Phosphate removal and recovery by lanthanum-based adsorbents: A review for current advances.

Controlling eutrophication and recovering phosphate from water bodies are hot issues in the 21st century. Adsorption is considered to be the best method for phosphate removal because of its high adsorption efficiency and fast removal rate. Among the many adsorbents, lanthanum (La)-based adsorbents have been paid more and more attention due to their strong affinity to phosphorus. This paper reviews research of phosphate adsorption on La-based adsorbents in different La forms, including lanthanum oxide/hydroxide, lanthanum mixed metal oxide/hydroxide, lanthanum carbonate, La3+, La-based metal-organic framework (La-MOF) and La-MOF derivatives. The La-based adsorbents can be loaded on many carriers, such as carbon material, clay minerals, porous silica, polymers, industrial wastes, and others. We find that lanthanum oxide/hydroxide and La3+ adsorbents are mostly studied, while those in the forms of lanthanum carbonate, La-MOF, and La-MOF derivatives are relatively few. The kinetic process of most phosphate adsorption is pseudo-second-order and the isotherm process is in accordance with the Langmuir model. The cost of La-based and other traditional adsorbents was compared. The adsorption mechanisms are categorized as electrostatic attraction, ligand exchange, Lewis acid-base interaction, ion exchange and surface precipitation. Besides, regeneration methods of La-based adsorbents are mainly acid, alkali, and salt-alkali. In addition, the La-based adsorbents after absorbing phosphate can be directly used as a slow-release fertilizer. This review provides a basis for the research on phosphate adsorption by La-based adsorbents. It should be carried out to further develop La-based materials with high adsorption capacity and good regeneration ability. Meanwhile, studies have been conducted on the reuse of phosphate after desorption, which needs more attention in future research.

FDA Perspectives on the Regulation of Neuromodulation Devices.

The United States Food and Drug Administration (FDA) ensures that patients in the United States have access to safe and effective medical devices. The division of neurological and physical medicine devices reviews medical technologies that interface with the nervous system, including many neuromodulation devices. This article focuses on neuromodulation devices and addresses how to navigate the FDA's regulatory landscape to successfully bring devices to patients.

The "induced hyperactivity" test for the de-risking of potential off-target activity of antihypertensive drugs.

INTRODUCTION: Compound X is a new proprietary antihypertensive agent that induces its pharmacodynamic effect at an approximate plasma Cmax.u of 0.6nmol/L (rat hypertension model). However, Compound X also shows potent off-target activity at PDE-10a (IC50~12nmol/L). Since PDE-10a is expressed predominantly in brain (striatum) and inhibition/knockout of PDE-10a have been reported to result in anti-psychotic effects, we have established the "induced hyperactivity" test for CNS de-risking of Compound X. METHODS: Male Wistar rats treated orally with vehicle or Compound X (single dose; 1-3-10mg/kg) were assessed for exploratory locomotor activity following induction of hyperactivity by d-amphetamine (2mg/kg) or the NMDA antagonist MK-801 (0.2mg/kg). The assay was validated with anti-psychotic drugs (haloperidol, clozapine). RESULTS: Induced hyperactivity was not antagonized by Compound X at doses relevant for its primary pharmacodynamic activity (0.1-0.3mg/kg, rat). Although sufficient plasma concentrations were reached with Compound X (Cmax.u up to ~8nmol/L at 10mg/kg) to show its PDE-10a activity, its low brain penetration (~10%) likely precluded any meaningful PDE-10a inhibition. In comparison, other blood pressure lowering agents such as prazosin (alpha-1 adrenoceptor antagonist) and isradipine (L-Type Ca(2+) channel blocker), but not the NO-donor ISDN, tended to attenuate induced hyperactivity in rats at high doses. CONCLUSION: The relevance of a potent in-vitro off-target hit (PDE-10a inhibition) by Compound X was attenuated by a robust in-vivo assay (rat induced hyperactivity test), hence lowering the potential liability profile of Compound X. Finally, this piece of investigative safety pharmacology work enabled early de-risking of Compound X based on its primary pharmacodynamic activity in a relevant rat model.

Social housing of non-rodents during cardiovascular recordings in safety pharmacology and toxicology studies.

INTRODUCTION: The Safety Pharmacology Society (SPS) and National Centre for the Replacement, Refinement & Reduction of Animals in Research (NC3Rs) conducted a survey and workshop in 2015 to define current industry practices relating to housing of non-rodents during telemetry recordings in safety pharmacology and toxicology studies. The aim was to share experiences, canvas opinion on the study procedures/designs that could be used and explore the barriers to social housing. METHODS: Thirty-nine sites, either running studies (Sponsors or Contract Research Organisations, CROs) and/or outsourcing work responded to the survey (51% from Europe; 41% from USA). RESULTS: During safety pharmacology studies, 84, 67 and 100% of respondents socially house dogs, minipigs and non-human primates (NHPs) respectively on non-recording days. However, on recording days 20, 20 and 33% of respondents socially house the animals, respectively. The main barriers for social housing were limitations in the recording equipment used, study design and animal temperament/activity. During toxicology studies, 94, 100 and 100% of respondents socially house dogs, minipigs and NHPs respectively on non-recording days. However, on recording days 31, 25 and 50% of respondents socially house the animals, respectively. The main barriers for social housing were risk of damage to and limitations in the recording equipment used, food consumption recording and temperament/activity of the animals. CONCLUSIONS: Although the majority of the industry does not yet socially house animals during telemetry recordings in safety pharmacology and toxicology studies, there is support to implement this refinement. Continued discussions, sharing of best practice and data from companies already socially housing, combined with technology improvements and investments in infrastructure are required to maintain the forward momentum of this refinement across the industry.

ECG telemetry in conscious guinea pigs.

INTRODUCTION: During preclinical drug development, monitoring of the electrocardiogram (ECG) is an important part of cardiac safety assessment. To detect potential pro-arrhythmic liabilities of a drug candidate and for internal decision-making during early stage drug development an in vivo model in small animals with translatability to human cardiac function is required. METHODS: Over the last years, modifications/improvements regarding animal housing, ECG electrode placement, and data evaluation have been introduced into an established model for ECG recordings using telemetry in conscious, freely moving guinea pigs. Pharmacological validation using selected reference compounds affecting different mechanisms relevant for cardiac electrophysiology (quinidine, flecainide, atenolol, dl-sotalol, dofetilide, nifedipine, moxifloxacin) was conducted and findings were compared with results obtained in telemetered Beagle dogs. RESULTS AND CONCLUSION: Under standardized conditions, reliable ECG data with low variability allowing largely automated evaluation were obtained from the telemetered guinea pig model. The model is sensitive to compounds blocking cardiac sodium channels, hERG K(+) channels and calcium channels, and appears to be even more sensitive to ß-blockers as observed in dogs at rest. QT interval correction according to Bazett and Sarma appears to be appropriate methods in conscious guinea pigs. Overall, the telemetered guinea pig is a suitable model for the conduct of early stage preclinical ECG assessment.

Absence of direction-specific cross-modal visual-auditory adaptation in motion-onset event-related potentials.

Adaptation to visual or auditory motion affects within-modality motion processing as reflected by visual or auditory free-field motion-onset evoked potentials (VEPs, AEPs). Here, a visual-auditory motion adaptation paradigm was used to investigate the effect of visual motion adaptation on VEPs and AEPs to leftward motion-onset test stimuli. Effects of visual adaptation to (i) scattered light flashes, and motion in the (ii) same or in the (iii) opposite direction of the test stimulus were compared. For the motion-onset VEPs, i.e. the intra-modal adaptation conditions, direction-specific adaptation was observed--the change-N2 (cN2) and change-P2 (cP2) amplitudes were significantly smaller after motion adaptation in the same than in the opposite direction. For the motion-onset AEPs, i.e. the cross-modal adaptation condition, there was an effect of motion history only in the change-P1 (cP1), and this effect was not direction-specific--cP1 was smaller after scatter than after motion adaptation to either direction. No effects were found for later components of motion-onset AEPs. While the VEP results provided clear evidence for the existence of a direction-specific effect of motion adaptation within the visual modality, the AEP findings suggested merely a motion-related, but not a direction-specific effect. In conclusion, the adaptation of veridical auditory motion detectors by visual motion is not reflected by the AEPs of the present study.

The effect of induction of CYP3A4 by St John's wort on ambrisentan plasma pharmacokinetics in volunteers of known CYP2C19 genotype.

To evaluate the impact of CYP2C19 polymorphisms on ambrisentan exposure and to assess its modification by St. John's wort (SJW), 20 healthy volunteers (10 CYP2C19 extensive, four poor and six ultrarapid metabolizers) received therapeutic doses of ambrisentan (5 mg qd po) for 20 days and concomitantly SJW (300 mg tid po) for the last 10 days. To quantify changes of CYP3A4 activity, midazolam (3 mg po) as a probe drug was used. Ambrisentan pharmacokinetics was assessed on days 1, 10 and 20, and midazolam pharmacokinetics before and on days 1, 10, 17 and 20. At steady state, ambrisentan exposure was similar in extensive and ultrarapid metabolizers but 43% larger in poor metabolizers (p < 0.01). In all volunteers, SJW reduced ambrisentan exposure and the relative change (17-26%) was similar in all genotype groups. The extent of this interaction did not correlate with the changes in CYP3A activity (midazolam clearance) (rs = 0.23, p = 0.34). Ambrisentan had no effect on midazolam pharmacokinetics. In conclusion, SJW significantly reduced exposure with ambrisentan irrespective of the CYP2C19 genotype. The extent of this interaction was small and thus likely without clinical relevance.

Identification of novel small molecules that inhibit protein-protein interactions between MAGE and KAP-1.

The Class I MAGE proteins are normally expressed only in developing germ cells but are often aberrantly expressed in malignancies, particularly melanoma, making them good therapeutic targets. MAGE proteins promote tumor survival by binding to the RBCC region of KAP-1 and suppressing p53. Although, suppression of MAGE expression, by RNA interference, relieves p53 suppression and inhibits tumor growth, its therapeutic uses are limited by lack of methods for systemic delivery of small interfering RNA. To overcome this barrier, we sought to discover chemical compounds that inhibit binding between MAGE and KAP-1 proteins. Based on previously published effects of MAGE suppression, we developed a strategy for screening a small molecule library based on selective death of MAGE positive cells, activation of p53 and lack of caspase activity. We screened the Maybridge HitFinder library of compounds and eight compounds fulfilled these criteria. Seven of these compounds interfered with co-precipitation of MAGE and KAP-1, and three interfered with binding of MAGE and KAP-1 in a mammalian two hybrid assay. We now report identification of three potential compounds that interfere with MAGE/KAP-1 binding and can be developed as novel chemo-therapeutic agents for treatment of advanced melanoma and other cancers.

QTc shortening with a new investigational cancer drug: a brief case study.

INTRODUCTION: BAY-79 is an inhibitor of receptor tyrosine kinases with high selectivity versus other kinases. Species scaling, complicated by nonlinear pharmacokinetics, predicted a C(max.u) of 36-178nmol/L at the human efficacious exposure. METHODS: Preclinical cardiovascular safety pharmacology studies assessed currents (hERG, I(Na)), action potential (AP, rabbit Purkinje fiber), hemodynamic/ECG parameters (anesthetized Beagle dogs, intravenous infusion), and proarrhythmic potential (rabbit Langendorff heart Screenit model). RESULTS: Both hERG K(+) current and hNav1.5 Na(+) current were inhibited with low potency (IC(20)>10micromol/L). Purkinje fiber APs remained unaffected at 10micromol/L, but at 100micromol/L displayed reverse use-dependent AP duration shortening (APD(90)-33% at 1Hz) and triangulation. Infusion of BAY-79 into anesthetized dogs was associated with moderate hemodynamic effects (increased heart rate and diastolic blood pressure, reduced stroke volume) and marked QTcV shortening (-25ms) starting at approximately 0.65micromol/L (unbound); QRS was not changed. Assessment of the proarrhythmic potential in the Screenit model showed effects (AP duration shortening, triangulation, instability, reduced coronary flow, slowed conduction) at > or =30micromol/L (0.5h/concentration) and at 3micromol/L with longer exposure (2.5h/concentration). DISCUSSION: BAY-79 at plasma concentrations slightly higher than those predicted to be therapeutically efficacious in humans is associated with QTc shortening in dogs but of unclear mechanistic basis. The QTc shortening associated proarrhythmic potential of BAY-79 together with other considerations finally resulted in an unfavorable risk-benefit assessment.

Motion-onset auditory-evoked potentials critically depend on history.

The aim of the present study was to determine whether motion history affects motion-onset auditory-evoked potentials (motion-onset AEPs). AEPs were recorded from 33 EEG channels in 16 subjects to the motion onset of a sound (white noise) virtually moving in the horizontal plane at a speed of 60 deg/s from straight ahead to the left (-30 degrees ). AEPs for baseline and adaptation were compared. A stimulus trial comprised three consecutive phases: 2,000 ms adaptation phase, 1,000 ms stationary phase, and 500 ms test phase. During the adaptation phase of the adaptation condition, a sound source moved twice from +30 degrees to -30 degrees to top up preceding adaptation. In the baseline condition, neither top-up nor pre-adaptation were exerted. For both conditions, a stationary sound was presented centrally in the stationary phase, moving leftwards in the test phase. Typical motion-onset AEPs were obtained for the baseline condition, namely a fronto-central response complex dominated by a negative and a positive component, the so-called change-N1 and change-P2 after around 180 and 250 ms, respectively. For the adaptation condition, this complex was shifted significantly into the positive range, indicating that adaptation abolished a negativity within a time window of approximately 160 to 270 ms. A respective shift into the negative range was evident at occipito-parietal sites. In conclusion, while adaptation has to be taken into account as a potential confound in the design of motion-AEP studies, it might also be of benefit in order to isolate AEP correlates of motion processing.

Improvement in left ventricular remodeling by the endothelial nitric oxide synthase enhancer AVE9488 after experimental myocardial infarction.

BACKGROUND: Reduced endothelial nitric oxide (NO) bioavailability contributes to the progression of heart failure. In this study, we investigated whether the transcription enhancer of endothelial NO synthase (eNOS) AVE9488 improves cardiac remodeling and heart failure after experimental myocardial infarction (MI). METHODS AND RESULTS: Starting 7 days after coronary artery ligation, rats with MI were treated with placebo or AVE9488 (25 ppm) as a dietary supplement for 9 weeks. AVE9488 therapy versus placebo substantially improved left ventricular (LV) function, reduced LV filling pressure, and prevented the rightward shift of the pressure-volume curve. AVE9488 also attenuated the extent of pulmonary edema, reduced LV fibrosis and myocyte cross-sectional area, and prevented the increases in LV gene expression of atrial natriuretic factor, brain natriuretic peptide, and endothelin-1. eNOS protein levels and calcium-dependent NOS activity were decreased in the surviving LV myocardium from placebo MI rats and normalized by AVE9488. The beneficial effects of AVE9488 on LV dysfunction and remodeling after MI were abrogated in eNOS-deficient mice. Aortic eNOS protein expression and endothelium-dependent NO-mediated vasorelaxation were significantly enhanced by AVE9488 treatment after infarction, whereas increased vascular superoxide anion formation was reduced. Moreover, AVE9488 prevented the marked depression of circulating endothelial progenitor cell levels in rats with heart failure after MI. CONCLUSIONS: Long-term treatment with the eNOS enhancer AVE9488 improved LV remodeling and contractile dysfunction after MI. Molecular alterations, circulating endothelial progenitor cell levels, and endothelial vasomotor dysfunction were improved by AVE9488. Pharmacological interventions designed to increase eNOS-derived NO constitute a promising therapeutic approach for the amelioration of postinfarction ventricular remodeling and heart failure.

Diagnosis and management of pathological laughter and crying.

Patients with various neurologic disorders exhibit exaggerated or inappropriate episodes of laughter, crying, or both without an apparent motivating stimulus or in response to stimuli that would not have elicited such an emotional response before the onset of the underlying disease. During these episodes, patients have difficulty controlling their emotional expression according to the contextual information. In contrast, patients with mood disorders have a pervasive and sustained change in their emotional experience and thus exhibit spells of laughter or crying because of an underlying mania or depression. This article focuses on the clinical presentation, diagnosis, prevalence, and proposed pathophysiological mechanisms of and available treatment options for this clinical phenomenon.

Potential of Trichogramma ostriniae (Hymenoptera: Trichogrammatidae) for biological control of European corn borer (Lepidoptera: Crambidae) in solanaceous crops.

We assessed the ability of Trichogramma ostriniae (Peng & Chen) to locate and parasitize Ostrinia nubilalis (Hübner) eggs in crops other than corn, and we evaluated the efficacy of inundative releases of the parasitoid in two solanaceous crops, pepper and potato. Despite a greater plant surface area to search, parasitism of O. nubilalis eggs was consistently higher in sweet corn than dicotyledonous crops such as pepper, snap bean, broccoli, potato, and melon, in choice and no-choice experiments. Nonetheless, in 2002 and 2003, we made four to five separate inundative releases of approximately 30,000-50,000 T. ostriniae per 0.02 ha in nine pepper fields in Virginia, Pennsylvania, and Massachusetts and compared O. nubilalis egg parasitization and fruit damage in those plots with spatially isolated nonrelease plots. Egg parasitization averaged 48.7% in T. ostriniae release plots, which was significantly higher than in nonrelease plots (1.9%). Also, cumulative pepper fruit damage averaged 8.7% in release plots, which was significantly less than in nonrelease plots (27.3%). In potatoes in 2002 and 2003, we made two releases of approximately 75,000 T. ostriniae per 0.2 ha in nine fields in Maine and Virginia and compared O. nubilalis damage in those plots with that in nonrelease plots. T. ostriniae releases significantly reduced the number of tunnel holes and number of O. nubilalis larvae in potato stems. We conclude that this parasitoid has great potential as a biocontrol agent for O. nubilalis in solanaceous crops.

Organization of the visual cortex in human albinism.

In albinism there is an abnormal projection of part of the temporal retina to the visual cortex contralateral to the eye. This projection, together with the normally routed fibers from nasal retina, provides a cortical hemisphere with visual input from more than the normal hemifield of visual space. In many mammalian models of albinism, a possible sensory mismatch in the visual cortex is avoided either by reorganization of the thalamocortical connections to give the abnormal input an exclusive cortical representation, or by the abnormal input being substantially suppressed. In this study we examine, with fMRI, how the human visual cortex topographically maps its input in albinism. We find that the input from temporal retina is not substantially suppressed and forms a retinotopic mapping that is superimposed on the mapping of the nasal retina in striate and extrastriate areas. The abnormal routing of temporal fibers is not total, with the line of decussation shifting to between 6 and 14 degrees into temporal retina. Our results indicate that the abnormal input to visual cortex in human albinism does not undergo topographic reorganization between the thalamus and cortex. Furthermore, the abnormal input is not significantly suppressed in either striate or extrastriate areas. The topographic mapping that we report in human does not conform, therefore, to the commonly observed patterns in other mammals but takes the form of the "true albino" pattern that has been reported rarely in cat and in the only other individual primate studied.