Chemicals and Drugs Commons^™

Cross-Sector Review Of Drivers And Available 3rs Approaches For Acute Systemic Toxicity Testing, Troy Seidle, Sally Robinson, Tom Holmes, Stuart Creton, Pilar Prieto, Julia Scheel, Magda Chlebus

Troy Seidle, PhD

Acute systemic toxicity studies are carried out in many sectors in which synthetic chemicals are manufactured or used and are among the most criticized of all toxicology tests on both scientific and ethical grounds. A review of the drivers for acute toxicity testing within the pharmaceutical industry led to a paradigm shift whereby in vivo acute toxicity data are no longer routinely required in advance of human clinical trials. Based on this experience, the following review was undertaken to identify (1) regulatory and scientific drivers for acute toxicity testing in other industrial sectors, (2) activities aimed at replacing, reducing, or …

Ideology Masquerading As Science: The Case Of Endocrine Disrupter Screening Programmes, Troy Seidle

Troy Seidle, PhD

The global move to develop novel testing methods and strategies to identify suspected endocrine disrupting chemicals offers a unique opportunity to move away from traditional animal testing paradigms in this new area of regulatory concern. Regrettably, the programmes under development, both in the USA and internationally through the OECD, have thus far failed to consider in vitro and other nonanimal test methods as more than “pre-screening” or “priority-setting” tools in a larger, animal-based testing strategy. Validation efforts to date have focused almost exclusively on the modification of existing animal tests to detect “endocrine effects”, with no demonstrable effort to promote …

Dual Engagement Of The Nlrp3 And Aim2 Inflammasomes By Plasmodium-Derived Hemozoin And Dna During Malaria, Parisa Kalantari, Rosane B. Deoliveira, Jennie Chan, Yolanda Corbett, Vijay A. K. Rathinam, Andrea Stutz, Eicke Latz, Ricardo T. Gazzinelli, Douglas T. Golenbock, Katherine A. Fitzgerald

Katherine A. Fitzgerald

Hemozoin (Hz) is the crystalline detoxification product of hemoglobin in Plasmodium-infected erythrocytes. We previously proposed that Hz can carry plasmodial DNA into a subcellular compartment that is accessible to Toll-like receptor 9 (TLR9), inducing an inflammatory signal. Hz also activates the NLRP3 inflammasome in primed cells. We found that Hz appears to colocalize with DNA in infected erythrocytes, even before RBC rupture or phagolysosomal digestion. Using synthetic Hz coated in vitro with plasmodial genomic DNA (gDNA) or CpG oligodeoxynucleotides, we observed that DNA-complexed Hz induced TLR9 translocation, providing a priming and an activation signal for inflammasomes. After phagocytosis, Hz and …

Synchronous Opening And Closing Motions Are Essential For Camp-Dependent Protein Kinase A Signaling, Atul K. Srivastava, Leanna R. Mcdonald, Alessandro Cembran, Jonggul Kim, Larry R. Masterson, Christopher L. Mcclendon, Susan S. Taylor, Gianluigi Veglia

Larry Masterson

Antispasmodic And Ca++ Antagonist Potential Of Marrubiin, A Labdane Type Diterpene From Phlomis Bracteosa, Javid Hussain, Riaz Ullah, Arif-Ullah Khan, Fazal Mabood, Mohammad Raza Shah, Ahmed Al-Harrasi, Anwar Gilani

Anwar Gilani

A tricyclic labdane type diterpene was isolated for the first time from ethyl acetate soluble part of Phlomis bracteosa. Its structure was confirmed by x-ray which was found to be marrubiin. When studied in isolated rabbit jejunum, marrubiin caused concentration-dependent relaxation of spontaneous and high K+ (80 mM)-induced contractions, like that caused by verapamil, indicating that marrubiin exhibits spasmolytic activity, possibly mediated through Ca++ channel blocking action.

Unique Diagnostic Challenges Of Cushings From Large Bilateral Adrenal Adenoma And Mifepristone Utilization For Hypercortisolism Prior To Surgery, Vasudev G. Magaji Md, Ms, Sarah Park Do, Maura Bucciarelli Do, Katie Mastoris Do, Scott Beman Md

Vasudev G Magaji MD, MS

No abstract provided.

Regulated Splicing Of The Alpha6 Integrin Cytoplasmic Domain Determines The Fate Of Breast Cancer Stem Cells, Hira Lal Goel, Tatiana Gritsko, Bryan Pursell, Cheng Chang, Leonard D. Shultz, Dale L. Greiner, Jens Henrik Norum, Rune Toftgard, Leslie M. Shaw, Arthur M. Mercurio

Arthur M. Mercurio

Although the alpha6beta1 integrin has been implicated in the function of breast and other cancer stem cells (CSCs), little is known about its regulation and relationship to mechanisms involved in the genesis of CSCs. We report that a CD44(high)/CD24(low) population, enriched for CSCs, is comprised of distinct epithelial and mesenchymal populations that differ in expression of the two alpha6 cytoplasmic domain splice variants: alpha6A and alpha6B. alpha6Bbeta1 expression defines the mesenchymal population and is necessary for CSC function, a function that cannot be executed by alpha6A integrins. The generation of alpha6Bbeta1 is tightly controlled and occurs as a consequence of …

Antipsychotic Use In Nursing Homes Varies By Psychiatric Consultant, Jennifer Tjia, Terry Field, Celeste Lemay, Kathleen Mazor, Michelle Pandolfi, Ann Spenard, Shih-Yieh Ho, Abir Kanaan, Jennifer Donovan, Jerry Gurwitz, Becky Briesacher

Jennifer Tjia

BACKGROUND: The relationship between psychiatric consultation and antipsychotic prescribing in nursing homes (NH) is unknown. OBJECTIVE: To identify the association between psychiatric consultant groups and NH-level antipsychotic prescribing after adjustment for resident case-mix and facility characteristics. RESEARCH DESIGN AND SUBJECTS: Nested cross-sectional study of 60 NHs in a cluster randomized trial. We linked facility leadership surveys to October 2009-September 2010 Minimum Data Set, Nursing Home Compare, the US Census, and pharmacy dispensing data. MEASURES: The main exposure is the psychiatric consultant group and the main outcome is NH-level prevalence of atypical antipsychotic use. We calculated annual means and interquartile ranges …

Behavioral Interactions Of Opioid Agonists And Antagonists With Serotonergic Systems, David J. Mokler, Richard H. Rech, Randall L. Commissaris, Judith W. Henck

David J. Mokler, Ph.D.

Morphine interacts with brain serotonergic (5-HT) systems; these systems have been implicated in morphine analgesia and dependence (see Cervo et al., 1981). The 5-HT agonist quipazine induces analgesia in rats that is attenuated by naloxone and 5-HT antagonists (Minnema et al., 1980; Samanin et al., 1976). Behavioral disruption by the hallucinogens LSD, DMT and mescaline, mediated primarily through brain 5-HT effects (Rech and Commissaris, 1982), is potentiated by naloxone and naltrexone (Commissaris et al., 1980; Ruffing and Domino, 1981) and is variably antagonized or potentiated by morphine and methadone (Ruffing and Domino, 1981). Cyclazocine causes a disruption of operant behavior …

Cancerous Contradictions: The Mis-Regulation Of Human Carcinogens Based On Animal Data, Andrew Knight, Jarrod Bailey, Jonathan Balcombe

Jonathan Balcombe, PhD

The regulation of human exposures to potential carcinogens constitutes society’s most important use of animal carcinogenicity data. However, for environmental contaminants of greatest U.S. concern, we found that in most cases (58.1%; 93/160) the U.S. Environmental Protection Agency (EPA) considered the animal data inadequate to support a classification of probable human carcinogen or noncarcinogen.

The World Health Organisation’s International Agency for Research on Cancer (IARC) is a leading international authority on carcinogenicity assessments. For chemicals lacking human exposure data (the great majority), IARC classifications of identical chemicals were significantly more conservative than EPA classifications (p

Comparison Of Insulin Infusion Protocols Targeting 110-140 Mg/Dl In Patients After Cardiac Surgery., Vasudev Magaji, Shriddha Nayak, Amy Donihi, Lauren Willard, Srinivasa Jampana, Parachur Nivedita, Raymond Eder, Jann Johnston, Mary Korytkowski

Vasudev G Magaji MD, MS

BACKGROUND: Continuous intravenous insulin infusion (CII) following coronary artery bypass graft (CABG) surgery reduces postoperative complications and hospitalization duration. Because of limited data evaluating outcomes of CII with revised glycemic targets (110-140 mg/dL) in cardiac surgery, this study compared efficacy and safety of two different CII protocols having revised targets. SUBJECTS AND METHODS: This is a retrospective study comparing two different protocols between August 2009 and March 2010. Protocol 1 consists of four algorithms, and Protocol 2 is a table to adjust CII. Blood glucose (BG) and CII rates were recorded for 48 h postoperatively or CII discontinuation. Efficacy was …

Antibiotics In Abdominal Wall Reconstruction, Joseph J. Stirparo Md, Michael D. Pasquale Md, Facs, Fccm

Michael D Pasquale MD, FACS, FCCM

No abstract provided.

Adverse Drug Events After Hospital Discharge In Older Adults: Types, Severity, And Involvement Of Beers Criteria Medications, Abir Kanaan, Jennifer Donovan, Nerissa Duchin, Terry Field, Jennifer Tjia, Sarah Cutrona, Shawn Gagne, Lawrence Garber, Peggy Preusse, Leslie Harrold, Jerry Gurwitz

Jennifer Tjia

OBJECTIVES: To characterize adverse drug events (ADEs) occurring within the high-risk 45-day period after hospitalization in older adults.

DESIGN: Clinical pharmacists reviewed the ambulatory records of 1,000 consecutive discharges.

SETTING: A large multispecialty group practice closely aligned with a Massachusetts-based health plan.

PARTICIPANTS: Hospitalized individuals aged 65 and older discharged home.

MEASUREMENTS: Possible drug-related incidents occurring during the 45-day period after hospitalization were identified and presented to a pair of physician-reviewers who classified incidents as to whether an ADE was present, whether the event was preventable, and the severity of the event. Medications implicated in ADEs were further characterized according …

A Nmr Experiment For Simultaneous Correlations Of Valine And Leucine/Isoleucine Methyls With Carbonyl Chemical Shifts In Proteins, Vitali Tugarinov, Vincenzo Venditti, G. Marius Clore

Vincenzo Venditti

A methyl-detected ‘out-and-back’ NMR experiment for obtaining simultaneous correlations of methyl resonances of valine and isoleucine/leucine residues with backbone carbonyl chemical shifts, SIM-HMCM(CGCBCA)CO, is described. The developed pulse-scheme serves the purpose of convenience in recording a single data set for all Ileδ1, Leuδ and Valγ (ILV) methyl positions instead of acquiring two separate spectra selective for valine or leucine/isoleucine residues. The SIM-HMCM(CGCBCA)CO experiment can be used for ILV methyl assignments in moderately sized protein systems (up to ~100 kDa) where the backbone chemical shifts of 13Cα, 13Cβ and 13CO are known from prior NMR studies and where some losses in …

Effects Of Polychlorinated Biphenyl (Pcb) On Response Perseveration And Ultrasonic Vocalization Emission In Rat During Development, Howard Cromwell

Howard Casey Cromwell

The 3 major symptoms of autistic spectrum disorders include 1) social behavioral alterations, 2) problems in communication and 3) higher-order motoric deficits of perseveration and stereotyped movements. Previous work has shown that early developmental exposure to polychlorinated biphenyls (PCBs) alters rat pup social motivation and juvenile rat social recognition/investigation. The present work extends this previous research by examining how perinatal PCB exposure alters motoric functions and communication abilities at different stages of development. Action perseveration was examined using performance measures from a T-maze environment. Communication abilities were evaluated by monitoring ultrasound emission in rat pups during a brief isolation from …

3,4,5-Trichloroaniline Nephrotoxicity In Vitro.Pdf

Deborah L Preston