Clinical outcomes of a pharmacist-managed anticoagulation service for breast cancer patients.

PURPOSE: Report descriptive outcome measures related to the quality of pharmacist-managed anticoagulation care with warfarin in patients with breast cancer since the formation of the anticoagulation management service (AMS). METHODS: Retrospective review of 145 patients with breast cancer (median age 54 years) receiving warfarin therapy for venous thromboembolism (VTE) managed by the pharmacist-run AMS between 1998 and 2005. RESULTS: The median time followed by the AMS was 151 days. Fifty three percent (n = 1651) of total lab draws (n = 3129) were within the target therapeutic INR range 2-3. Recurrent thrombosis occurred in 4.1% of patients. Minor bleeding occurred in 18.6% of patients and major bleeding occurred in three patients (2.1%, gastrointestinal, intra-abdominal, and subdural hematoma). CONCLUSION: To date, this is the largest known published database of cancer patients receiving anticoagulation in a pharmacist-managed anticoagulation service. Recurrent VTE rates, major and minor bleeding rates, and percentage of time spent within the therapeutic range are slightly different in our patient population compared to an oncology population receiving warfarin and a non-oncology population with warfarin managed by AMS. Oral anticoagulation with warfarin is an effective, albeit complicated, treatment for venous thromboembolism in the oncology population. Although low-molecular weight heparin (LMWH) therapy is now the preferred treatment for thrombosis in malignancy, warfarin is still relevant in patients who are unable to receive treatment with LMWH. This report provides valuable information supporting coordinated anticoagulation therapy with a pharmacist-managed service in a breast cancer-specific population, and contributes to the growing data supporting the challenging nature of maintaining warfarin anticoagulation in patients with cancer.

Covalent arylation of metallothionein by oxidized dopamine products: a possible mechanism for zinc-mediated enhancement of dopaminergic neuron survival.

Metallothioneins are a group of low molecular weight proteins which can be induced upon exposure to metal ions, including Zn(II). These cysteine-rich proteins are believed to have antioxidant-like properties due to their ability to scavenge free radicals with their multiple sulfhydryl groups. Dopamine is a neurotransmitter that can form toxic quinone and semi-quinone products in an oxidative environment. While Zn(II) is known to be toxic to some neuron subtypes, here we report a beneficial effect of Zn(II) on dopaminergic neurons and identify a mechanism through which metallothionein may scavenge toxic dopamine oxidation products. Cultured embryonic neurons were treated with Zn(II), and the number of dopaminergic neurons surviving after two or three weeks in culture was determined. We demonstrate that under these conditions metallothionein is upregulated and is able to form covalent arylation products with dopamine and 6-hydroxydopamine both in vitro and in culture. These experiments suggest that Zn(II) enhances the survival of dopaminergic neurons, and we propose that as a mechanism, upregulated metallothioneins form covalent adducts with both dopamine and 6-hydroxydopamine, resulting in the observed neuroprotective effect of Zn(II) on these cells. As Zn(II) homeostasis and modulation of metallothionein expression are hallmarks of neurodegeneration, these studies may have significant implications for understanding the underlying basis of degenerative diseases involving dopaminergic neurons, including Parkinson's disease.

The impact of night vision goggles on way-finding performance and the acquisition of spatial knowledge.

OBJECTIVE: This study examined the effects of night vision goggles (NVGs) on navigation and way-finding performance and the acquisition of spatial knowledge. BACKGROUND: Although numerous studies have examined the effects of NVGs on visual perception, few have examined the effects of using NVGs on the acquisition and expression of spatial cognition. METHOD: Participants learned the environment through active navigation and way finding, searching for targets within a life-sized maze with or without NVGs. Knowledge of the environment was then tested with two spatial memory tests. RESULTS: Findings show that navigation and way finding with NVGs appear to be harder, as indicated by longer navigation times and additional, unnecessary turns, than they are without NVGs. Moreover, change in navigation performance over the course of the way-finding trials varied as a function of group assignment indicating that NVGs influenced the learning process. NVG users demonstrated a significant decrease in navigation times earlier as well as significant decreases in navigational legs compared with the control group. In judging the positions of objects relative to target objects in different rooms in the maze, performance was better for participants without NVGs than for those with NVGs. In a map-drawing task, participants in the NVG group were more likely to position objects incorrectly and to receive worse scores than the controls. CONCLUSION: These results demonstrate that NVGs affected not only spatial navigation and way-finding performance but also the acquisition of spatial knowledge. APPLICATION: These degradations in spatial knowledge should be considered in operational planning and NVG training programs.

Paclitaxel in breast cancer.

Paclitaxel, a chemotherapeutic drug isolated from the Pacific yew, was approved for the treatment of metastatic breast cancer in 1994 and remains one of the most important agents in the treatment of patients with this disease. It is currently approved for the adjuvant treatment of node-positive breast cancer, administered sequentially after a standard doxorubicin-containing regimen, and for metastatic disease after failure of combination chemotherapy or relapse within 6 months of adjuvant chemotherapy. In this article, data on the pharmacology, clinical efficacy and safety of paclitaxel for the treatment of breast cancer will be reviewed.

Intracerebroventricular D-Pen2, D-Pen5-enkephalin administration soon after stressor imposition influences behavioral responsivity to a subsequent stressor encounter in CD-1 mice.

Endogenous opioid peptide systems diminish stress-induced autonomic nervous system, neuroendocrine (hypothalamic-pituitary-adrenal axis) and behavioral responses, attenuating a collection of physiological symptoms basic to emotional and affective states. Neurogenic stressors may incite specific central changes in opioid peptide availability as well as changes in mu and delta-opioid receptor function. The present investigation evaluated the proactive influence of an intracerebroventricular injection of the opioid receptor agonist D-Pen2, D-Pen5-enkephalin (DPDPE) (0 microg, 0.005 microg, 1.0 microg or 2.5 microg) on locomotor behavior of mice following uncontrollable footshock (Shock) or novel shock chamber exposure (No Shock). It was expected that DPDPE administration following Shock on Day 1 would restore locomotor activity up to 1 week and prevent shock-associated behavior of mice encountering a brief session of footshock 18 days later. Exposure to Shock reduced horizontal locomotor and vertical locomotor (rearing) activity of mice while 2.5 microg DPDPE restored behavior. Eighteen days following Shock and DPDPE challenge, mice were exposed to either an abbreviated session of footshock (Mild Stress) or the shock chamber (Cues). Mice in the No Shock and Shock groups administered 2.5 microg DPDPE on Day 1 did not exhibit any locomotor deficits in response to Mild Stress on Day 18. Mice in the Shock group administered 0.005 microg DPDPE on Day 1, did not exhibit exaggerated rearing deficits following ensuing Mild Stressor encounter relative to mice reexposed to Cues on Day 18. Taken together, these data show that (a) footshock differentially affects rearing and locomotor activity, (b) DPDPE administration increases locomotor activity for up to 1 week following footshock and DPDPE administration, (c) reexposure to Mild Stress affects rearing and locomotor performance differently depending on previous stressor history and DPDPE dose, (d) DPDPE affords long-lasting protection to previously non-stressed mice against the deleterious effects of subsequent mild stress on locomotor activity, while a low dose of DPDE is sufficient to prevent shock-induced sensitization of rearing deficits, 18 days following original stressor and drug presentation. Finally, our investigation demonstrates that DPDPE administration alters the behavioral impact of future stressful encounters and emphasizes the importance of investigating opioid mechanisms in chronic stress disorders.

Brief exposure to predator odor and resultant anxiety enhances mesocorticolimbic activity and enkephalin expression in CD-1 mice.

The present study assessed alterations in mesolimbic enkephalin (ENK) mRNA levels after predator [2,5-dihydro-2,4,5-trimethylethiazoline (TMT)] and non-predator (butyric acid) odor encounter and/or light-dark (LD) testing in CD-1 mice immediately, 24, 48 and 168 h after the initial odor encounter and/or LD testing. The nucleus accumbens, ventral tegmental area, basolateral (BLA), central (CEA) and medial amygdaloid nuclei, prelimbic and infralimbic cortex were assessed for fos-related antigen (FRA) and/or ENK mRNA as well as neuronal activation of ENK neurons (FRA/ENK). Mice exposed to TMT displayed enhanced freezing and spent less time in the light of the immediate LD test relative to saline- or butyric acid-treated mice. Among mice exposed to TMT, LD anxiety-like behavior was associated with increased FRA in the prelimbic cortex and accumbal shell and decreased ENK-positive neurons in the accumbal core. Mice displaying high TMT-induced LD anxiety exhibited increased ENK-positive neurons in the BLA, CEA and medial amygdaloid nuclei relative to mice that displayed low anxiety-like behavior in the LD test after TMT exposure. In the BLA and CEA, 'high-anxiety' mice also displayed increased FRA/ENK after TMT exposure and LD testing. In contrast to neural cell counts, the level of ENK transcript was decreased in the BLA and CEA of 'high-anxiety' mice after TMT exposure and LD testing. These data suggest that increased FRA may regulate stressor-responsive genes and mediate long-term behavioral changes. Indeed, increased ENK availability in mesolimbic sites may promote behavioral responses that detract from the aversiveness of the stressor experience.

Exposure of mice to a predator odor increases acoustic startle but does not disrupt the rewarding properties of VTA intracranial self-stimulation.

The present investigation assessed the propensity of an acute psychogenic stressor exposure to induce behavioral change in paradigms assessing fear/anxiety (acoustic startle) and motivation/anhedonia (intracranial self-stimulation) in CD-1 mice. In the acoustic startle paradigm, a 10-min exposure of 2-4 month old mice (young adult mice) to fox odor (2,5-dihydro-2,4,5-trimethylthiazoline; TMT) was associated with decreased acoustic startle relative to mice exposed to the control odor, butyric acid (BA), immediately and relative to both saline and BA exposure 24 h following odor exposure in the home cage. In contrast, a 2-min exposure of young adult mice to TMT was associated with an increase in startle relative to saline and BA during the immediate post-odor test session only. In young adult mice a 2-min and a 10-min exposure to BA resulted in a startle profile of mice reminiscent of saline-treated mice. In comparison to young adult mice, a 2-min exposure of mature adult mice (5-7 months old) to TMT enhanced startle for up to 48 h relative to both saline and BA, while a 10-min exposure of mature adult mice to TMT enhanced startle for 168 h post-odor exposure relative to saline-exposed mice only. However, the greatest increase in startle amplitude (i.e. 48 h) was acquired following the 2-min exposure of mature mice to TMT. Among mature adult mice, a 10-min exposure to BA in the home cage eventuated in enhanced startle relative to saline-exposed animals 168 h following odor exposure. In comparison, exposure of mice to 10 min of TMT depressed responding for VTA brain stimulation at the initial 80 Hz frequency, but was ineffective in elevating reward thresholds relative to mice merely exposed to saline. Mice assessed in the ICSS paradigm were approximately 2-4 months old at the time of surgery and 5-7 months old at the completion of testing. These data suggest that acute odor exposure may induce a fear gradient dependent upon the perceived stressor severity and that the resultant anxiety-like effects are dependent on the duration of odor exposure, age of the animals and the temporal interval between odor presentation and behavioral testing. Moreover, the anxiogenic properties of psychogenic stressors can be separated from their anhedonic effects. The implications of these data for clinical psychopathology are discussed.