were performed in immunized ovalbumin-challenged BALB/C mice with and without treatment.
The inhaled tetrasaccharide fraction was the minimal effective chain length to show anti-allergic activity. This fraction showed activity in both groups of sheep; it was also effective in inhibiting LAR and AHR, when administered after the antigen challenge. Tetrasaccharide failed to modify the bronchoconstrictor responses to airway smooth muscle agonists (histamine, carbachol and LTD4), and had no effect on antigen-induced histamine release in bronchoalveolar lavage fluid in sheep. In mice, inhaled tetrasaccharide also attenuated the ovalbumin-induced peribronchial inflammatory response and eosinophil influx in the bronchoalveolar lavage fluid. Chemical analysis identified the active structure to be a pentasulfated tetrasaccharide ([IdoU2S (1→4)GlcNS6S (1→4) IdoU2S (1→4) AMan-6S]) which lacked anti-coagulant activity.
These results demonstrate that heparin tetrasaccharide possesses potent anti-allergic and anti-inflammatory properties, and that the domains responsible for anti-allergic and anti-coagulant activity are distinctly different.
Respiratory research 01/2012; 13:6. · 3.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Asthma is a chronic inflammatory lung disease with considerable unmet medical needs for new and effective therapies. Cytosolic phospholipase A(2)α (cPLA(2)α) is the rate-limiting enzyme that is ultimately responsible for the production of eicosanoids implicated in the pathogenesis of asthma. We investigated a novel cPLA(2)α inhibitor, PF-5212372, to establish the potential of this drug as a treatment for asthma. PF-5212372 was a potent inhibitor of cPLA(2)α (7 nM) and was able to inhibit prostaglandin (PG)D(2) and cysteinyl leukotriene release from anti-IgE-stimulated human lung mast cells (0.29 and 0.45 nM, respectively). In a mixed human lung cell population, PF-5212372 was able to inhibit ionomycin-stimulated release of leukotriene B(4), thromboxane A(2), and PGD(2) (2.6, 2.6, and 4.0 nM, respectively) but was significantly less effective against PGE(2) release (>301 nM; p < 0.05). In an in vitro cell retention assay, PF-5212372 retained its potency up to 24 h after being washed off. In a sheep model of allergic inflammation, inhalation of PF-5212372 significantly inhibited late-phase bronchoconstriction (78% inhibition; p < 0.001) and airway hyper-responsiveness (94% inhibition; p < 0.001), and isolated sheep lung mast cell assays confirmed species translation via effective inhibition of PGD(2) release (0.78 nM). Finally, PF-5212372 was assessed for its ability to inhibit the contraction of human bronchi induced by AMP. PF5212372 significantly inhibited AMP-induced contraction of human bronchi (81% inhibition; p < 0.001); this finding, together with the ability of this drug to be effective in a wide range of preclinical asthma models, suggests that inhibition of cPLA(2)α with PF-5212372 may represent a new therapeutic option for the treatment of asthma.
Journal of Pharmacology and Experimental Therapeutics 12/2011; 340(3):656-65. · 3.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Having demonstrated significant and persistent adverse changes in pulmonary function for asthmatics after 1 hour exposure to brevetoxins in Florida red tide (Karenia brevis bloom) aerosols, we assessed the possible longer term health effects in asthmatics from intermittent environmental exposure to brevetoxins over 7 years. 125 asthmatic subjects were assessed for their pulmonary function and reported symptoms before and after 1 hour of environmental exposure to Florida red tide aerosols for upto 11 studies over seven years. As a group, the asthmatics came to the studies with normal standardized percent predicted pulmonary function values. The 38 asthmatics who participated in only one exposure study were more reactive compared to the 36 asthmatics who participated in ≥4 exposure studies. The 36 asthmatics participating in ≥4 exposure studies demonstrated no significant change in their standardized percent predicted pre-exposure pulmonary function over the 7 years of the study. These results indicate that stable asthmatics living in areas with intermittent Florida red tides do not exhibit chronic respiratory effects from intermittent environmental exposure to aerosolized brevetoxins over a 7 year period.
[Show abstract][Hide abstract] ABSTRACT: During a Florida red tide, brevetoxins (PbTxs) produced by Karenia brevis become aerosolized and can cause both immediate and prolonged airway symptoms in humans, especially in those with preexisting airway disease (e.g., asthma). Although environmental monitoring indicates that toxins remain airborne for up to 4 consecutive days, there is little information on airway responses after multiple-day exposures.
To delineate putative mechanisms leading to pulmonary dysfunction after PbTx exposure, we studied airway responses before and after multiple exposures to aerosol PbTx-3, the most potent PbTx produced, in nonallergic (healthy) and in allergic sheep, which serve as a surrogate for patients with compromised airways.
Both groups were exposed to 20 breaths of increasing concentrations of PbTx-3 (30-300 pg/mL) for 4 consecutive days. Airway responsiveness to carbachol (1 and 8 days after) and airway inflammation as assessed by bronchoalveolar lavage (0 and 7 days after) were measured.
Both groups developed airway hyperresponsiveness (AHR) 1 day after challenge; the severity was concentration dependent and more severe in the allergic group. AHR remained after 8 days, but the difference in the severity between the groups was lost. Both groups developed an inflammatory response after exposure to 300 pg/mL PbTx-3. Immediately after exposure, lung neutrophilia was prominent. This neutrophilia persisted for 7 days in addition to increases in total cells and macrophages.
Repeated exposures to PbTx-3 result in prolonged AHR and lung inflammation. These pathophysiologic responses could be underlying contributors to the prolonged respiratory symptoms in humans after red tides.
[Show abstract][Hide abstract] ABSTRACT: Blooms of the toxic dinoflagellate, Karenia brevis, produce potent neurotoxins in marine aerosols. Recent studies have demonstrated acute changes in both symptoms and pulmonary function in asthmatics after only 1 h of beach exposure to these aerosols. This study investigated if there were latent and/or sustained effects in asthmatics in the days following the initial beach exposure during periods with and without an active Florida red tide.Symptom data and spirometry data were collected before and after 1 h of beach exposure. Subjects kept daily symptom diaries and measured their peak flow each morning for 5 days following beach exposure. During non-exposure periods, there were no significant changes in symptoms or pulmonary function either acutely or over 5 days of follow-up. After the beach exposure during an active Florida red tide, subjects had elevated mean symptoms which did not return to the pre-exposure baseline for at least 4 days. The peak flow measurements decreased after the initial beach exposure, decreased further within 24 h, and continued to be suppressed even after 5 days. Asthmatics may continue to have increased symptoms and delayed respiratory function suppression for several days after 1 h of exposure to the Florida red tide toxin aerosols.
[Show abstract][Hide abstract] ABSTRACT: This paper reviews the literature describing research performed over the past decade on the known and possible exposures and human health effects associated with Florida red tides. These harmful algal blooms are caused by the dinoflagellate, Karenia brevis, and similar organisms, all of which produce a suite of natural toxins known as brevetoxins. Florida red tide research has benefited from a consistently funded, long-term research program, that has allowed an interdisciplinary team of researchers to focus their attention on this specific environmental issue—one that is critically important to Gulf of Mexico and other coastal communities. This long-term interdisciplinary approach has allowed the team to engage the local community, identify measures to protect public health, take emerging technologies into the field, forge advances in natural products chemistry, and develop a valuable pharmaceutical product. The review includes a brief discussion of the Florida red tide organisms and their toxins, and then focuses on the effects of these toxins on animals and humans, including how these effects predict what we might expect to see in exposed people.
[Show abstract][Hide abstract] ABSTRACT: Matrix metalloproteinase (MMP)-12-mediated pathologic degradation of the extracellular matrix and the subsequent repair cycles influence the airway changes in patients with asthma and chronic obstructive pulmonary disease (COPD). The common serine variant at codon 357 of the MMP12 gene (rs652438) is associated with clinical manifestations consistent with more aggressive matrix degradation in other tissues.
We sought to explore the hypothesis that MMP12 represents a novel therapeutic target in asthma.
The role of the rs652438 variant on clinical phenotype was explored in young asthmatic patients and patients with COPD. Candidate MMP-12 inhibitors were identified on the basis of potency and selectivity against a panel of other MMPs. The role of MMP-12-specific inhibition was tested in vitro, as well as in animal models of allergic airway inflammation.
The odds ratio for having greater asthma severity was 2.00 (95% CI, 1.24-3.24; P = .004) when comparing asthmatic patients with at least 1 copy of the serine variant with those with none. The carrier frequency for the variant increased in line with asthma treatment step (P = .000). The presence of the variant nearly doubled the odds in favor of asthmatic exacerbations (odds ratio, 1.90; 95% CI, 1.19-3.04; P = .008) over the previous 6 months. The serine variant was also associated with increased disease severity in patients with COPD (P = .016). Prior administration of an MMP-12-specific inhibitor attenuated the early airway response and completely blocked the late airway response with subsequent Ascaris suum challenge in sheep.
Studies on human participants with asthma and COPD show that the risk MMP12 gene variant is associated with disease severity. In allergen-sensitized sheep pharmacologic inhibition of MMP12 downregulates both early and late airway responses in response to allergic stimuli.
The Journal of allergy and clinical immunology 07/2010; 126(1):70-6.e16. · 12.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Florida red tides occur as the result of blooms of the marine dinoflagellate Karenia brevis. K. brevis is known to produce several families of fused polyether ladder compounds. The most notable compounds are the brevetoxins, potent neurotoxins that activate mammalian sodium channels. Additional fused polyether ladder compounds produced by K. brevis include brevenal, brevisin, and hemibrevetoxin B, all with varying affinities for the same binding site on voltage-sensitive sodium channels. The structure elucidation and biological activity of two additional fused polyether ladder compounds containing seven fused ether rings will be described in this paper. Tamulamide A (MW = 638.30) and tamulamide B (MW = 624.29) were isolated from K. brevis cultures, and their structures elucidated using a combination of NMR spectroscopy and high-resolution mass spectrometry. Tamulamides A and B were both found to compete with tritiated brevetoxin-3 ([(3)H]-PbTx-3) for its binding site on rat brain synaptosomes. However, unlike the brevetoxins, tamulamides A and B showed no toxicity to fish at doses up to 200 nM and did not cause significant bronchoconstriction in sheep pulmonary assays.
Journal of Natural Products 03/2010; 73(4):536-40. · 3.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hematopoietic prostaglandin D synthase (HPGDS) is primarly expressed in mast cells, antigen-presenting cells, and Th-2 cells. HPGDS converts PGH2 into PGD2, a mediator thought to play a pivotal role in airway allergy and inflammatory processes. In this letter, we report the discovery of an orally potent and selective inhibitor of HPGDS that reduces the antigen-induced response in allergic sheep.Keywords: Hematopoietic prostaglandin D synthase (HPGDS); PGH2; PGD2; airway allergy; inflammatory processes, cyclooxygenase (COX)
[Show abstract][Hide abstract] ABSTRACT: Previous in vitro research demonstrated that ascorbate enhances potency and duration of activity of agonists binding to alpha 1 adrenergic and histamine receptors.
Extending this work to beta 2 adrenergic systems in vitro and in vivo.
Ultraviolet spectroscopy was used to study ascorbate binding to adrenergic receptor preparations and peptides. Force transduction studies on acetylcholine-contracted trachealis preparations from pigs and guinea pigs measured the effect of ascorbate on relaxation due to submaximal doses of beta adrenergic agonists. The effect of inhaled albuterol with and without ascorbate was tested on horses with heaves and sheep with carbachol-induced bronchoconstriction.
Binding constants for ascorbate binding to beta adrenergic receptor were derived from concentration-dependent spectral shifts. Dose- dependence curves were obtained for the relaxation of pre-contracted trachealis preparations due to beta agonists in the presence and absence of varied ascorbate. Tachyphylaxis and fade were also measured. Dose response curves were determined for the effect of albuterol plus-and-minus ascorbate on airway resistance in horses and sheep.
Ascorbate binds to the beta 2 adrenergic receptor at physiological concentrations. The receptor recycles dehydroascorbate. Physiological and supra-physiological concentrations of ascorbate enhance submaximal epinephrine and isoproterenol relaxation of trachealis, producing a 3-10-fold increase in sensitivity, preventing tachyphylaxis, and reversing fade. In vivo, ascorbate improves albuterol's effect on heaves and produces a 10-fold enhancement of albuterol activity in "asthmatic" sheep.
Ascorbate enhances beta-adrenergic activity via a novel receptor-mediated mechanism; increases potency and duration of beta adrenergic agonists effective in asthma and COPD; prevents tachyphylaxis; and reverses fade. These novel effects are probably caused by a novel mechanism involving phosphorylation of aminergic receptors and have clinical and drug-development applications.
PLoS ONE 01/2010; 5(12):e15130. · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: MMP-12 plays a significant role in airway inflammation and remodeling. Increased expression and production of MMP-12 have been observed in the lungs of asthmatic patients. Compound 27 was identified as a potent and selective MMP-12 inhibitor possessing good physicochemical properties. In pharmacological studies, the compound was orally efficacious in an MMP-12 induced ear-swelling inflammation model in the mouse with a good dose response. This compound also exhibited oral efficacy in a naturally Ascaris-sensitized sheep asthma model showing significant inhibition of the late phase response to allergen challenge. This compound has been considered for further development as a treatment therapy for asthma.
Journal of Medicinal Chemistry 10/2009; 52(17):5408-19. · 5.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mast cells and neutrophils are key contributors to the pathophysiological inflammatory processes that underpin asthma and chronic obstructive pulmonary disease, partly through the release of noxious serine proteases, including cathepsin G (Cat G) and chymase. From this standpoint, a dual inhibitor of neutrophil Cat G and mast cell chymase could protect against these disease-related inflammatory responses.
We examined the antiinflammatory pharmacology of RWJ-355871, a dual inhibitor of Cat G and chymase, in animal models of inflammation that evince pathophysiological pathways relevant to asthma and chronic obstructive pulmonary disease to determine the therapeutic potential of this compound.
In an ovalbumin (OVA)-sensitized rat model, RWJ-355871 was administered to block the mast-cell-mediated increase in paw volume caused by OVA injection. In a sheep asthma model, antigen-induced airway responses were assessed with and without aerosol treatment with RWJ-355871. In a murine tobacco-smoke model of airway inflammation, the effect of RWJ-355871 on smoke-induced neutrophilia was determined.
Intravenous treatment of OVA-sensitized rats with RWJ-355871 provided dose-dependent reduction in the increase in rat paw volume. In allergic sheep, aerosol pretreatment with RWJ-355871 showed dose-dependent inhibition of the antigen-induced early response, late response, and post-antigen-induced airway hyperreponsiveness. In tobacco-smoke-exposed mice, nebulized RWJ-355871 significantly reduced the smoke-induced neutrophilia from the levels observed in untreated mice.
The preclinical antiinflammatory effects of RWJ-355871 in these animal models of inflammation indicate that this dual inhibitor may have therapeutic utility for treating airway inflammatory diseases involving mechanisms that depend on Cat G and/or chymase.
American Journal of Respiratory and Critical Care Medicine 10/2009; 181(3):247-53. · 11.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 1. The aim of the present study was to examine the effects of inhibition of the Na(+)/H(+) exchanger (NHE-1) on cardiopulmonary performance, oxygen carrying capacity and tissue inflammation in a pig model of traumatic haemorrhage-resuscitation. 2. In 12 instrumented anaesthetized pigs, traumatic haemorrhage was modelled by producing tibia fractures, followed by haemorrhage of 25 mL/kg for 20 min, and then a 4 mm hepatic arterial tear with surgical repair after 20 min. Animals then underwent low-volume fluid resuscitation with either Hextend (vehicle; n = 6; Hospira, Lake Forest, IL, USA) or 3 mg/kg BIIB513 (an NHE-1 inhibitor) + Hextend (n = 6). The experiment was terminated 6 h after the beginning of resuscitation. 3. Compared with vehicle-treated controls, the addition of NHE-1 inhibition with BIIB513 significantly improved the left ventricle stroke work index and attenuated increases in pulmonary arterial pressure and pulmonary vascular resistance. Furthermore, BIIB513 treatment significantly increased the oxygenated haemoglobin ratio, blood oxygen content and mixed venous blood oxygen saturation and improved blood oxygen delivery. In addition, BIIB513 treatment reduced lung tissue levels of interleukin-6 by 80%, tumour necrosis factor-alpha by 37% and myeloperoxidase activity by 38%. Nuclear factor-kappaB DNA binding activity in the lung was also slightly and significantly attenuated following BIIB513 treatment. 4. In conclusion, the present study shows that NHE-1 inhibition facilitates the response to fluid resuscitation after traumatic haemorrhage by improving cardiac function, pulmonary vascular function and oxygen carrying capacity, which results in reduced tissue inflammatory injury.
Clinical and Experimental Pharmacology and Physiology 09/2009; 37(3):337-42. · 2.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In previous studies we demonstrated statistically significant changes in reported symptoms for lifeguards, general beach goers, and persons with asthma, as well as statistically significant changes in pulmonary function tests (PFTs) in asthmatics, after exposure to brevetoxins in Florida red tide (Karenia brevis bloom) aerosols.
In this study we explored the use of different methods of intensive ambient and personal air monitoring to characterize these exposures to predict self-reported health effects in our asthmatic study population.
We evaluated health effects in 87 subjects with asthma before and after 1 hr of exposure to Florida red tide aerosols and assessed for aerosolized brevetoxin exposure using personal and ambient samplers.
After only 1 hr of exposure to Florida red tide aerosols containing brevetoxin concentrations > 57 ng/m(3), asthmatics had statistically significant increases in self-reported respiratory symptoms and total symptom scores. However, we did not see the expected corresponding changes in PFT results. Significant increases in self-reported symptoms were also observed for those not using asthma medication and those living >/= 1 mile from the coast.
These results provide additional evidence of health effects in asthmatics from ambient exposure to aerosols containing very low concentrations of brevetoxins, possibly at the lower threshold for inducing a biologic response (i.e., toxicity). Consistent with the literature describing self-reported symptoms as an accurate measure of asthmatic distress, our results suggest that self-reported symptoms are a valuable measure of the extent of health effects from exposure to aerosolized brevetoxins in asthmatic populations.
Environmental Health Perspectives 07/2009; 117(7):1095-100. · 7.26 Impact Factor