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Solutions to global issues demand the involvement of scientists, yet concern exists about retention rates in science as students pass through school into University. Young children are curious about science, yet are considered incapable of grappling with abstract and microscopic concepts such as atoms, sub-atomic particles, molecules and DNA. School curricula for primary (elementary) aged children reflect this by their limitation to examining only what phenomena are without providing any explanatory frameworks for how or why they occur. This research challenges the assumption that atomic-molecular theory is too difficult for young children, examining new ways of introducing atomic theory to 9 year olds and seeks to verify their efficacy in producing genuine learning in the participants. Early results in three cases in different schools indicate these novel methods fostered further interest in science, allowed diverse children to engage and learn aspects of atomic theory, and satisfied the children's desire for intellectual challenge. Learning exceeded expectations as demonstrated in the post-interview findings. Learning was also remarkably robust, as demonstrated in two schools 8 weeks after the intervention and, in one school, 1 year after their first exposure to ideas about atoms, elements and molecules. [ABSTRACT FROM AUTHOR]

The American College of Chest Physicians guidelines recommend unfractionated heparin (UFH), low molecular weight heparins (LMWHs) or fondaparinux for prevention of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), in medically-ill patients. Direct oral anticoagulants (DOACs) have been evaluated relative to enoxaparin for VTE prophylaxis though head-to-head comparisons of these agents are lacking. Therefore, we conducted a mixed treatment comparisons meta-analysis to evaluate the safety and efficacy of established treatments and DOACs for VTE prophylaxis in medically-ill patients. A comprehensive literature search was conducted to identify randomized trials evaluating UFH, LMWHs or DOACS for the prevention of VTE in medically ill patients. Articles were retrieved and cross-referenced for additional trials, evaluated and entered into ADDIS (version 1.16.6) to generate direct and indirect treatment comparisons for VTE, DVT, PE, death from any cause, and bleeding. Ten articles were included and eight anticoagulants were evaluated in a treatment network representing data on 28,382 patients. We found each treatment had similar efficacy in preventing VTE, DVT, PE, death from any cause and each had similar risk of minor and major bleeding. Overall, placebo was associated with more VTE and DVT events compared to LMWHs and DOACs. We found that UFH, LMWHs and DOACs are comparable in preventing VTE, DVT, PE, and death from any cause and in association with minor and major bleeding. Anticoagulant selection for VTE prophylaxis in medically-ill patients should be individualized by patient characteristics, risks and preferences along with specific pharmacokinetic and pharmacodynamic considerations. [ABSTRACT FROM AUTHOR]

Many hospitals have implemented warfarin dosing nomograms to improve patient safety. To our knowledge, no study has assessed the impact inpatient warfarin initiation has in both medical and surgical patients, on safety outcomes post discharge. To evaluate the impact of a suggested institutional nomogram for the initiation of warfarin, the primary endpoint was the incidence of bleeding throughout follow up. Secondary endpoints included the composite of INR changes ≥0.5/day and INR >4. Patients were followed for a period of 2 weeks post-discharge. The composite endpoint was evaluated for an effect on reaching therapeutic INR, time to reach therapeutic INR, and bleeding events throughout follow up. A single center retrospective study comparing the safety of adherence vs. non-adherence to a warfarin nomogram. A total of 206 patients were included, 73 patients in the nomogram adherence vs. 133 in the nonadherence arm. There was no difference in the proportion of patients who bled throughout the follow up period, adherence 9.6% vs. nonadherence to the nomogram 13.5%, p = 0.407. There was however a statistical difference in the mean total number of bleeding events, 0.096 (7/73) in the adherence vs. 0.158 (21/133) in the non-adherence arm, p = 0.022. There was also no difference in the composite endpoint, 19.2% in the adherence vs. 28.6% in the non-adherence arm p = 0.180. A positive correlation between the inpatient composite and risk of bleeding throughout follow up was noted. The findings of this study support adherence to the nomogram as opposed to non-adherence. [ABSTRACT FROM AUTHOR]

The United States Pharmacopeia recently changed the standards for unfractionated heparin (UFH) resulting in reduction in potency by about 10 %. Despite the reduction in potency, no new recommendations for UFH dosing were recommended. A retrospective review was conducted on patients receiving UFH and at least one activated partial thromboplastin time (aPTT) after start of infusion. Patients receiving UFH prior to April 2010 were collected as old UFH potency patients versus those receiving UFH after May 1st, 2010 were defined as new UFH potency patients. The primary endpoint was time to a therapeutic aPTT. Secondary endpoints included the number venous thrombotic events (VTE) and bleeding events during hospitalization through 30 days post discharge. Thrombotic events were defined as acute coronary syndrome, ischemic stroke, and VTE. Bleeding was defined in accordance with the GUSTO bleeding scale. A total of 359 patients were included for evaluation, 181 in the old UFH group and 178 in the new UFH group. The primary endpoint was similar between groups with an average time of 18.8 ± 25.4 versus 20.8 ± 22.2 h in the old and new UFH groups respectively ( p = 0.092). Patients receiving old UFH and an initial bolus had higher aPTTs (96.6 ± 43.7 s) than those receiving new UFH and an initial bolus (76.7 ± 34.5 s) ( p = 0.003). There was no difference found between groups in regards to bleeding or thrombotic events during hospitalization or through 30 days. In patients receiving UFH, dosed per the institutions' nomogram, no clinically significant outcomes were found between the old and new UFH potencies. [ABSTRACT FROM AUTHOR]

The objectives of this retrospective cohort study are to evaluate the accuracy of pharmacogenetic warfarin dosing algorithms in predicting therapeutic dose and to determine if this degree of accuracy warrants the routine use of genotyping to prospectively dose patients newly started on warfarin. Seventy-one patients of an outpatient anticoagulation clinic at an academic medical center who were age 18 years or older on a stable, therapeutic warfarin dose with international normalized ratio (INR) goal between 2.0 and 3.0, and cytochrome P450 isoenzyme 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) genotypes available between January 1, 2007 and September 30, 2008 were included. Six pharmacogenetic warfarin dosing algorithms were identified from the medical literature. Additionally, a 5 mg fixed dose approach was evaluated. Three algorithms, Zhu et al. (Clin Chem 53:1199–1205, 2007), Gage et al. (J Clin Ther 84:326–331, 2008), and International Warfarin Pharmacogenetic Consortium (IWPC) (N Engl J Med 360:753–764, 2009) were similar in the primary accuracy endpoints with mean absolute error (MAE) ranging from 1.7 to 1.8 mg/day and coefficient of determination R2 from 0.61 to 0.66. However, the Zhu et al. algorithm severely over-predicted dose (defined as ≥2× or ≥2 mg/day more than actual dose) in twice as many (14 vs. 7%) patients as Gage et al. 2008 and IWPC 2009. In conclusion, the algorithms published by Gage et al. 2008 and the IWPC 2009 were the two most accurate pharmacogenetically based equations available in the medical literature in predicting therapeutic warfarin dose in our study population. However, the degree of accuracy demonstrated does not support the routine use of genotyping to prospectively dose all patients newly started on warfarin. [ABSTRACT FROM AUTHOR]

Few intergalactic, plausibly primordial clouds of neutral atomic hydrogen (H i) have been found in the local Universe, suggesting that such structures have either dispersed, become ionized or produced a stellar population on gigayear timescales. The Leo ring, a massive (MH i ≈ 1.8 × 109, denoting the solar mass), 200-kpc-wide structure orbiting the galaxies M105 and NGC 3384 with a 4-Gyr period, is a candidate primordial cloud. Despite repeated atttempts, it has previously been seen only from H i emission, suggesting the absence of a stellar population. Here we report the detection of ultraviolet light from gaseous substructures of the Leo ring, which we attribute to recent massive star formation. The ultraviolet colour of the detected complexes is blue, implying the onset of a burst of star formation or continuous star formation of moderate (∼108-yr) duration. Measured ultraviolet–visible photometry favours models with low metallicity (Z ≈ /50–/5, denoting the solar metallicity), that is, a low proportion of elements heavier than helium, although spectroscopic confirmation is needed. We speculate that the complexes are dwarf galaxies observed during their formation, but distinguished by their lack of a dark matter component. In this regard, they resemble tidal dwarf galaxies, although without the enrichment preceding tidal stripping. If structures like the Leo ring were common in the early Universe, they may have produced a large, yet undetected, population of faint, metal-poor, halo-lacking dwarf galaxies. [ABSTRACT FROM AUTHOR]

Introduction: We sought to compare antiemetic use after acetaminophen poisoning in patients treated with oral or intravenous (IV) N-acetylcysteine (NAC). Methods: Our retrospective chart review identified 20 orally treated patients and 17 IV-treated patients. For both groups, we calculated the total number of antiemetic doses given, their associated cost, and also determined parameters that correlated with antiemetic use. Results: IV-treated patients received fewer total antiemetic doses than those receiving oral NAC (1.1±0.2 vs. 2.8±0.7; P=0.04). Antiemetic cost correlated with doses received for both groups; however, because the regression lines differed (P=0.02), antiemetic therapy cost was less in IV-treated patients. In addition, serum acetaminophen concentration correlated with total antiemetic doses in oral NAC patients (P<0.002) but not with IV treatment patients (P=0.78). Conclusions: Intravenous NAC reduced antiemetic utilization, and it costs less than oral therapy. Furthermore, antiemetic use appeared to be determined by a combination of acetaminophen concentration and NAC administration route. [ABSTRACT FROM AUTHOR]

Risperidone (RSP) and its major active metabolite, 9-hydroxy-risperidone (paliperidone, PALI), are substrates of the drug transporter P-glycoprotein (P-gp). The goal of this study was to examine the in vitro effects of RSP and PALI on P-gp-mediated transport. The intracellular accumulation of rhodamine123 (Rh123) and doxorubicin (DOX) were examined in LLC-PK1/MDR1 cells to evaluate P-gp inhibition by RSP and PALI. Both compounds significantly increased the intracellular accumulation of Rh123 and DOX in a concentration-dependent manner. The IC50 values of RSP for inhibiting P-gp-mediated transport of Rh123 and DOX were 63.26 and 15.78 μM, respectively, whereas the IC50 values of PALI were >100 μM, indicating that PALI is a less potent P-gp inhibitor. Caco-2 and primary cultured rat brain microvessel endothelial cells (RBMECs) were utilized to investigate the possible influence of RSP on intestinal absorption and blood–brain barrier (BBB) transport of coadministered drugs that are P-gp substrates. RSP, 1–50 μM, significantly enhanced the intracellular accumulation of Rh123 in Caco-2 cells by inhibiting P-gp activity with an IC50 value of 5.87 μM. Following exposure to 10 μM RSP, the apparent permeability coefficient of Rh123 across Caco-2 and RBMECs monolayers was increased to 2.02 and 2.63-fold in the apical to basolateral direction, but decreased to 0.37 and 0.21-fold in the basolateral to apical direction, respectively. These data suggest that RSP and PALI, to a lesser extent, have a potential to influence the pharmacokinetics and hence the pharmacodynamics of coadministered drugs via inhibition of P-gp-mediated transport. However, no human data exist that address this issue. In particular, RSP may interact with its own active metabolite PALI by promoting its brain concentration through inhibiting P-gp-mediated efflux of PALI across endothelial cells of the BBB.Neuropsychopharmacology (2007) 32, 757–764. doi:10.1038/sj.npp.1301181; published online 23 August 2006 [ABSTRACT FROM AUTHOR]

Rationale The multidrug resistance transporter, P-glycoprotein (P-gp), is involved in efflux transport of several antipsychotics in the blood-brain barrier (BBB). Objectives In the present study, we evaluated the inhibitory effect of the antipsychotics, i.e., risperidone, olanzapine, quetiapine, clozapine, haloperidol, chlorpromazine, a major metabolite of risperidone, 9-OH-risperidone, and a positive control inhibitor, PSC833, on the cellular uptake of prototypic substrate of P-gp, rhodamine (Rhd) 123, in LLC-PK1 and L-MDR1 cells. Materials and methods After incubation of the antipsychotics (1-100 µM) and the positive (10 µM PSC833) or negative (1% dimethyl sulfoxide) controls with 5 µM Rhd 123 for 1 h, the effects of the antipsychotics on the intracellular accumulation of Rhd 123 were examined using a flow cytometric method. Results All the antipsychotics showed various degrees of inhibitory effects on P-gp activity. The rank order of the concentration of inhibitor to cause 50% of the maximal increment of intracellular Rhd 123 fluorescence (EC50) was: PSC833 (0.5 µM) < olanzapine (3.9 µM) < chlorpromazine (5.8 µM) < risperidone (6.6 µM) < haloperidol (9.1 µM) < quetiapine (9.8 µM) < 9-OH-risperidone (12.5 µM) < clozapine (30 µM). Considering that the antipsychotics' plasma concentrations are generally lower than 1 µM, the present results suggest that olanzapine and risperidone are the only agents that may inhibit P-gp activity in the BBB. However, most of the antipsychotics are extensively accumulated in tissues. In addition, when given orally, the drug concentrations in the gastrointestinal tract are likely to be high. Conclusions Pharmacokinetic interactions due to inhibition of P-gp activity by the antipsychotics appear possible and warrant further investigation. [ABSTRACT FROM AUTHOR]

Rationale: Accumulating evidence indicates that modulation of the activity of cytochrome P450 (CYP) enzymes and the multidrug resistance transporter Pglycoprotein (P-gp) is responsible for many drug-drug interactions. Objectives: The potential interaction of risperidone (RISP), which is metabolized by 2D6 and transported across the blood brain barrier (BBB) by P-gp, was studied in combination with bupropion (BUP) and also with sertraline (SERT). Methods: BUP, SERT, and RISP were administered intraperitoneally into CF1 mice at doses of 100, 10, and 1µg/g mouse, respectively. Plasma and brain samples were collected at timed intervals from 0.5 to 6 h. A pharmacokinetic analysis was performed using both traditional compartmental modeling and a population pharmacokinetic approach. Results: BUP increased the RISP plasma (5.9-fold, P<0.01) and brain (2.2-fold, P<0.01) area under the drug concentration vs time curve (AUC), but did not alter the brain-to-plasma concentration ratio. SERT did not significantly change the plasma AUC of RISP and 9-hydroxy-RISP, but increased the brain AUC of RISP and 9-hydroxy-RISP 1.5-fold (P<0.05) and 5-fold (P<0.01), respectively. RISP did not produce significant alterations of plasma or brain concentrations of BUP. It increased the plasma AUC and elimination half-life (T1/2e) of desmethyl-SERT 12.5-fold (P<0.01) and 107-fold (P<0.01), respectively. Conclusions: These results suggest that pharmacokinetic interactions exist among these three psychoactive drugs involving inhibition of drug metabolizing enzymes and/or P-gp and other drug transporters present in the BBB. The mechanisms and consequences of these interactions require further study in humans to establish clinical relevance. [ABSTRACT FROM AUTHOR]

Objective: To determine if modafinil, a putative treatment for cocaine dependence, influences the pharmacokinetics of intravenous cocaine in otherwise healthy cocaine-dependent volunteers.Methods: Cocaine 20 or 40 mg was administered intravenously on consecutive days over 1 minute at baseline and after modafinil administration at each of two dosages of 400 and 800 mg/day for 7 days.Results: Twelve subjects completed the clinical protocol. Compared with baseline, the cocaine peak plasma concentration was decreased after both the 20 and 40 mg cocaine infusions, but the reduction was only statistically significant after the 40 mg cocaine infusion (p < 0.01 after modafinil 400 mg/day; p < 0.05 after modafinil 800 mg/day). The area under the cocaine plasma concentration-time curve from 0 to 180 minutes (AUC180) was significantly decreased by modafinil administration (p < 0.01 and p < 0.001 for modafinil 400 and 800 mg/day, respectively, for the cocaine 20mg dose; p < 0.001 for the cocaine 40 mg dose at both modafinil levels). There were no significant changes in total AUC, clearance or elimination half-life of cocaine.Conclusion: This study did not find evidence for a harmful pharmacokinetic interaction between modafinil and cocaine. In contrast, long-term administration of modafinil significantly decreased systemic exposure to cocaine during the first 180 minutes following intravenous cocaine administration. [ABSTRACT FROM AUTHOR]

Rationale. Methadone maintenance treatment is complicated by the wide variability of efficacy among patients. The large interindividual variability of the plasma concentrations of methadone was previously thought to be responsible for the variable therapeutic efficacy. However, recent studies suggested that methadone may be a substrate of P-glycoprotein (P-gp). Therefore, the function of P-gp in blood–brain barrier (BBB) may affect the concentration of methadone at its site(s) of action in the central nervous system, thereby contributing to its therapeutic efficacy and/or adverse events. Objective. To investigate the effect of P-gp on brain penetration of methadone (R)- and (S)-enantiomers and their major oxidative metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). Methods. We compared the tissue distribution of methadone (R)- and (S)-enantiomers and EDDP in the Abcb1a-/- gene knockout mice and the Abcb1a+/+ wild-type mice 1 h following intraperitoneal administration of 15 μg Rac-methadone/g mouse. Results. Plasma concentrations of (R)- and (S)-methadone were similar between the two animal groups. However, the brain concentrations of (R)- and (S)-methadone in the Abcb1a-/- mice were markedly higher (15- and 23-fold, respectively, P<0.0001) than those of the Abcb1a+/+ wild-type mice. No statistically significant difference was found for other organs between the mutants and controls. No organ difference was found for EDDP between the mutants and controls. Conclusions. (R)- and (S)-methadone are substrates of P-gp. The P-gp in BBB greatly limits the brain entry of (R)- and (S)-methadone to their central nervous system acting sites. The interindividual variation in expression of P-gp in BBB may represent a source of variation for the access and effects of methadone in the brain. [ABSTRACT FROM AUTHOR]

The transmembrane energy-dependent efflux transporter P-glycoprotein (P-gp) limits a range of drugs from penetrating cells and deposits them into the extracellular space. P-gp is highly expressed in several normal tissues, including the luminal surface of capillary endothelial cells in the brain of humans. In this study, we tested whether olanzapine distribution to tissues highly expressing P-gp or devoid of this transporter was similar in Abcb 1a (-/-) mice lacking P-gp and control animals. At 1 h following the intraperitoneal injection of 2.5 µg olanzapine/g mouse, olanzapine concentrations were statistically and significantly higher in brain (three-fold), liver (2.6-fold), and kidney (1.8-fold) of Abcb 1a (-/-) mice than those of the control FVB Abcb 1a (+/+) mice, and not statistically different in plasma, spleen, or penile tissue. Similar differences were also found for the ratios of organ:plasma and organ:spleen between the two groups. This is the first report that the presence of the Abcb 1a gene is an important factor controlling brain access to olanzapine. The finding that the brain penetration of olanzapine is limited by P-gp implies that the highly prevalent functional polymorphisms of ABCB 1 in humans may be a factor contributing to variability in dose requirements for this antipsychotic drug. [ABSTRACT FROM AUTHOR]

Heparin-induced thrombocytopenia (HIT) is a rare immune-mediated complication associated with unfractionated heparin and to a lesser extent with low-molecular weight heparins. The American College of Chest Physicians recommends treating patients with suspected HIT with a non-heparin product regardless if thrombosis is present. The direct thrombin inhibitors are the preferred agents for the treatment of acute HIT (lepirudin, argatroban [Grade 1C]). Fondaparinux is also suggested as an alternative with a lower level of evidence (Grade 2C). The evidence supporting the use of fondaparinux in the treatment of HIT is limited, but the evidence of fondaparinux causing HIT is even less. We present a case of a patient who developed complications with fondaparinux when used in the acute setting of HIT. [ABSTRACT FROM AUTHOR]