Inhibition of allergen-induced pulmonary responses by the selective tryptase inhibitor 1,5-bis-[4-[(3-carbamimidoyl-benzenesulfonylamino)-methyl]-phenoxy]-pen tane (AMG-126737).

Emerging evidence suggests that mast cell tryptase is a therapeutic target for the treatment of asthma. The effects of this serine protease are associated with both pathophysiologic pulmonary responses and pathologic changes of the asthmatic airway. In this study, the tryptase inhibitor 1,5-bis-[4-[(3-carbamimidoyl-benzenesulfonylamino)-methyl]-p henoxy]-pentane (AMG-126737) was evaluated for its pharmacologic effects against allergen-induced airway responses. AMG-126737 is a potent inhibitor of human lung mast cell tryptase (Ki = 90 nM), with greater than 10- to 200-fold selectivity versus other serine proteases. Intratracheal administration of AMG-126737 inhibited the development of airway hyperresponsiveness in allergen-challenged guinea pigs with an ED50 of 0.015 mg/kg. In addition, the compound exhibited oral activity in the guinea pig model. The in vivo activity of AMG-126737 was confirmed in a sheep model of allergen-induced airway responses, where the compound inhibited early and late phase bronchoconstriction responses and the development of airway hyperresponsiveness. These results support the proposed role of tryptase in the pathology of asthma and suggest that AMG-126737 has potential therapeutic utility in this pulmonary disorder.

Secretory leukocyte protease inhibitor prevents allergen-induced pulmonary responses in animal models of asthma.

Secretory leukocyte protease inhibitor (SLPI) is a naturally occurring protein of human airways that exhibits broad spectrum inhibitory activity against mast cell and leukocyte serine proteases implicated in asthma pathology. To assess the potential therapeutic utility of SLPI in this disorder, its effects on antigen-induced pulmonary responses were evaluated. In Ascaris-sensitized sheep, SLPI (3 mg) administered by aerosol daily for 4 days, with the final dose 0.5 h before antigen challenge, reduced the areas under the curve for early- and late-phase bronchoconstriction (73 and 95%, respectively; p <.05 versus control responses). SLPI also inhibited the development of airway hyperresponsiveness to carbachol (84%, p <. 05 versus control response) measured 24 h after antigen challenge. In ovalbumin-sensitized guinea pigs, intratracheal administration of SLPI daily for 3 days, with the final dose 1 h before antigen challenge, inhibited the development of airway hyperresponsiveness to histamine with an ED50 of <0.05 mg/kg. Prolonged pharmacodynamic activity of SLPI was observed in both species. In a murine model of atopic asthma, SLPI inhibited leukocyte influx into the airways after chronic allergen challenge. SLPI administered to sheep by the predosing protocol described above also prevented the antigen-induced decrease of tracheal mucus velocity (p <.05). In addition, a single aerosol administration of SLPI (30 mg) to sheep 1 h after antigen challenge inhibited the subsequent late-phase bronchoconstriction and development of hyperresponsiveness and reversed the stimulated decrease in tracheal mucus velocity. These results suggest that SLPI may provide therapeutic intervention against the pathophysiology of asthma and its underlying pathology.

Intravenous keratinocyte growth factor protects against experimental pulmonary injury.

Keratinocyte growth factor (KGF) administered by intratracheal instillation is well documented to stimulate the proliferation of alveolar and bronchial cells. In the present study, intravenous KGF was also shown to stimulate the proliferation of alveolar and bronchial cells in mice and rats, although to a lesser degree than intratracheal KGF. Despite the decreased potency of intravenous KGF on pulmonary cell 5-bromo-2'-deoxyuridine incorporation compared with intratracheal KGF, intravenous KGF was very effective in preventing experimental bleomycin-induced pulmonary dysfunction, weight loss, and mortality in either mice or rats and experimental hyperoxia-induced mortality in mice. The effectiveness of intravenous administration of KGF in preventing lung injury suggests that the mechanisms of the protective effect of KGF may involve more than pulmonary cell proliferation and also suggests the potential use of systemic KGF for clinical trials in settings of pulmonary injury.

Tryptase mediates hyperresponsiveness in isolated guinea pig bronchi.

Hyperresponsiveness of airway smooth muscle to allergens and environmental factors has long been associated with the pathophysiology of asthma. Tryptase, a serine protease of lung mast cells, has been implicated as one of the mediators involved in the induction of hyperresponsiveness. As a consequence, tryptase inhibitors have become the subject of study as potential novel therapeutic agents for asthma. Secretory leukocyte protease inhibitor (SLPI) is a naturally occurring protein of human airways which exhibits anti-tryptase activity. To assess the potential therapeutic utility of SLPI in asthma, its effects were evaluated using in vitro and ex vivo models of airway hyperresponsiveness and compared with the effects of the small molecule tryptase inhibitor APC-366. Our results demonstrate that SLPI inhibits tryptase-mediated hyperresponsiveness in vitro and attenuates the hyperresponsiveness observed in airway smooth muscle from antigen-sensitized animals subjected to antigen exposure. The small molecule tryptase inhibitor APC-366 has a similar inhibitory effect. Thus, tryptase appears to be a significant contributor to the development of hyperresponsiveness in these models. To the extent that tryptase contributes to the development and progression of asthma, SLPI may possess therapeutic potential in this disease setting.

Prevention of bleomycin-induced lung injury in rats by keratinocyte growth factor.

Intratracheal instillation of bleomycin produces pulmonary fibrosis in rats. Alveolar type II cell proliferation is thought to minimize the fibrotic response after lung injury. Because keratinocyte growth factor (KGF) stimulates type II cell proliferation in the rat, we designed experiments to evaluate whether intratracheal KGF before or after intratracheal bleomycin would prevent pulmonary fibrosis. Intratracheal bleomycin without KGF resulted in moderate to severe lung injury and subsequent fibrosis. Conversely, intratracheal KGF pretreatment at 48 or 72 hr before bleomycin resulted in minimal to no visible lung injury. Rats pretreated with phosphate buffered saline before bleomycin had significantly more neutrophils and protein in bronchoalveolar lavage fluid at 4 and 6 days and higher hydroxyproline levels after bleomycin as compared to KGF-pretreated rats. Pretreatment with KGF at 48 hr protected against bleomycin-induced alterations in pulmonary physiology and increased surfactant protein C-positive (SP-C)-positive cells and SP-A, SP-B, SP-C, and SP-D mRNA levels after bleomycin instillation when compared to saline pretreated rats on day 1 or day 7. KGF posttreatment protocols did not prevent bleomycin lung injury and fibrosis. We conclude that KGF pretreatment attenuates bleomycin lung injury and increases type II cell proliferation and surfactant protein gene expression after bleomycin instillation in the rat.

Financial impact of the Medicare Fee Schedule on a department of anesthesiology in an academic medical center: two scenarios.

The purpose of this study was to model the financial impact of the Medicare Fee Schedule (MFS) on an anesthesiology department in a large academic medical center under two different scenarios. Scenario 1 assumes continued use of actual-time units throughout the five-year transition period. Scenario 2 assumes a change to the use of average-time units by the time the MFS is fully implemented in 1996. Twelve months of actual payments and frequencies for services billed to Medicare in 1991 were used as baseline data. It was assumed there would be no change in volume of services, billing practices, or staffing patterns. It was estimated that upon full implementation of the MFS, the anesthesiology department that was studied would lose $244,000 (13%) under Scenario 1 and $945,000 (51%) under Scenario 2. There is a full transition to final fee schedule rates in Year 1 of the MFS transition under Scenario 1, whereas there are additional incremental losses in each successive year under Scenario 2. This study shows that HCFA's future policy decisions with regard to anesthesiology reimbursement will have substantial financial consequences for many practicing anesthesiologists.

Financial impact of the Medicare Fee Schedule on a large multispecialty faculty practice in an academic medical center.

Although there have been preliminary studies of the financial impact of the Medicare Fee Schedule (MFS) on specialty-specific groups of practicing physicians in an academic setting, there has been no published report of the financial impact of the MFS on an entire multispecialty academic faculty practice. This 1992 study reports the estimated financial impact of the MFS on the faculty practice at the University of Michigan Medical School (UMMS). The authors calculated the difference between the Medicare payments to be received when the MFS is completely implemented in 1996 and the payments received in 1991, and then repeated this process for each year of the transition period, 1992-1996. The UMMS will experience a $1.2 million (-4.7%) loss under the fully implemented MFS. The medical departments project an 8% gain, while substantial losses are projected for the surgical departments (-10%) and hospital-based departments (-15%). Projections indicate that obstetrics-gynecology and ophthalmology will lose nearly 20% and that surgery will lose 9%. But large percentage gains are projected for neurology (+43%), physical medicine (+25%), and family practice (+17%). Analysis of the MFS transition's effects shows an abrupt and unpredictable financial impact in the first year. Faculty practice plans may be more disadvantaged under the MFS than other physician groups, yet the uncertain impact of the MFS in the first year (1992) may inhibit accurate financial planning for all physician groups.

Organizational growth, survival and death in the U.S. hospital industry: a population ecology perspective.

This article develops an analytic framework for predicting organizational survival, growth and death in the U.S. hospital industry. The population ecology perspective is used to identify the environmental conditions under which health service organizations with specialist or generalist characteristics will survive. Hypotheses derived from the framework focus on the particular form hospitals and multihospital systems will take, how they are likely to develop and the configuration of the health care delivery system under different assumptions about the environment.