Safety, bioavailability and mechanism of action of nitric oxide to control Bovine Respiratory Disease Complex in calves entering a feedlot.

Bovine Respiratory Disease Complex (BRDc), a multi-factorial disease, negatively impacts the cattle industry. Nitric oxide (NO), a naturally occurring molecule, may have utility controlling incidence of BRDc. Safety, bioavailability, toxicology and tolerance/stress of administering NO to cattle is evaluated herein. Thirteen, crossbred, multiple-sourced, commingled commercial weaned beef calves were treated multiple times intranasally over a 4 week period with either a nitric oxide releasing solution (treatment) or saline (control). Exhaled NO, methemoglobin percent (MetHg) and serum nitrites demonstrated biological availability as a result of treatment. Cortisol levels, tissue nitrites, behavior and gross and macroscopic pathology of organs were all normal. Moreover, preliminary in vitro studies using Mannheimia haemolytica, Infectious Bovine Rhinotracheitis, Bovine Parainfluenza-3 and Bovine Respiratory Syncytial Virus, suggest a potential explanation for the previously demonstrated efficacy for BRDc. These data confirm the bioavailability, safety and lack of residual of NO treatment to cattle, along with the bactericidal and virucidal effects.

Selection of natural health products for clinical trials: a preclinical template.

In preparation for a clinical trial on the efficacy of Echinacea products with a pediatric population, a rational method for selection of test products was developed, based on phytochemical and bioassay evaluation. Ten currently available commercial products of Echinacea angustifolia (EA) or Echinacea purpurea (EP) were selected, and 3 bottles of each of 2 different lots were purchased for each product. Investigators were blinded to product identity before phytochemical analysis. Lot-to-lot variation was small, but product variation due to species and formulation was large. Products derived from ethanol extracts had low polysaccharide content and high levels of alkamides (EA), echinacoside (EA), cynarin (EA), cichoric acid (EP), and caftaric acid (EP). These products possessed high antiviral activities that differed between EA and EP products, but limited immune activation properties. In contrast, products derived without ethanol extraction had higher polysaccharide levels, but low levels of other components. These aqueous compounds showed immunostimulant activity as measured in a mouse macrophage model and a somewhat different antiviral profile. The choice of Echinacea product for clinical trial must therefore consider the impact of immune enhancement, the specific viral infection targeted, and the potential to reduce symptoms via antiinflammatory activity. Product selection may also depend on whether the intent of the trial is prophylaxis or treatment.

Pathogenesis of COPD. Part I. The role of protease-antiprotease imbalance in emphysema.

This review covers protease-antiprotease imbalance in the development of emphysema in smokers. This imbalance is likely to play a major pathogenic role in the development of emphysema in subjects with severe alpha1-antitrypsin deficiency who smoke because of a deficient antiprotease protection against neutrophil elastase release in the lung. Neutrophil elastase is a potent elastolytic enzyme, and its instillation in the lungs of animals results in emphysema. Smoking attracts neutrophils to the lungs and there is an additional accumulation of neutrophils, because the abnormal antitrypsin polymerizes in the lungs and acts as a chemo-attractant to neutrophils. In subjects who do not have antitrypsin deficiency, the case for elastolytic injury by neutrophils causing emphysema is less definite, because of the lack of a severe deficiency of active alpha1-ntitrypsin leading to unopposed elastolysis by neutrophil elastase. It is likely that alveolar macrophages play a pathogenic role in emphysema; they express potent elastolytic enzymes, cathepsins and matrix metalloproteases (MMPs), which are induced by smoking. The numbers of macrophages are increased in the region of the respiratory bronchiole, where centrilobular emphysema develops in smokers. Macrophage cathepsins are inhibited by an antiprotease cystatin C, while the MMPs are inhibited by the tissue inhibitors of metalloproteases (TIMPs). Some pro-inflammatory mediators induce release of MMPs from macrophages without inducing increase in TIMPs, leading to possible protease-antiprotease imbalance. Studies of proteases in alveolar macrophages obtained by bronchoalveolar lavage and studies on lung tissue indicate increased protease expression in subjects with chronic obstructive pulmonary disease (COPD) compared to subjects without COPD.