Discovery of GW870086: a potent anti-inflammatory steroid with a unique pharmacological profile.

BACKGROUND AND PURPOSE: Glucocorticoids are highly effective therapies for a range of inflammatory diseases. Advances in the understanding of the diverse molecular mechanisms underpinning glucocorticoid action suggest that anti-inflammatory molecules with reduced side effect liabilities can be discovered. Here we set out to explore whether modification of the 17α position of the steroid nucleus could generate molecules with a unique pharmacological profile and to determine whether such molecules would retain anti-inflammatory activity. EXPERIMENTAL APPROACH: The pharmacological properties of GW870086 were compared with fluticasone propionate (FP) using a range of cellular and in vivo model systems, including extensive gene expression profiling. KEY RESULTS: GW870086 repressed inflammatory cytokine release from lung epithelial cells in a similar manner to FP but antagonized the effect of dexamethasone on MMTV-driven reporter gene transactivation. GW870086 had a strong effect on the expression of some glucocorticoid-regulated genes (such as PTGS2), while having minimal impact on the expression of other known target genes (such as SGK). GW870086 retained the ability to strengthen tight junctions in epithelial cell culture but, unlike FP, was unable to protect the culture from elastase-mediated damage. In murine models of irritant-induced contact dermatitis and ovalbumin-induced allergic inflammation, GW870086 showed comparable anti-inflammatory efficacy to FP. CONCLUSION AND IMPLICATIONS: GW870086 is a potent anti-inflammatory compound with a unique ability to regulate only a subset of those genes that are normally affected by classical glucocorticoids. It has the potential to become a new topical steroid with a different safety profile to existing therapies.

A replication competent lentivirus (RCL) assay for equine infectious anaemia virus (EIAV)-based lentiviral vectors.

Lentiviral vectors are being developed to satisfy a wide range of currently unmet medical needs. Vectors destined for clinical evaluation have been rendered multiply defective by deletion of all viral coding sequences and nonessential cis-acting sequences from the transfer genome. The viral envelope and accessory proteins are excluded from the production system. The vectors are produced from separate expression plasmids that are designed to minimize the potential for homologous recombination. These features ensure that the regeneration of the starting virus is impossible. It is a regulatory requirement to confirm the absence of any replication competent virus, so we describe here the development and validation of a replication competent lentivirus (RCL) assay for equine infectious anaemia virus (EIAV)-based vectors. The assay is based on the guidelines developed for testing retroviral vectors, and uses the F-PERT (fluorescent-product enhanced reverse transcriptase) assay to test for the presence of a transmissible reverse transcriptase. We have empirically modelled the replication kinetics of an EIAV-like entity in human cells and devised an amplification protocol by comparison with a replication competent MLV. The RCL assay has been validated at the 20 litre manufacturing scale, during which no RCL was detected. The assay is theoretically applicable to any lentiviral vector and pseudotype combination.

New strategies for ER admissions.

Henry Ford Hospital, Detroit, operates a Level 1 emergency department. Last year, nearly 89,000 adults and children were treated; one-third were brought in with life-threatening conditions. This year, the emergency department expects to handle more than 100,000 patients. Patients with nonemergency problems sometimes wait four to six hours before being seen by a physician. Others get discouraged and leave.

Two are better than one.

On March 29, 1996, Marwan Abouljoud, MD, and Francisco Escobar III, MD, of Henry Ford Hospital, Detroit, performed the first split liver transplant in Michigan on two patients who were both dying from liver disease. At that time, fewer than 20 such procedures had been done nationwide.

Prevent and empower.

In an effort to short health care from ¿diagnose and treat¿ to ¿prevent and empower,¿ Henry Ford Health System (HFHS) launched the Center for Health Promotion and Disease Prevention, directed by Ronald M. Davis, MD, former chief medical officer of the Michigan Department of Public Health and former director of the Office on Smoking and Health at the US Centers for Disease Control and Prevention. He also headed up three Surgeon General's reports on smoking, including the 1988 report linking smoking to nicotine dependence.

Improved diffraction efficiency of silver halide (sensitized) gelatin.

A modification of the silver halide (sensitized) gelatin process is described. We demonstrate a phase process utilizing commercially available photographic emulsions and processing which has the sensitometric properties of silver halide emulsion and the holographic performance characteristics found in dichromated gelatinbased processes.

Internal derangement of the temporomandibular joint: detection by single-photon emission computed tomography. Work in progress.

The diagnostic accuracy of both planar and single-photon emission computed tomography (SPECT) bone scintigraphy, radionuclide angiography, arthrography, and conventional radiography was evaluated in 36 patients with temporomandibular joint (TMJ) dysfunction undergoing preoperative testing. The sensitivity of SPECT bone scintigraphy (0.94) was comparable with arthrography (0.96) and significantly better than planar bone scintigraphy (0.76), radionuclide angiography (0.35), and transcranial lateral radiographs (0.04). While data for a larger asymptomatic control population are needed, preliminary results give SPECT a diagnostic specificity of 0.70 for internal derangements of the TMJ requiring surgical correction. It is concluded that SPECT bone scintigraphy is a useful noninvasive imaging test to screen for internal derangement of the TMJ.

Interference by inhibitors of the renin-angiotensin system with neurogenic vasoconstriction.

In the pithed rat preparation captopril, enalapril, teprotide and saralasin given intravenously attenuated pressor responses to both spinal sympathetic nerve stimulation and exogenous noradrenaline, indicating that angiotensin has a potent adrenergic facilitating action. Bi-lateral nephrectomy abolished the effects of captopril on nerve stimulation but responses to noradrenaline were still inhibited following nephrectomy, indicating that part of the post-junctional actions of captopril might not be angiotensin dependent. Both phenylephrine and clonidine are also inhibited by captopril in the pithed rat. It is thus not clear whether captopril is interacting with post-junctional alpha 1- or alpha 2-adrenoceptors. Vasoconstrictor responses to nerve stimulation are greater in SHR than WKY and captopril is more effective at inhibiting responses in the SHR than it is in WKY. These interactions between captopril and the sympathetic nervous system could explain the effectiveness of ACE inhibitors as antihypertensive agents.