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The purpose of this study was to predict a safe starting dose of AMG 181, a human anti‐α4β7 antibody for treating inflammatory bowel diseases, based on cynomolgus monkey pharmacokinetic (PK) and pharmacodynamic (PD) data. A two‐compartment model with parallel linear and target‐mediated drug disposition for AMG 181 PK in cynomolgus monkey was developed. The estimated parameters were allometrically scaled to predict human PK. An Emax PD model was used to relate AMG 181 concentration and free α4β7 receptor data in cynomolgus monkey. AMG 181 clinical doses were selected based on observed exposures at the no adverse effect level of 80 mg·kg−1 in monkeys, the predicted human exposures, and AMG 181 concentration expected to produce greater than 50% α4β7 receptor occupancy in humans. The predicted human AMG 181 clearance and central volume of distribution were 144 mL·day−1 and 2900 mL, respectively. The estimated EC50 for free α4β7 receptor was 14 ng·mL−1. At the 0.7 mg starting dose in humans, the predicted exposure margins were greater than 490,000 and AMG 181 concentrations were predicted to only briefly cover the free α4β7 receptor EC10. Predictions for both Cmax and AUC matched with those observed in the first‐in‐human study within the 7 mg subcutaneous to 420 mg intravenous dose range. The developed model aided in selection of a safe starting dose and a pharmacological relevant dose escalation strategy for testing of AMG 181 in humans. The clinically observed human AMG 181 PK data validated the modeling approach based on cynomolgus monkey data alone. e00098

The purpose of this study was to predict a safe starting dose of AMG 181, a human anti‐ α 4 β 7 antibody for treating inflammatory bowel diseases, based on cynomolgus monkey pharmacokinetic ( PK ) and pharmacodynamic ( PD ) data. A two‐compartment model with parallel linear and target‐mediated drug disposition for AMG 181 PK in cynomolgus monkey was developed. The estimated parameters were allometrically scaled to predict human PK . An E max PD model was used to relate AMG 181 concentration and free α 4 β 7 receptor data in cynomolgus monkey. AMG 181 clinical doses were selected based on observed exposures at the no adverse effect level of 80 mg·kg −1 in monkeys, the predicted human exposures, and AMG 181 concentration expected to produce greater than 50% α 4 β 7 receptor occupancy in humans. The predicted human AMG 181 clearance and central volume of distribution were 144 mL·day −1 and 2900 mL, respectively. The estimated EC 50 for free α 4 β 7 receptor was 14 ng·mL −1 . At the 0.7 mg starting dose in humans, the predicted exposure margins were greater than 490,000 and AMG 181 concentrations were predicted to only briefly cover the free α 4 β 7 receptor EC 10 . Predictions for both C max and AUC matched with those observed in the first‐in‐human study within the 7 mg subcutaneous to 420 mg intravenous dose range. The developed model aided in selection of a safe starting dose and a pharmacological relevant dose escalation strategy for testing of AMG 181 in humans. The clinically observed human AMG 181 PK data validated the modeling approach based on cynomolgus monkey data alone. e00098

Isoxazolines are oral insecticidal drugs currently licensed for ectoparasite control in companion animals. Here we propose their use in humans for the reduction of vector-borne disease incidence. Fluralaner and afoxolaner rapidly killed Anopheles, Aedes, and Culex mosquitoes and Phlebotomus sand flies after feeding on a drug-supplemented blood meal, with IC50 values ranging from 33 to 575 nM, and were fully active against strains with preexisting resistance to common insecticides. Based on allometric scaling of preclinical pharmacokinetics data, we predict that a single human median dose of 260 mg (IQR, 177–407 mg) for afoxolaner, or 410 mg (IQR, 278–648 mg) for fluralaner, could provide an insecticidal effect lasting 50–90 days against mosquitoes and Phlebotomus sand flies. Computational modeling showed that seasonal mass drug administration of such a single dose to a fraction of a regional population would dramatically reduce clinical cases of Zika and malaria in endemic settings. Isoxazolines therefore represent a promising new component of drug-based vector control.

Macrophages (Mϕs) play an important role in the inflammatory response during injury by participating in the removal of injurious stimuli, such as bacteria, and promoting tissue healing to restore homeostasis. Mϕs can acquire distinct functional phenotypes along a spectrum between two opposite stages (M1/M2) during activation. In the present study, we induced a stress response in Mϕs via heat shock (HS) and found that it incurred an increase in phagocytosis (1.6-fold, P  < 0.05) and bacterial killing (2.8-fold, P  < 0.01). Upon heat stress activation, Mϕs respond to group B Streptococcus (GBS) infection with lower levels of pro-inflammatory cytokines, TNF-α (2.25-fold, P  < 0.01), IL-6 (7-fold, P  < 0.001), and inducible nitric oxide synthase (iNOS) (2.22-fold, P  < 0.05), but higher levels of the anti-inflammatory cytokine IL-10 (3.9-fold, P  < 0.01). Stressed Mϕs exposed to GBS display rapid phagosome maturation, increased extracellular trap (ET) formation and elevated cathelicidin antimicrobial peptide expression (2.5-fold, P  < 0.001). These findings are consistent with a heretofore uncharacterized Mϕ activation state formed in response to stress, associated with secretion of large quantities of anti-inflammatory mediators and redirection of antimicrobial mechanisms to NADPH-oxidase-independent pathways. This “friendly activation” of Mϕs is characterized by increased bactericidal activity and more rapid and controlled resolution of the inflammatory response. Key Messages Macrophages form a dual pro-bactericidal and anti-inflammatory state. Stress in the setting of infection triggers friendly activation in macrophages. Heat shock plus infection increases macrophage bactericidal activity. Heat shock plus infection increases macrophage extracellular trap formation. Heat shock plus infection increases macrophage production of cathelicidin and IL-10.

The asian citrus psyllid [Diaphorina citri (Sternorrhyncha: Psyllidae)] is a detrimental pest to citrus (Citrus spp.) crops when it serves as a vector of the pathogen that causes greening (huanglongbing). Transmission of this disease causes mottling, chlorosis, dieback, and reductions in fruit size and quality. Citrus producers have found that many pesticides, when applied properly, are very effective at suppressing or eliminating asian citrus psyllids in groves. Due to the threat of greening, several pesticides have been granted Special Local Needs registration for use in the state of Florida if the product is sprayed with a volume median diameter of 90 µm or greater. A number of studies involving numerous citrus sprayers and a.i. were conducted to determine the droplet sizes generated by different sprayers operating under user-established settings and the adjustments required to those settings for the sprayers to meet the 90-µm requirement. In the sprayer tests, it was found that reductions in engine speed or increases in flow rate were required to increase droplet sizes to meet the product label-required droplet size. As the equipment tested here represent the most typical application equipment used in Florida for asian citrus psyllid control, these results will provide applicators, growers, and extension agents with general guidelines to ensure that spray systems are operated in a manner that complies with label restrictions.

Recent malaria drug discovery approaches have been extensively focused on the development of oral, smallmolecule inhibitors for disease treatment whereas parenteral routes of administration have been avoided due to limitations in deploying a shelf-stable injectable even though it could be dosed less frequently. However, an updated target candidate profile from Medicines for Malaria Venture (MMV) and stakeholders have advocated for long-acting injectable chemopreventive agents as an important interventive tool to improve malaria prevention. Here, we present strategies for the development of a long-acting, intramuscular, injectable atovaquone prophylactic therapy. We have generated three prodrug approaches that are contrasted by their differential physiochemical properties and pharmacokinetic profiles: mCBK068, a docosahexaenoic acid ester of atovaquone formulated in sesame oil, mCKX352, a heptanoic acid ester of atovaquone formulated as a solution in sesame oil, and mCBE161, an acetic acid ester of atovaquone formulated as an aqueous suspension. As a result, from a single 20 mg/kg intramuscular injection, mCKX352 and mCBE161 maintain blood plasma exposure of atovaquone above the minimal efficacious concentration for >70 days and >30 days, respectively, in cynomolgus monkeys. The differences in plasma exposure are reflective of the prodrug strategy, which imparts altered chemical properties that ultimately influence aqueous solubility and depot release kinetics. On the strength of the pharmacokinetic and safety profiles, mCBE161 is being advanced as a first-in-class clinical candidate for first-in-human trials.

The only resource to examine police interventions cross-nationally, this collection analyzes a wide array of policing styles. Focusing on Italy, France, Germany, Great Britain, Switzerland, Spain, the United States, and South Africa, the contributors look at cultures and political power to examine the methods and the consequences of policing protest. Contributors: Rocco De Biasi, Olivier Fillieule, Oscar Jaime-Jiménez, Fabien Jobard, Hanspeter Kriesi,Gary T. Marx, John McCarthy, Clark McPhail, Fernando Reinares, Robert Reiner, David Schweingruber, P. A. J. Waddington, Martin Winter, and Dominique Wisler.

A laboratory has many factors to consider before incorporating CAD/CAM restorations into their services. Tracking PFM versus all-ceramic restorations fabricated in your lab will provide information on your current volume and future growth patterns. With the rising cost of gold, many labs are choosing all-ceramic as an alternative solution because of the fixed costs associated with all-ceramic restorations. One critical factor in this decision is whether or not outsourcing will be profitable. Due to the high expense and training costs of integrating a milling system in your own laboratory, many are choosing to outsource to milling centers. Before partnering with a milling center, it is important to consider the type of support you will receive. Technical support is important, but having marketing and knowledgeable local repre- sentatives to assist your business are also key ingrethents for suc- cess. The milling center you choose should have strong clinical data and technical research to support the use of their particular brand and provide confidence to you and your dentist clients. Laboratories need to partner with a milling cen- ter that has the expertise to pro- vide exceptional restorations that have precise fit of the coping to the die, marginal integrity, and uniform porcelain support. A working relationship should be established with a milling center to clarify the following: bridge span length, framework design, preparation requirements, type of model work needed, type of stone, turnaround time, coping thickness, scannable blockout wax, zirconia frame color charts, and shipping costs. The relationship between the laboratory and the milling center must be profitable for both parties. How does a lab convert doctors to the new technology? Provide data, articles and information on CAD/CAM and zirconia-based ceramics. Provide educational seminars to clients and roundtable discussions on adopting new technology. Offer trial programs to your customer dentists in order for them to see the finished product of zirconia ceramic restorations. Utilize study models of prep designs with before and after photographs for education. Zirconia based restorations offer several key advantages to dentists: metal free restorations with comparable strength to PFM, biocompatibility and positive tissue response, fixed costs and consistent pricing per unit, excellent esthetics and simplicity of cementation. The future of CAD/CAM is very positive. Zirconia-based ceramics provides an intimacy of fit and superior esthetics that has excellent vitality and translucency. Costs are very competitive with other types of all-ceramic restorations. Long-term clinical data now exists on Lava crowns and bridges, as well as other all-ceramic restorations. Additional studies are needed on full contour zirconia crowns in contact with enamel (wear rates), as well as the shading of zirconia. All-ceramic restorations have proven their efficacy. It is important to be knowledgeable and remember that all zirconia ceramics and CAD/CAM systems are not created equal. Mixing and matching copings with veneering ceramics is not recommended; work within a system of manufacturer guidelines for success. Zirconia-based ceramics and CAD/CAM, along with digital dentistry are the future due to labor costs and consistency of automation. Laboratories can get involved with minimal investment and choosing the right outsourcing partnership. Together with dentists, laboratories can learn and grow with this new technology as it changes and develops into the future. CAD/CAM Smart-Sourcing involves a thorough review of the way you do business and how to successfully partner with others. Decisions need to be made by the laboratory on how to deliver consistent esthetic results to dentist clients with a profitable return on investment. Future success depends on your ability to view technology and outsourcing as a positive solution to your daily challenges.

Organophosphorus ester-induced delayed neuropathy (OPIDN) is a distal axonopathy induced by only some of the organophosphorus (OP) compounds: tri-ortho-cresyl phosphate (TOCP) and diisopropyl fluorophosphate (DFP) both induce OPIDN, whereas paraoxon does not. Although inhibition of neuropathy target esterase (NTE) has been correlated with the development of OPIDN, the actual biochemical mechanism remains unresolved. These studies were undertaken to evaluate whether OP-induced changes in intracellular calcium ( (Ca$\\sp{2+}$) $\\sb{\\rm i}$) predictably presage development of the axonopathy. Naive hens were pretreated with atropine sulfate (10 mg/kg, i.v.) and then dosed with either TOCP (750 mg/kg, p.o.), paraoxon (10 mg/kg, p.o.) or corn oil (control) and sacrificed after 24, 48, or 72 hours. NTE activity was significantly inhibited by TOCP (p $<$ 0.05) at all time points. Synaptosomes prepared from spinal cords of TOCP-treated hens exhibited significantly elevated (Ca$\\sp{2+}$) $\\sb{\\rm i}$ at 48 and 72 hours compared to (Ca$\\sp{2+}$) $\\sb{\\rm i}$ in controls, as measured by the fluorescent dye FURA-2. (Ca$\\sp{2+}$) $\\sb{\\rm i}$ was not elevated by paraoxon. Ca$\\sp{2+}$/K$\\sp+$-ATPase (CKA) and Na$\\sp+$/K$\\sp+$-ATPase (NKA) have been reported to be inhibited by some OP's and, if inhibited, could alter (Ca$\\sp{2+}$) $\\sb{\\rm i}$. DFP in vitro had no effect on NKA activity in synaptosomes from hen spinal cord. TOCP in vivo had no inhibitory effect on CKA or NKA activities in microsomes from hen spinal cord or brain. TOCP also had no effect on conjugated diene formation, an indication of lipid peroxidation, in hen spinal cord preparations. Ca$\\sp{2+}$ channel antagonists have been reported to be partially effective in preventing the early development of OPIDN. DFP in vitro had no effect on Ca$\\sp{2+}$ uptake into rat brain synaptosomes. In a separate series of experiments, NTE activity was found to be positively correlated with CKA activity in cardiac sarcoplasmic membrane reticular vesicles and their subfractions isolated from naive mongrel dogs. These data suggested that the OPIDN marker NTE may be associated with sarcoplasmic reticulum, an organelle central to (Ca$\\sp{2+}$) $\\sb{\\rm i}$ regulation. These findings suggest that intracellular calcium is elevated during the early development of OPIDN. This could be consistent with a calcium mediated neurotoxicity. The mechanism(s) for this alteration of calcium homeostasis remains unknown.