A phase Ib study evaluating the recommended phase II dose, safety, tolerability, and efficacy of mivavotinib in combination with nivolumab in advanced solid tumors.

Mivavotinib (TAK-659/CB-659), a dual SYK/FLT3 inhibitor, reduced immunosuppressive immune cell populations and suppressed tumor growth in combination with anti-PD-1 therapy in cancer models. This dose-escalation/expansion study investigated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of mivavotinib plus nivolumab in patients with advanced solid tumors. Patients received oral mivavotinib 60-100 mg once-daily plus intravenous nivolumab 3 mg/kg on days 1 and 15 in 28-day cycles until disease progression or unacceptable toxicity. The dose-escalation phase evaluated the recommended phase II dose (RP2D; primary endpoint). The expansion phase evaluated overall response rate (primary end point) at the RP2D in patients with triple-negative breast cancer (TNBC). During dose-escalation (n = 24), two dose-limiting toxicities (grade 4 lipase increased and grade 3 pyrexia) occurred in patients who received mivavotinib 80 mg and 100 mg, respectively. The determined RP2D was once-daily mivavotinib 80 mg plus nivolumab 3 mg/kg. The expansion phase was terminated at ~50% enrollment (n = 17) after failing to meet an ad hoc efficacy futility threshold. Among all 41 patients, common treatment-emergent adverse events (TEAEs) included dyspnea (48.8%), aspartate aminotransferase increased, and pyrexia (46.3% each). Common grade ≥3 TEAEs were hypophosphatemia and anemia (26.8% each). Mivavotinib plasma exposure was generally dose-proportional (60-100 mg). One patient had a partial response. Mivavotinib 80 mg plus nivolumab 3 mg/kg was well tolerated with no new safety signals beyond those of single-agent mivavotinib or nivolumab. Low response rates highlight the challenges of treating unresponsive tumor types, such as TNBC, with this combination and immunotherapies in general. TRIAL REGISTRATION ID: NCT02834247.

Assessing nicotine dependence using an oral nicotine free-choice paradigm in mice.

Models to assess the addictive-like properties of nicotine in mice are limited. Therefore, we aimed to characterize and validate an addiction index by using an oral nicotine free-choice paradigm in mice. Adult C57BL/6J, DBA/2J, or genetically modified mice carrying deletions for nicotinic acetylcholine receptor (nAChR) subunits, (n = 8-10/sex/group) were given a choice of water or nicotine (10-960 µg/ml) solution using a two-bottle free-choice (2BC) paradigm. In general, oral nicotine intake and preference were higher in female mice compared to males. Absence of nicotine led to withdrawal, and intermittent access resulted in an escalation in consumption and greater nicotine withdrawal than continuous exposure. Additionally, oral nicotine consumption increased nucleus accumbens tyrosine hydroxylase levels. While ß2 and α6 KO mice showed a significant decrease in nicotine intake, deletion of α5 nAChRs increased nicotine consumption at high concentrations. Deletion of the α7 subunit altered the observed sex difference in nicotine consumption, with females consuming less than males. The α4ß2 partial agonist varenicline decreased oral nicotine consumption. Although addition of quinine to the nicotine solution lowered nicotine intake, mice primed with nicotine did not lower their intake after quinine addition. Nicotine deprivation followed by re-exposure showed increased nicotine consumption, and DBA/2J mice consumed less nicotine compared to C57BL/6J. We validated the mouse 2BC paradigm to study nicotine's addictive-like properties including nicotine intake, preference, withdrawal, and escalation of nicotine consumption during binge drinking or after reinstatement of a deprivation period.

Nursing students' commitment and the mediating effect of stress.

OBJECTIVES: Knowing there is a shortage of qualified nurses throughout the healthcare industry, it is imperative that program administrators understand the factors that affect nursing students as they select and commit to their academic major. They should consider key influences on potential students as new recruiting and retention tactics are developed and employed. Thus, we develop the current study to understand factors that shape students' commitment to nursing. Specifically, we attempt to discern how potential career growth, students' understanding of available occupational specialties, family members, and instructors affect nursing students' commitment to their chosen academic program. In addition, we analyze the mediating effect of stress in order to explain why some factors have more influence than others do. By conducting this research, we hope to provide insight into how to better recruit potential students and retain existing students already enrolled in nursing programs. DESIGN/SETTING/METHODS: Data collection took place in 2016 at one public and one private nursing program. The sample is understanding of available occupational specialties of 167 nursing student who completed a structured survey. Career growth, occupational specialties, instructors' and family influence were measured to understand how they affected major commitment and by extension intention to stay with their nursing program. We also assessed the potential mediating effect of stress on students' commitment to the nursing major. Ordinary least squares regression (SPSS version 22) was then used to evaluate both direct and mediated relationships. RESULTS: Based on the analysis, potential career growth, students' understanding of available occupational specialties, and family members directly affect nursing students' level of commitment to their chosen academic major. Results indicate that when students learn about the growth potential of the nursing profession or the different occupational specialties available that they will be more committed to the chosen major. The students likely believe the nursing profession aligns with their personal ambitions and skillsets. In addition, results indicate that stress fully mediates the level of commitment a student has towards nursing as an academic major. Evidence from the nursing students in this study indicates that their level of commitment to nursing programs is harmed by high levels of experienced stress. Students may feel that they identify with this area of study, but if they are stressed they may believe they lack the necessary abilities to succeed and/or perceive the nursing profession as undesirable to them personally. CONCLUSION: Understanding factors that influence students' commitment to an academic major is important to administrators as they work to improve the number of students enrolled in accredited nursing programs. Specifically, they can use insights from this study to better develop recruitment and retention programs by enabling students to garner feelings of pride, enthusiasm, and positively identify with the nursing profession.

Free-hand transperineal prostate biopsy provides acceptable cancer detection and minimizes risk of infection: evolving experience with a 10-sector template.

INTRODUCTION AND OBJECTIVES: Free-hand transperineal prostate (fTP-Bx) biopsy offers an alternative to transrectal prostate biopsy (TRUS-Bx) in the diagnosis of prostate cancer. Our objectives were to determine whether fTP-Bx achieves cancer detection rates comparable to historic TRUS-Bx cohorts; to determine infectious and other complications associated with fTP-B; and to propose a standardized fTP-Bx template. PATIENTS AND METHODS: We present a single institution, retrospective review of fTP-Bx in 1,000 men with elevated prostate-specific antigen, abnormal digital rectal examination, or on an active surveillance protocol. A fan-like biopsy scheme was used in 883 patients. A 10-sector prostate biopsy template was developed for use in the final 117 patients. The primary outcome was detection of any cancer and detection of clinically significant cancer (Grade Group ≥ 2). Secondary outcomes included procedural specifics and complications. Chi Square and Mann-Whitney U were used for analysis of categorical and continuous variables, respectively. RESULTS: The median age of the cohort was 68 (interquartile range 61-74) years, and the median prostate-specific antigen was 7.9 (interquartile range 5.5-11.9) ng/ml. Total cancer (60.7%) and clinically significant cancer (40.3%) detection for fTP-Bx were comparable to those reported for TRUS-Bx. Detection of any cancer (70.9% vs. 59.3%, P < 0.01) and clinically significant cancer (51.3% vs. 38.9%, P = 0.01) was higher using the 10-sector biopsy template relative to the fan-like pattern. No patients were hospitalized for sepsis and no culture-proven urinary tract infections were diagnosed. CONCLUSION: Cancer detection rates using fTP-Bx are comparable to TRUS-Bx, and fTP-Bx nearly eliminates the risk of infection. We propose a 10-sector biopsy template for fTP-Bx that easily translates to established MRI prostate sector maps for use in clinical care and future research studies exploring the efficacy of MRI-guided fTP-Bx.

Update on Guidelines for Perioperative Antibiotic Selection and Administration From the Surgical Care Improvement Project (SCIP) and American Society of Health-System Pharmacists.

Antibiotic prophylaxis plays an important role in the prevention of surgical site infections. For healthcare institutions to receive reimbursement, compliance with current measures introduced by the Surgical Care Improvement Project is required. Anesthesia providers commonly administer prophylactic antibiotics and are in the position to provide valuable input in the perioperative setting. This review provides a summary of the most common antibiotics used in the surgical setting-cefazolin, clindamycin, and vancomycin-and their implications to the anesthesia provider, such as proper dosing, targeting bacteria, and side effects.

A Review of the Effectiveness of Neuroimaging Modalities for the Detection of Traumatic Brain Injury.

The incidence of traumatic brain injury (TBI) in the United States was 3.5 million cases in 2009, according to the Centers for Disease Control and Prevention. It is a contributing factor in 30.5% of injury-related deaths among civilians. Additionally, since 2000, more than 260,000 service members were diagnosed with TBI, with the vast majority classified as mild or concussive (76%). The objective assessment of TBI via imaging is a critical research gap, both in the military and civilian communities. In 2011, the Department of Defense (DoD) prepared a congressional report summarizing the effectiveness of seven neuroimaging modalities (computed tomography [CT], magnetic resonance imaging [MRI], transcranial Doppler [TCD], positron emission tomography, single photon emission computed tomography, electrophysiologic techniques [magnetoencephalography and electroencephalography], and functional near-infrared spectroscopy) to assess the spectrum of TBI from concussion to coma. For this report, neuroimaging experts identified the most relevant peer-reviewed publications and assessed the quality of the literature for each of these imaging technique in the clinical and research settings. Although CT, MRI, and TCD were determined to be the most useful modalities in the clinical setting, no single imaging modality proved sufficient for all patients due to the heterogeneity of TBI. All imaging modalities reviewed demonstrated the potential to emerge as part of future clinical care. This paper describes and updates the results of the DoD report and also expands on the use of angiography in patients with TBI.

The histamine H4 receptor mediates inflammation and Th17 responses in preclinical models of arthritis.

OBJECTIVE: The histamine H4 receptor (H4R) has been shown to drive inflammatory responses in models of asthma, colitis and dermatitis, and in these models it appears to affect both innate and adaptive immune responses. In this study, we used both H4R-deficient mice and a specific H4R antagonist, JNJ 28307474, to investigate the involvement of the H4R in mouse arthritis models. METHODS: H4R-deficient mice and wild-type mice administered the H4R antagonist were studied in models of collagen antibody-induced arthritis (CAIA) and collagen-induced arthritis (CIA). The impact on Th17 cells was assessed by restimulation of inguinal lymphocytes in the disease or immunisation models and with in vitro stimulation of whole blood. RESULTS: Both H4R-deficient mice and mice treated with the H4R antagonist exhibited reduced arthritis disease severity in both CAIA and CIA models. This was evident from the reduction in disease score and in joint histology. In the CIA model, treatment with the H4R antagonist reduced the number of interleukin (IL)-17 positive cells in the lymph node and the total production of IL-17. Th17 cell development in vivo was reduced in H4R-deficient mice or in mice treated with an H4R antagonist. Finally, treatment of both mouse and human blood with an H4R antagonist reduced the production of IL-17 when cells were stimulated in vitro. CONCLUSIONS: These results implicate the H4R in disease progression in arthritis and in the production of IL-17 from Th17 cells. This work supports future clinical exploration of H4R antagonists for the treatment of rheumatoid arthritis.

Mast cell mediators cause early allergic bronchoconstriction in guinea-pigs in vivo: a model of relevance to asthma.

One feature of allergic asthma, the EAR (early allergic reaction), is not present in the commonly used mouse models. We therefore investigated the mediators involved in EAR in a guinea-pig in vivo model of allergic airway inflammation. Animals were sensitized using a single OVA (ovalbumin)/alum injection and challenged with aerosolized OVA on day 14. On day 15, airway resistance was assessed after challenge with OVA or MCh (methacholine) using the forced oscillation technique, and lung tissue was prepared for histology. The contribution of mast cell mediators was investigated using inhibitors of the main mast cell mediators [histamine (pyrilamine) and CysLTs (cysteinyl-leukotrienes) (montelukast) and prostanoids (indomethacin)]. OVA-sensitized and challenged animals demonstrated AHR (airway hyper-responsiveness) to MCh, and lung tissue eosinophilic inflammation. Antigen challenge induced a strong EAR in the sensitized animals. Treatment with a single compound, or indomethacin together with pyrilamine or montelukast, did not reduce the antigen-induced airway resistance. In contrast, dual treatment with pyrilamine together with montelukast, or triple inhibitor treatment, attenuated approximately 70% of the EAR. We conclude that, as in humans, the guinea-pig allergic inflammation model exhibits both EAR and AHR, supporting its suitability for in vivo identification of mast cell mediators that contribute to the development of asthma. Moreover, the known mast cell mediators histamine and leukotrienes were major contributors of the EAR. The data also lend further support to the concept that combination therapy with selective inhibitors of key mediators could improve asthma management.

Antagonism of the histamine H4 receptor reduces LPS-induced TNF production in vivo.

OBJECTIVE: Antagonism of the histamine H4 receptor (H4R) has been shown to be anti-inflammatory in a number of preclinical disease models, however the exact mechanisms behind this are still being uncovered. In vitro, the receptor interacts with TLR and impacts inflammatory mediator production from a number of different cell types. Here it is shown that this interaction also occurs in vivo. MATERIALS AND METHODS: Wild-type and H4R deficient BALB/c mice received an i.p. injection of LPS in PBS in conjunction with p.o. JNJ 7777120 or JNJ 28307474 (H4R antagonists). Two hours later blood was collected and TNF was measured. RESULTS: Two different H4R antagonists inhibited LPS-induced TNF production in mice and this production was also reduced in H4R-deficient mice. The TNF mRNA analysis showed that the major source of the cytokine was the liver and not blood, and that the H4R antagonist only reduced the expression levels in the liver. Depletion or inactivation of macrophages reduced the TNF levels and eliminated the H4R sensitivity. Treatment with an H4R antagonist also reduced LPS-induced liver injury and blocked LPS-enhanced lung inflammation in mice. CONCLUSION: The data support an interaction between H4R and TLR activation in vivo that can drive inflammatory responses.

Identification of benzofuran central cores for the inhibition of leukotriene A(4) hydrolase.

Leukotrienes (LT's) are known to play a physiological role in inflammatory immune response. Leukotriene A(4) hydrolase (LTA(4)H) is a cystolic enzyme that stereospecifically catalyzes the transformation of LTA(4) to LTB(4). LTB(4) is a known pro-inflammatory mediator. This paper describes the identification and synthesis of substituted benzofurans as LTH(4)H inhibitors. The benzofuran series demonstrated reduced mouse and human whole blood LTB(4) levels in vitro and led to the identification one analog for advanced profiling. Benzofuran 28 showed dose responsive target engagement and provides a useful tool to explore a LTA(4)H inhibitor for the treatment of inflammatory diseases, such as asthma and inflammatory bowel disease (IBD).

Effects of multiple scattering on fluorescence correlation spectroscopy measurements of particles moving within optically dense media.

Fluorescence correlation spectroscopy (FCS) is increasingly being used to assess the movement of particles diffusing in complex, optically dense surroundings, in which case measurement conditions may complicate data interpretation. It is considered how a single-photon FCS measurement can be affected if the sample properties result in scattering of the incident light. FCS autocorrelation functions of Atto 488 dye molecules diffusing in solutions of polystyrene beads are measured, which acted as scatterers. Data indicated that a scattering-linked increase in the illuminated volume, as much as two fold, resulted in minimal increase in diffusivity. To analyze the illuminated beam profile, Monte-Carlo simulations were employed, which indicated a larger broadening of the beam along the axial than the radial directions, and a reduction of the incident intensity at the focal point. The broadening of the volume in the axial direction has only negligible effect on the measured diffusion time, since intensity fluctuations due to diffusion events in the radial direction are dominant in FCS measurements. Collectively, results indicate that multiple scattering does not result in FCS measurement artifacts and thus, when sufficient signal intensity is attainable, single-photon FCS can be a useful technique for measuring probe diffusivity in optically dense media.

Azabenzthiazole inhibitors of leukotriene A4 hydrolase.

Previously, benzthiazole containing LTA(4)H inhibitors were discovered that were potent (1-3), but were associated with the potential for a hERG liability. Utilizing medicinal chemistry first principles (e.g., introducing rigidity, lowering cLogD) a new benzthiazole series was designed, congeners of 1-3, which led to compounds 7a, 7c, 12a-d which exhibited LTA(4)H IC(50)=3-6 nM and hERG Dofetilide Binding IC(50)=8.9-> >10 µM.

Normative database of judgment of complexity task with functional near infrared spectroscopy--application for TBI.

The ability to assess frontal lobe function in a rapid, objective, and standardized way, without the need for expertise in cognitive test administration might be particularly helpful in mild traumatic brain injury (TBI), where objective measures are needed. Functional near infrared spectroscopy (fNIRS) is a reliable technique to noninvasively measure local hemodynamic changes in brain areas near the head surface. In this paper, we are combining fNIRS and frameless stereotaxy which allowed us to co-register the functional images with previously acquired anatomical MRI volumes. In our experiment, the subjects were asked to perform a task, evaluating the complexity of daily life activities, previously shown with fMRI to activate areas of the anterior frontal cortex. We reconstructed averaged oxyhemoglobin and deoxyhemoglobin data from 20 healthy subjects in a spherical coordinate. The spherical coordinate is a natural representation of surface brain activation projection. Our results show surface activation projected from the medial frontopolar cortex which is consistent with previous fMRI results. With this original technique, we will construct a normative database for a simple cognitive test which can be useful in evaluating cognitive disability such as mild traumatic brain injury.

A hematoma detector-a practical application of instrumental motion as signal in near infra-red imaging.

In this paper we discuss results based on using instrumental motion as a signal rather than treating it as noise in Near Infra-Red (NIR) imaging. As a practical application to demonstrate this approach we show the design of a novel NIR hematoma detection device. The proposed device is based on a simplified single source configuration with a dual separation detector array and uses motion as a signal for detecting changes in blood volume in the dural regions of the head. The rapid triage of hematomas in the emergency room will lead to improved use of more sophisticated/expensive imaging facilities such as CT/MRI units. We present simulation results demonstrating the viability of such a device and initial phantom results from a proof of principle device. The results demonstrate excellent localization of inclusions as well as good quantitative comparisons.

Quantitative principal component model for skin chromophore mapping using multi-spectral images and spatial priors.

We describe a novel reconstruction algorithm based on Principal Component Analysis (PCA) applied to multi-spectral imaging data. Using numerical phantoms, based on a two layered skin model developed previously, we found analytical expressions, which convert qualitative PCA results into quantitative blood volume and oxygenation values, assuming the epidermal thickness to be known. We also evaluate the limits of accuracy of this method when the value of the epidermal thickness is not known. We show that blood volume can reliably be extracted (less than 6% error) even if the assumed thickness deviates 0.04mm from the actual value, whereas the error in blood oxygenation can be as large as 25% for the same deviation in thickness. This PCA based reconstruction was found to extract blood volume and blood oxygenation with less than 8% error, if the underlying structure is known. We then apply the method to in vivo multi-spectral images from a healthy volunteer's lower forearm, complemented by images of the same area using Optical Coherence Tomography (OCT) for measuring the epidermal thickness. Reconstruction of the imaging results using a two layered analytical skin model was compared to PCA based reconstruction results. A point wise correlation was found, showing the proof of principle of using PCA based reconstruction for blood volume and oxygenation extraction.

Principal component model of multispectral data for near real-time skin chromophore mapping.

Multispectral images of skin contain information on the spatial distribution of biological chromophores, such as blood and melanin. From this, parameters such as blood volume and blood oxygenation can be retrieved using reconstruction algorithms. Most such approaches use some form of pixelwise or volumetric reconstruction code. We explore the use of principal component analysis (PCA) of multispectral images to access blood volume and blood oxygenation in near real time. We present data from healthy volunteers under arterial occlusion of the forearm, experiencing ischemia and reactive hyperemia. Using a two-layered analytical skin model, we show reconstruction results of blood volume and oxygenation and compare it to the results obtained from our new spectral analysis based on PCA. We demonstrate that PCA applied to multispectral images gives near equivalent results for skin chromophore mapping and quantification with the advantage of being three orders of magnitude faster than the reconstruction algorithm.

Direct curvature correction for noncontact imaging modalities applied to multispectral imaging.

Noncontact optical imaging of curved objects can result in strong artifacts due to the object's shape, leading to curvature biased intensity distributions. This artifact can mask variations due to the object's optical properties, and makes reconstruction of optical/physiological properties difficult. In this work we demonstrate a curvature correction method that removes this artifact and recovers the underlying data, without the necessity of measuring the object's shape. This method is applicable to many optical imaging modalities that suffer from shape-based intensity biases. By separating the spatially varying data (e.g., physiological changes) from the background signal (dc component), we show that the curvature can be extracted by either averaging or fitting the rows and columns of the images. Numerical simulations show that our method is equivalent to directly removing the curvature, when the object's shape is known, and accurately recovers the underlying data. Experiments on phantoms validate the numerical results and show that for a given image with 16.5% error due to curvature, the method reduces that error to 1.2%. Finally, diffuse multispectral images are acquired on forearms in vivo. We demonstrate the enhancement in image quality on intensity images, and consequently on reconstruction results of blood volume and oxygenation distributions.

Histamine H4 receptor antagonism diminishes existing airway inflammation and dysfunction via modulation of Th2 cytokines.

BACKGROUND: Airway remodeling and dysfunction are characteristic features of asthma thought to be caused by aberrant production of Th2 cytokines. Histamine H4 receptor (H4R) perturbation has previously been shown to modify acute inflammation and Th2 cytokine production in a murine model of asthma. We examined the ability of H4R antagonists to therapeutically modify the effects of Th2 cytokine production such as goblet cell hyperplasia (GCH), and collagen deposition in a sub-chronic model of asthma. In addition, effects on Th2 mediated lung dysfunction were also determined. METHODS: Mice were sensitized to ovalbumin (OVA) followed by repeated airway challenge with OVA. After inflammation was established mice were dosed with the H4R antagonist, JNJ 7777120, or anti-IL-13 antibody for comparison. Airway hyperreactivity (AHR) was measured, lungs lavaged and tissues collected for analysis. RESULTS: Therapeutic H4R antagonism inhibited T cell infiltration in to the lung and decreased Th2 cytokines IL-13 and IL-5. IL-13 dependent remodeling parameters such as GCH and lung collagen were reduced. Intervention with H4R antagonist also improved measures of central and peripheral airway dysfunction. CONCLUSIONS: These data demonstrate that therapeutic H4R antagonism can significantly ameliorate allergen induced, Th2 cytokine driven pathologies such as lung remodeling and airway dysfunction. The ability of H4R antagonists to affect these key manifestations of asthma suggests their potential as novel human therapeutics.

Leukotriene A(4) hydrolase inhibition attenuates allergic airway inflammation and hyperresponsiveness.

RATIONALE: Allergic asthma is characterized by reversible airway obstruction, lung inflammation, and airway hyperresponsiveness (AHR). Previous studies using leukotriene B(4) (LTB(4)) receptor 1-deficient mice and adoptive transfer experiments have suggested that LTB(4) plays a role in lung inflammation and AHR. OBJECTIVES: In this study, we used a leukotriene A(4) hydrolase (LTA(4)H) inhibitor as a pharmacological tool to directly examine the role of LTB(4) in a mast cell-dependent murine model of allergic airway inflammation. METHODS: We used the forced oscillation technique to test the effects of an LTA(4)H inhibitor dosed during the challenge phase on AHR. Lung tissue and lavage were collected for analysis. MEASUREMENTS AND MAIN RESULTS: Treatment with an LTA(4)H inhibitor improved multiple parameters encompassing AHR and lung function. Significant decreases in inflammatory leukocytes, cytokines, and mucin were observed in the lung lumen. Serum levels of antigen-specific IgE and IgG1 were also decreased. Labeled antigen uptake by lung dendritic cells and subsequent trafficking to draining lymph nodes and the lung were decreased on LTA(4)H inhibitor treatment. Provocatively, inhibition of LTA(4)H increased lipoxin A(4) levels in lung lavage fluid. CONCLUSIONS: These data suggest that LTB(4) plays a key role in driving lung inflammation and AHR. Mechanistically, we provide evidence that inhibition of LTA(4)H, affects recruitment of both CD4(+) and CD8(+) T cells, as well as trafficking of dendritic cells to draining lymph nodes, and may beneficially modulate other pro- and antiinflammatory eicosanoids in the lung. Inhibition of LTA(4)H is thus a potential therapeutic strategy that could modulate key aspects of asthma.

Identification of a potent, selective, and orally active leukotriene a4 hydrolase inhibitor with anti-inflammatory activity.

LTA 4H is a ubiquitously distributed 69 kDa zinc-containing cytosolic enzyme with both hydrolase and aminopeptidase activity. As a hydrolase, LTA 4H stereospecifically catalyzes the transformation of the unstable epoxide LTA 4 to the diol LTB 4, a potent chemoattractant and activator of neutrophils and a chemoattractant of eosinophils, macrophages, mast cells, and T cells. Inhibiting the formation of LTB 4 is expected to be beneficial in the treatment of inflammatory diseases such as inflammatory bowel disease (IBD), asthma, and atherosclerosis. We developed a pharmacophore model using a known inhibitor manually docked into the active site of LTA 4H to identify a subset of compounds for screening. From this work we identified a series of benzoxazole, benzthiazole, and benzimidazole inhibitors. SAR studies resulted in the identification of several potent inhibitors with an appropriate cross-reactivity profile and excellent PK/PD properties. Our efforts focused on further profiling JNJ 27265732, which showed encouraging efficacy in a disease model relevant to IBD.