John B. Hogan

Bristol-Myers Squibb (United States)

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Mark D. Lindner

Center for Scientific Review

Clotilde Bourin

Research & Development Institute

Lawrence G. Iben

Bristol-Myers Squibb (United States)

Ildiko Antal‐Zimanyi

Bristol-Myers Squibb (Germany)

Graham S. Poindexter

Bristol-Myers Squibb (Germany)

Mendi A. Higgins

Bristol-Myers Squibb (United States)

Gail K. Mattson

Bristol-Myers Squibb (United States)

Donald B. Hodges

Vertex Pharmaceuticals (United States)

John W. Russell

University of Hawaiʻi at Mānoa

Kim A. Johnson

University of Iowa

Cooperative Institutions

Bristol-Myers Squibb (United States)

Bristol-Myers Squibb (Germany)

Pfizer (United States)

Yale University

Biocon (India)

Eli Lilly (United States)

Lexicon Pharmaceuticals (United States)

Merck & Co., Inc., Rahway, NJ, USA (United States)

Coastal Connecticut Research (United States)

Armed Forces Institute of Pathology

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CCDC 1508841: Experimental Crystal Structure Determination

The Cambridge Structural Database (2016)

Mendi A. Higgins Lawrence R. Marcin F. Christopher Zusi Robert G. Gentles Min Ding

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

10.5517/ccdc.csd.cc1mn29n

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Citations (0)

Establishment of an animal model to evaluate the biological effects of intramuscularly embedded depleted uranium fragments. Technical report

Carlos Alberto Castro K. A. Benson Victor Bogo Eric G. Daxon John B. Hogan

During the Persian Gulf War, 36 U.S. soldiers were wounded by depleted uranium (DU) munitions. Based on medical guidelines for conventional shrapnel injuries (nonradioactive), many DU fragments were left in soldiers. Unfortunately, health risks associated with embedded DU were unknown, and an animal model to investigate this did not exist. The purpose of this study was to develop an animal model to examine the health risks associated with DU shrapnel injuries. Twelve rats were surgically implanted intramuscularly with 8 DU pellets (1 mm in diameter x 2 mm in length) or 8 chemically inert tantalum (Ta) pellets of similar size. Urinary uranium levels were measured on days 1, 3,7, 14, 28, 60, and 120 after implantation of DU pellets. Physiological and behavioral parameters, including locomotor activity, forelimb and hindlimb grip strength, food and water consumption, and urinary output, were measured 5 and 3 days before surgery and on days 1, 3,7, 14,28, 60, and 120 after surgery. Urinary uranium levels for Ta-implanted rats remained at background levels. In contrast, the average urinary uranium level for DU-implanted rats was significantly elevated on day 1(28.69 ug U/I) after implantation and remained elevated until day 120 (204.56 ug U/I). There was no significantmore » difference between DU- and Ta-implanted rats in any behavioral or physiological measures. Results indicate that the rat is an appropriate animal model for evaluating biological effects of embedded DU fragments.« less

Animal model

Depleted Uranium

Experimental animal

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Citations (2)

Urinary and serum mutagenicity studies with rats implanted with depleted uranium or tantalum pellets

Mutagenesis (1998)

Alexandra C. Miller Alfred F. Fuciarelli William E. Jackson E.J. Ejnik Christy A. Emond

During the 1991 Persian Gulf War several US military personnel were wounded by shrapnel fragments consisting of depleted uranium. These fragments were treated as conventional shrapnel and were not surgically removed to spare excessive tissue damage. Uranium bioassays conducted over a year after the initial uranium injury indicated a significant increase in urine uranium levels above natural background levels. The potential mutagenic effects of depleted uranium are unknown. To assess the potential mutagenic effects of long-term exposure to internalized depleted uranium, Sprague-Dawley rats were implanted with depleted uranium and their urine and serum were evaluated for mutagenic potential at various times after pellet implantation using the Ames Salmonella reversion assay. Tantalum, an inert metal widely used in prosthetic devices was used for comparison. Enhancement of mutagenic activity in Salmonella typhiurium strain TA98 and the Ames IITM mixed strains (TA7001–7006) was observed in urine samples from animals implanted with depleted uranium pellets. In contrast, urine samples from animals implanted with tantalum did not show a significant enhancement of mutagenic activity in these strains. In depleted uranium-implanted animals, urine mutagenicity increased in a dose- and time-dependent manner demonstrating a strong positive correlation with urine uranium levels (r = 0.995, P < 0.001). There was no mutagenic enhancement of any bacterial strain detected in the sera of animals implanted with either depleted uranium or tantalum pellets. The results suggest that uranium content in the urine is correlated with urine mutagenicity and that urinary mutagenicity might be used as a biomarker to detect exposure to internalized uranium.

Depleted Uranium

Ames test

10.1093/mutage/13.6.643

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Citations (101)

Discovery of a Novel Class of Bicyclo[3.1.0]hexanylpiperazines as Noncompetitive Neuropeptide Y Y1 Antagonists

ACS Medicinal Chemistry Letters (2012)

Shuanghua Hu Yazhong Huang Milind Deshpande Guanglin Luo Marc A. Bruce

A novel class of bicyclo[3.1.0]hexanylpiperazine neuropeptide Y (NPY) Y1 antagonists has been designed and synthesized. Scatchard binding analysis showed these compounds to be noncompetitive with [(125)I]PYY binding to the Y1 receptor. The most potent member, 1-((1α,3α,5α,6β)-6-(3-ethoxyphenyl)-3-methylbicyclo[3.1.0]hexan-6-yl)-4-phenylpiperazine (2) had an IC50 = 62 nM and displayed excellent oral bioavailability in rat (% F po = 80), as well as good brain penetration (B/P ratio = 0.61). In a spontaneous nocturnal feeding study with male Sprague-Dawley rats, 2 significantly reduced food intake during a 12 h period.

10.1021/ml200265m

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Citations (2)

Soluble Aβ and cognitive function in aged F-344 rats and Tg2576 mice

Behavioural Brain Research (2006)

Mark D. Lindner John B. Hogan R. M. Krause Frederic Machet Clotilde Bourin

Vulnerability

Amyloid (mycology)

Scopolamine

Cognitive Decline

10.1016/j.bbr.2006.06.003

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Citations (18)

Radioprotective and locomotor responses of mice treated with nimodipine alone and in combination with WR‐151327

Journal of Applied Toxicology (2001)

Michael R. Landauer Carl A. Castro Ken Benson John B. Hogan Joseph F. Weiss

The effect of combining a radiation-protective phosphorothioate with another agent was investigated in an attempt to increase radioprotection and reduce toxicity. The calcium channel blocker nimodipine (NIMO) was administered alone (1 or 10 mg kg-1) or in combination with 200 mg kg-1 of the phosphorothioate radioprotector WR-151327 (WR) (S-3-(3-methylaminopropylamino)propylphosphorothioic acid). Radioprotection as measured (30-day survival) of mice treated i.p. 30 min before (60)Co irradiation at a dose rate of 1 Gy min-1 was evaluated in CD2F1 male mice. The effects of nimodipine and WR-151327 on locomotor activity were investigated also in a separate group of non-irradiated mice. The LD(50/30) for the Emulphor vehicle control group was 8.56. For nimodipine alone (1 or 10 mg kg-1) the LD(50/30)was 8.39 and 10.21 Gy, respectively, yielding dose modification factors (DMFs) of 0.98 and 1.19, respectively. When WR-151327 was given alone, the

Nimodipine

Locomotor activity

10.1002/jat.728

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Citations (27)

An Assessment of the Effects of Serotonin 6 (5-HT6) Receptor Antagonists in Rodent Models of Learning

Journal of Pharmacology and Experimental Therapeutics (2003)

Mark D. Lindner Donald B. Hodges John B. Hogan Anitra F. Orie Jason A. Corsa

Antagonists of serotonin 6 (5-HT6) receptors have been reported to enhance cognition in animal models of learning, although this finding has not been universal. We have assessed the therapeutic potential of the specific 5-HT6 receptor antagonists 4-amino-N-(2,6-bis-methylamino-pyrimidin-4-yl)-benzenesulfonamide (Ro 04-6790) and 5-chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulfonamide (SB-271046) in rodent models of cognitive function. Although mice express the 5-HT6 receptor and the function of this receptor has been investigated in mice, all reports of activity with 5-HT6 receptor antagonists have used rat models. In the present study, receptor binding revealed that the pharmacological properties of the mouse receptor are different from the rat and human receptor: Ro 04-6790 does not bind to the mouse 5-HT6 receptor, so all in vivo testing included in the present report was conducted in rats. We replicated previous reports that 5-HT6 receptor antagonists produce a stretching syndrome previously shown to be mediated through cholinergic mechanisms, but Ro 04-6790 and SB-271046 failed to attenuate scopolamine-induced deficits in a test of contextual fear conditioning. We also failed to replicate the significant effects reported previously in both an autoshaping task and in a version of the Morris water maze. The results of our experiments are not consistent with previous reports that suggested that 5-HT6 antagonists might have therapeutic potential for cognitive disorders.

5-HT6 receptor

Serotonin Antagonists

10.1124/jpet.103.056002

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Citations (102)

Behavioral effects of vehicles: DMSO, ethanol, Tween-20, Tween-80, and emulphor-620

Pharmacology Biochemistry and Behavior (1995)

Carl A. Castro John B. Hogan Kimberly Benson Christina W. Shehata Michael R. Landauer

Locomotor activity

10.1016/0091-3057(94)00331-9

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Citations (105)