Atypical antipsychotics and hyperglycemic emergencies: multicentre, retrospective cohort study of administrative data.

Objective: To evaluate the relationship between initiation of atypical antipsychotic agents and the risk of hyperglycemic emergencies.

Method: We conducted a multicentre retrospective cohort study using administrative health data from 7 Canadian provinces and the UK Clinical Practice Research Datalink. Hospitalizations for hyperglycemic emergencies (hyperglycemia, diabetic ketoacidosis, hyperosmolar hyperglycemic state) were compared between new users of risperidone (reference), and new users of olanzapine, other atypical antipsychotics, and typical antipsychotics.

IgE induces proliferation in human airway smooth muscle cells: role of MAPK and STAT3 pathways.

Airway remodeling is not specifically targeted by current asthma medications, partly owing to the lack of understanding of remodeling mechanisms, altogether posing great challenges in asthma treatment. Increased airway smooth muscle (ASM) mass due to hyperplasia/hypertrophy contributes significantly to overall airway remodeling and correlates with decline in lung function. Recent evidence suggests that IgE sensitization can enhance the survival and mediator release in inflammatory cells.

Treatment Strategies for Recurrent Clostridium difficile Infection.

Background: Recurrent Clostridium difficile infection represents a major clinical challenge. Treatment is often based on empiric selection from relatively few options supported by limited clinical evidence.

Objective: To review and evaluate the literature on therapeutic alternatives for recurrent C.

Quantification of three chiral flavonoids with reported bioactivity in selected licensed Canadian natural health products and US marketed dietary supplements.

Purpose: Research indicating potentially beneficial bioactivity of flavonoids has produced a market and demand for natural health products and dietary supplements containing flavonoids. Implementation of the Canadian natural health product (NHP) regulations in January of 2004 increased regulation and oversight of NHP manufacture and marketing leading many consumers and clinicians to assume a similar pathway of development and approval to over-the-counter or prescription drugs.

Methods: Three stereospecific liquid chromatograph/mass spectrometry (LC/MS) methods were used to assess the flavonoids, liquiritigenin, pinocembrin, and pinostrobin, in selected Canadian licensed NHP's and US marketed dietary supplements.

Molecular mechanisms of the biological activity of the anticancer drug elesclomol and its complexes with Cu(II), Ni(II) and Pt(II).

The bis(thiohydrazide) amide elesclomol has extremely potent antiproliferative activity and is currently in clinical trials as an anticancer agent. Elesclomol strongly binds copper and may be exerting its cell growth inhibitory effects by generating copper-mediated oxidative stress. Nickel(II) and platinum(II) complexes of elesclomol were synthesized and characterized in order to investigate if these biologically redox inactive metal complexes could also inhibit cell growth.

Pharmacometrics of 3-methoxypterostilbene: a component of traditional chinese medicinal plants.

3-Methoxypterostilbene is a naturally occurring stilbene with potential in the treatment of diabetes. The preclinical pharmacokinetics and pharmacodynamics of 3-methoxypterostilbene were evaluated in the present study. The right jugular veins of male Sprague-Dawley rats were cannulated.

The anticancer multi-kinase inhibitor dovitinib also targets topoisomerase I and topoisomerase II.

Dovitinib (TKI258/CHIR258) is a multi-kinase inhibitor in phase III development for the treatment of several cancers. Dovitinib is a benzimidazole-quinolinone compound that structurally resembles the bisbenzimidazole minor groove binding dye Hoechst 33258. Dovitinib bound to DNA as shown by its ability to increase the DNA melting temperature and by increases in its fluorescence spectrum that occurred upon the addition of DNA.

The dual-targeted HER1/HER2 tyrosine kinase inhibitor lapatinib strongly potentiates the cardiac myocyte-damaging effects of doxorubicin.

The anticancer drug lapatinib (Tykerb) is a dual tyrosine kinase inhibitor targeting the HER2 (ERBB2) and EGFR (ERBB1, HER1) pathways that have been shown in clinical trials to display some cardiotoxicity. Because trastuzumab also targets HER2 receptors, the lapatinib/doxorubicin combination provides a good model to probe the mechanism of the increased cardiotoxicity caused by the concurrent use of trastuzumab and doxorubicin. Using a neonatal rat cardiac myocyte model, we have investigated the ability of lapatinib alone and in combination with doxorubicin to damage myocytes.

The high affinity IgE receptor (FcεRI) expression and function in airway smooth muscle.

The airway smooth muscle (ASM) is no longer considered as merely a contractile apparatus and passive recipient of growth factors, neurotransmitters and inflammatory mediators signal but a critical player in the perpetuation and modulation of airway inflammation and remodeling. In recent years, a molecular link between ASM and IgE has been established through Fc epsilon receptors (FcεRs) in modulating the phenotype and function of these cells. Particularly, the expression of high affinity IgE receptor (FcεRI) has been noted in primary human ASM cells in vitro and in vivo within bronchial biopsies of allergic asthmatic subjects.

Ten years of antipsychotic prescribing to children: a Canadian population-based study.

Objective: To report the prescribing of antipsychotics to the youth population of the Canadian province of Manitoba during the course of a decade.

Methods: Use of antipsychotics in children and adolescents (aged 18 years or younger) was described using data collected from the administrative health databases of Manitoba Health and the Statistics Canada census between the fiscal years of 1999 and 2008.

Results: The prevalence of antipsychotic use in this segment of the population increased with the introduction of the second-generation antipsychotics (SGAs) from 1.

Design, synthesis, and biological evaluation of a novel series of bisintercalating DNA-binding piperazine-linked bisanthrapyrazole compounds as anticancer agents.

A series of bisintercalating DNA binding bisanthrapyrazole compounds containing piperazine linkers were designed by molecular modeling and docking techniques. Because the anthrapyrazoles are not quinones they are unable to be reductively activated like doxorubicin and other anthracyclines and thus they should not be cardiotoxic. The concentration dependent increase in DNA melting temperature was used to determine the strength of DNA binding and the bisintercalation potential of the compounds.

Dissolution testing of sublingual tablets: a novel in vitro method.

In the sublingual (SL) cavity, compared with the gastrointestinal tract, tablets are subjected to minimal physiological agitation, and a limited volume of saliva is available to facilitate disintegration and dissolution. None of the official compendial dissolution apparatuses and methods simulate these SL conditions. In this study, a custom-made dissolution apparatus was constructed, and a novel in vitro method that simulates SL conditions was evaluated.

Cadmium is a catalytic inhibitor of DNA topoisomerase II.

Cadmium (Cd(2+)) is a highly toxic and carcinogenic metal that is an environmental and occupational hazard. DNA topoisomerase II is an essential nuclear enzyme and its inhibition can result in the formation of genotoxic and recombinogenic DNA double strand breaks. In this study we showed that cadmium chloride strongly inhibited the DNA decatenation activity of human topoisomerase IIα in the low micromolar concentration range and that its inhibitory effects were reduced by glutathione.

The lack of target specificity of small molecule anticancer kinase inhibitors is correlated with their ability to damage myocytes in vitro.

Many new targeted small molecule anticancer kinase inhibitors are actively being developed. However, the clinical use of some kinase inhibitors has been shown to result in cardiotoxicity. In most cases the mechanisms by which they exert their cardiotoxicity are not well understood.

An electronic tongue: evaluation of the masking efficacy of sweetening and/or flavoring agents on the bitter taste of epinephrine.

An epinephrine (E) tablet is under development for sublingual (SL) administration for the first-aid treatment of anaphylaxis; however, the inherent bitterness of E may hinder acceptability by patients, especially children. To assess the degree of E bitterness and to predict the masking effects of sweetening and/or flavoring non-medicinal ingredients (NMIs), the potential usefulness of an electronic tongue (e-Tongue) was evaluated. The e-Tongue sensors were conditioned, calibrated, and tested for taste discrimination.

Altering the specificity of NK:target cell interactions by genetic manipulation of NK receptor expression on primary mouse NK cells.

A balance of signals generated via stimulatory and inhibitory NK receptors determines both target cell specificity and the outcome of NK-target cell interactions. The feasibility of introducing naturally occurring or genetically engineered chimeric NK receptors at the effector cell level may prove useful in NK cell-based immunotherapies. Here, we utilized a previously established lentiviral transduction system to over-express a model NKR-P1B inhibitory receptor on primary mouse NK cells.

Kinamycin F downregulates cyclin D3 in human leukemia K562 cells.

The bacterial metabolite kinamycin F, which contains an unusual and potentially reactive diazo group, is being investigated as an antitumor agent with a potentially novel target. Treatment of K562 cells with kinamycin F induced erythroid differentiation, a rapid apoptotic response, induction of caspase-3/7 activities and a delayed cell cycle progression through the S and G(2)/M phases. Kinamycin F caused a selective reduction of cyclin D3 protein, which appeared to be mediated at the level of transcription, rather than by affecting the stability of either cyclin D3 protein or mRNA.

The cardiotoxicity and myocyte damage caused by small molecule anticancer tyrosine kinase inhibitors is correlated with lack of target specificity.

The use of the new anticancer tyrosine kinase inhibitors (TKI) has revolutionized the treatment of certain cancers. However, the use of some of these results in cardiotoxicity. Large-scale profiling data recently made available for the binding of 7 of the 9 FDA-approved tyrosine kinase inhibitors to a panel of 317 kinases has allowed us to correlate kinase inhibitor binding selectivity scores with TKI-induced damage to neonatal rat cardiac myocytes.

Mechanisms of myocyte cytotoxicity induced by the multikinase inhibitor sorafenib.

The use of the anticancer multikinase inhibitor sorafenib is associated with cardiac ischemia or infarction and an increase in hypertension. We investigated various mechanisms that might be responsible for its cardiotoxicity in a neonatal rat myocyte model. As measured by lactate dehydrogenase release, sorafenib treatment of myocytes caused dose-dependent damage at therapeutically relevant concentrations.

TAPP2 links phosphoinositide 3-kinase signaling to B-cell adhesion through interaction with the cytoskeletal protein utrophin: expression of a novel cell adhesion-promoting complex in B-cell leukemia.

Tandem pleckstrin homology domain proteins (TAPPs) are recruited to the plasma membrane via binding to phosphoinositides produced by phosphoinositide 3-kinases (PI3Ks). Whereas PI3Ks are critical for B-cell activation, the functions of TAPP proteins in B cells are unknown. We have identified 40 potential interaction partners of TAPP2 in B cells, including proteins involved in cytoskeletal rearrangement, signal transduction and endocytic trafficking.

Experimental autoimmune encephalomyelitis-induced upregulation of tumor necrosis factor-alpha in the dorsal root ganglia.

Background: Multiple sclerosis (MS) is a chronic, neurological disease characterized by targeted destruction of central nervous system (CNS) myelin. The autoimmune theory is the most widely accepted explanation of disease pathology. Circulating Th(1) cells become activated by exposure to CNS-specific antigens such as myelin basic protein.

Mechanisms of myocyte cytotoxicity induced by the multiple receptor tyrosine kinase inhibitor sunitinib.

The anticancer tyrosine kinase inhibitor sunitinib has been shown recently to be cardiotoxic. Using a neonatal rat myocyte model, we investigated various mechanisms that might be responsible for its cardiotoxicity. Sunitinib potently inhibited the enzyme activity of both AMP-activated protein kinase (AMPK) and the ribosomal S6 kinase RSK1 at therapeutically relevant concentrations.