A Population Pharmacokinetic Assessment of the Effect of Food on Selumetinib in Patients with Neurofibromatosis Type 1-Related Plexiform Neurofibromas and Healthy Volunteers.

Selumetinib is clinically used for pediatric patients with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas. Until recently, selumetinib had to be taken twice daily, after 2 hours of fasting and followed by 1 hour of fasting, which could be inconvenient. This population analysis evaluated the effect of low- and high-fat meals on the pharmacokinetic (PK) parameters of selumetinib and its active metabolite N-desmethyl selumetinib. The dataset comprised 511 subjects from 15 clinical trials who received ≥1 dose of selumetinib and provided ≥1 measurable postdose concentration of selumetinib and N-desmethyl selumetinib. A 2-compartment model with sequential 0- and 1st-order delayed absorption and 1st-order elimination adequately described selumetinib PK characteristics. A 1-compartment model reasonably described N-desmethyl selumetinib PK characteristics over time simultaneously with selumetinib. Selumetinib geometric mean area under the concentration-time curve ratio (1-sided 90% confidence interval [CI] lower bound) was 76.9% (73.3%) with a low-fat meal and 79.3% (76.3%) with a high-fat meal versus fasting. The lower bound of the 1-sided 90% CI demonstrated a difference of <30% between fed and fasted states. Considering the flat exposure-response relationship within the dose range (20-30 mg/m2), the observed range of exposure, and the variability in the SPRINT trial, this was not considered clinically relevant.

STGATE: Spatial-temporal graph attention network with a transformer encoder for EEG-based emotion recognition.

Electroencephalogram (EEG) is a crucial and widely utilized technique in neuroscience research. In this paper, we introduce a novel graph neural network called the spatial-temporal graph attention network with a transformer encoder (STGATE) to learn graph representations of emotion EEG signals and improve emotion recognition performance. In STGATE, a transformer-encoder is applied for capturing time-frequency features which are fed into a spatial-temporal graph attention for emotion classification. Using a dynamic adjacency matrix, the proposed STGATE adaptively learns intrinsic connections between different EEG channels. To evaluate the cross-subject emotion recognition performance, leave-one-subject-out experiments are carried out on three public emotion recognition datasets, i.e., SEED, SEED-IV, and DREAMER. The proposed STGATE model achieved a state-of-the-art EEG-based emotion recognition performance accuracy of 90.37% in SEED, 76.43% in SEED-IV, and 76.35% in DREAMER dataset, respectively. The experiments demonstrated the effectiveness of the proposed STGATE model for cross-subject EEG emotion recognition and its potential for graph-based neuroscience research.

Pharmacokinetics of Asfotase Alfa in Adult Patients With Pediatric-Onset Hypophosphatasia.

Hypophosphatasia is a rare metabolic disease resulting from variant(s) in the gene-encoding tissue-nonspecific isozyme of alkaline phosphatase. In this 13-week, phase 2a, multicenter, randomized, open-label, dose-response study (ClinicalTrials.gov: NCT02797821), the pharmacokinetics of asfotase alfa, an enzyme replacement therapy approved for the treatment of hypophosphatasia, was assessed in adult patients with pediatric-onset hypophosphatasia. In total, 27 adults were randomly assigned 1:1:1 to a single subcutaneous dose of asfotase alfa (0.5, 2.0, or 3.0 mg/kg) during week 1. From week 3 to week 9, patients received 0.5, 2.0, or 3.0 mg/kg subcutaneously 3 times per week (equivalent to 1.5, 6.0, or 9.0 mg/kg/wk, respectively). Noncompartmental analysis revealed exposure (maximum concentration in the dosing interval and area under the concentration-time curve from time 0 to infinity) to asfotase alfa increased between single- and multiple-dose administration and with increasing doses; however, extensive interindividual variability was observed in the concentration-time profiles within each dose cohort. Median terminal elimination half-life was ≈5 days following multiple-dose administration, with steady state achieved by approximately day 29. Dose-normalized exposure data indicated that asfotase alfa activity was approximately dose-proportional within the studied dose range. Additionally, dose-normalized exposure was comparable across body mass index categories of <25, ≥25 to <30, and ≥30 kg/m2 , indicating that asfotase alfa dosing bioavailability was consistent in these patients, including those who were obese. These data, together with previously published pharmacodynamic results in this study population, support the use of asfotase alfa at the recommended dose of 6 mg/kg/wk in adults with pediatric-onset hypophosphatasia.

Brominated flame retardants in home dust and its contribution to brominated flame retardants bioaccumulation in children hair.

Brominated flame retardants (BFRs) in house dust have raised significant concern around the world. However, few studies have reported the correlation between BFR concentrations in house dust and children's hair samples. In this study, BFR concentrations in house dust and children's hair were measured. Chemical analysis showed that the total concentrations of polybrominated diphenyl ethers (PBDEs) in house dust ranged from 334 to 4444 ng g-1, with a median of 442 ng g-1, and the concentrations in children's hair ranged from 352 to 655 ng g-1, with a median of 530 ng g-1. In addition, two alternative flame retardants, pentabromoethylbenzene (PBEB) and hexabromobenzene, were frequently detected in house dust and human hair. BDE209 was the most abundant PBDE congener detected in both house dust and children's hair. A significant correlation was found between the integrated PCA score of BFR concentrations in house dust and in children's hair (r2 = 0.31, P < 0.05), indicating the great contribution of house dust to the bodily burden of PBDEs in children. Risk assessment indicated that children's exposure to PBDEs via non-dietary intake of house dust should be recognized as an important exposure pathway.

Percutaneous Penetration and Metabolism of Plasticizers by Skin Cells and Its Implication in Dermal Exposure to Plasticizers by Skin Wipes.

Numerous studies focused on the human exposure to plasticizers via dermal contact; however, the percutaneous penetration of plasticizers was seldom considered in exposure assessment. In the present study, skin wipes of palms, back-of-hands, and forehead were collected from 114 participants (ages: 18-27). There was no significant difference between the levels of phthalates from palms and back-of-hand, while all phthalates collected from the forehead were significantly higher than those from palms and back-of-hand (p < 0.001); di(2-ethylhexyl)phthalate levels were substantially higher than other detected phthalates followed by di(n-butyl)phthalate and di(isobutyl)phthalate (DiBP), and for alternative plasticizers, bis-2-ethylhexyl terephthalate levels were substantially higher than acetyltributyl citrate and bis-2-ethylhexyladipate. Skin permeation and metabolism of phthalates was assessed using human skin equivalent models. The permeability coefficient (kp) values of phthalates were significantly negatively correlated with their log octanol-water partition coefficient (log Kow), while a significantly positive correlation was found between the log Kow and the cumulative amounts of phthalates in the cells. The proportion of phthalate intake via dermal exposure to skin wipes ranges from 1.3% (for dimethyl phthalate) to 8.6% (for DiBP) and suggests that dermal absorption is a significant route for adult phthalate exposure.

Comparison of sorption kinetics of PAHs by sorptive sinks and caco-2 cell and the correlation between bioaccessibility and bioavailability of PAHs in indoor dust.

Sorptive sinks are extensively used in the bioaccessibility of organic contaminants, but their suitability for simulating the intestinal cell is seldom reported. In the present study, the sorption efficiency of PAHs by sorptive sinks including silica, poly(ethylene-co-vinyl acetate) (polyE), tenax, and C18 were compared with that by caco-2 cells. The elimination rate constants of phenanthrene, fluoranthene, pyrene, benzo(a)pyrene by caco-2 cell were 0.0417 ±â€¯0.006 min-1, 0.0411 ±â€¯0.0074 min-1, 0.0362 ±â€¯0.006 min-1, and 0.0526 ±â€¯0.0037 min-1, respectively, which were more closely to that of silica and polyE compared to other materials. This indicated that these materials might be the preferable sorptive sinks to simulate absorption of PAHs by intestinal cells. The bioaccessibility of phenanthrene, fluoranthene, pyrene, benzo(a)pyrene in indoor dust ranged from 15.5-43.5%, 9.10-38.8%, 10.0-37.9%, and 6.00-21.9%, respectively, based on physiologically based extraction test (PBET) and the sorptive sinks added in the intestinal solution led to 1.17 to 8.47-fold enhancement of bioaccessibility. The correlation of in vivo PAHs relative bioavailability (RBA) and in vitro digestion bioaccessibility with or without the sorptive sinks of indoor dust were measured, and the results indicated that silica and polyE were more likely to predict PAHs RBA of indoor dust, which was consistent with the results of sorption kinetics assay. The present results indicate that silica and polyE have the potential to simulate caco-2 cell and the inclusion of these materials in the PBET is likely to predict PAHs RBA in indoor dust. Capsule: Silica and polyE were more likely to simulate absorption of PAHs by intestinal cells, and to predict PAHs RBA of indoor dust.

In vitro digestion and absorption of BDE-28, -47, -99 and -153 in indoor dust and its implication in risk assessment.

The bioaccessibility of polybrominated diphenyl ethers (PBDEs) in indoor dust was estimated by a series of in vitro digestion methods. However, the absorption of PBDEs by intestinal cells after in vitro digestion was seldom studied. In the present study, the bioaccessibility of BDE-28, 47, 99 and 153 in indoor dust was firstly investigated by using the in vitro digestion method. Bioaccessibility in intestinal phase (BDE-28: 24.5-30.1%; BDE-47: 6.99-13.0; BDE-99: 1.61-14.2%; and BDE-153 5.97-24.4%.) was higher than that in gastric phase (BDE-28: 38.3-58.0; BDE-47: 9.62-30.9%; BDE-99: 9.71-24.3%; and BDE-153: 13.8-57.4%). The organic matter contents in indoor dust showed variable influence on the bioaccessibility of PBDEs. For the Caco-2 uptake assay, the BDE-28 showed greatest transport rate from medium to cell (Kmc: 0.525h-1), followed by -47, -99 and -153. The Kmc of PBDEs was significantly negative correlated with its corresponding KOW value. Similar pattern was found for the maximum uptake flux (Ju, max) and the transport rate from cell to medium (Kcm). The combination of bioacessibility and the absorption factor by Caco-2 cells could be used to estimate human intake of PBDEs via indoor dust would avoid overestimate the health risk.

Comparison of in vitro digestion model with in vivo relative bioavailability of BDE-209 in indoor dust and combination of in vitro digestion/Caco-2 cell model to estimate the daily intake of BDE-209 via indoor dust.

There is limited information on the BDE-209 relative bioavailability (RBA) of indoor dust and the absorption of BDE-209 after in vitro digestion was seldom studied. In the present study, BDE-209 RBA in 6 household dust samples measured using an in vivo mouse model was compared to BDE-209 bioaccessibility determined using physiologically based extraction test (PBET) and solubility bioaccessibility research consortium method (SBRC) assays. BDE-209 RBA obtained ranged from 45.9 ± 16.1 to 96.0 ± 17.4% and exhibited a significant relationship with PBET gastric phase (r2 = 0.578, p = 0.080), small intestinal phase (r2 = 0.728, p = 0.031) and total BDE-209 bioaccessibility (r2 = 0.728, p = 0.031), which indicated PBET assay can serve as a surrogate to predict BDE-209 RBA to refine human health exposure. In addition, the absorption of BDE-209 by Caco-2 cell line was assessed. With the consideration of the corresponding bioaccessibility and absorption of BDE-209 by Caco-2 cell line, the human daily intake of BDE-209 via dust ingestion for adults and children was much lower than that estimated by total concentration.

Bioaccessibility of heavy metals in vegetables and its association with the physicochemical characteristics.

The bioaccessibilites of heavy metals in vegetables grown around a waste-incinerator site were estimated using the physiologically based extraction test (PBET) method, to assess potential health risk to the local consumers. The average gastric and intestinal bioaccessibilities of Cd, Cr, Cu, Ni, and Pb in vegetables varied within 3.2-9.4 and 0.8-5.3 %, 1.4-2.3 and 1.1-1.9 %, 25-46 and 13-26 %, 6.6-30 and 2.6-5.3 %, 11-29 and 7.1-23 %, respectively. Strong negative correlations were found between electrochemical potential (ΔE 0) and bioaccessibility for leaf mustard samples (r (2) = 0.857) and leaf lettuce samples (r (2) = 0.696). In addition, softness index (σp) and electrochemical potential (ΔE 0) exhibited a moderate but not significant relationship with bioaccessibilities on the basis of the multiple regression analysis (0.05 < p < 0.1). The total bioaccessible target hazard quotient (TBTHQ) of the five heavy metals was 2.5, with Pb being the major risk contributor. According to the TBTHQs of each group of vegetables, local consumers are experiencing adverse health effects by consuming most of the vegetables around waste-incinerator site.

Assessment of relative bioavailability of heavy metals in soil using in vivo mouse model and its implication for risk assessment compared with bioaccessibility using in vitro assay.

There is limited study to simultaneously determine the relative bioavailability of heavy metals such as Cd, Pb, Cu, Cr(VI), and Ni in soil samples. In the present study, the bioaccessibility of heavy metals using in vitro assay was compared with the relative bioavailability of heavy metals using in vivo mouse model. The bioaccessibility of heavy metals ranged from 9.05 ± 0.97 % (Cr) to 42.8 ± 3.52 % (Cd). The uptake profile of heavy metals in soil and solution samples in mouse revealed that the uptake kinetics could be fitted to a two-compartment model. The relative bioavailability of heavy meals ranged from 34.8 ± 7.0 % (Ni) to 131 ± 20.3 % (Cu). Poor correlation between bioaccessibility and relative bioavailability of heavy metals was observed (r (2) = 0.11, p > 0.05). The relative bioavailability of heavy metals was significantly higher than the bioaccessibility of heavy metals (p < 0.05). The present study indicated that the in vitro digestion method should be carefully employed in risk assessment.

Concentration and transportation of heavy metals in vegetables and risk assessment of human exposure to bioaccessible heavy metals in soil near a waste-incinerator site, South China.

There is limited study focusing on the bioaccumulation of heavy metals in vegetables and human exposure to bioaccessible heavy metals in soil. In the present study, heavy metal concentrations (Cr, Ni, Cu, Pb and Cd) were measured in five types of vegetables, soil, root, and settled air particle samples from two sites (at a domestic waste incinerator and at 20km away from the incinerator) in Guangzhou, South China. Heavy metal concentrations in soil were greater than those in aerial parts of vegetables and roots, which indicated that vegetables bioaccumulated low amount of heavy metals from soil. The similar pattern of heavy metal (Cr, Cd) was found in the settled air particle samples and aerial parts of vegetables from two sites, which may suggest that foliar uptake may be an important pathway of heavy metal from the environment to vegetables. The highest levels of heavy metals were found in leaf lettuce (125.52µg/g, dry weight) and bitter lettuce (71.2µg/g) for sites A and B, respectively, followed by bitter lettuce and leaf lettuce for sites A and B, respectively. Swamp morning glory accumulated the lowest amount of heavy metals (81.02µg/g for site A and 53.2µg/g for site B) at both sites. The bioaccessibility of heavy metals in soil ranged from Cr (2%) to Cu (71.78%). Risk assessment showed that Cd and Pb in soil samples resulted in the highest non-cancer risk and Cd would result in unacceptable cancer risk for children and risk. The non-dietary intake of soil was the most important exposure pathway, when the bioaccessibility of heavy metals was taken into account.

Prediction of clinical pharmacokinetics of AMG 181, a human anti-α 4 ß 7 monoclonal antibody for treating inflammatory bowel diseases.

The purpose of this study was to predict a safe starting dose of AMG 181, a human anti-α 4 ß 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 ß 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 ß 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 EC50 for free α 4 ß 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 ß 7 receptor EC10. 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.

Clinical pharmacology of AMG 181, a gut-specific human anti-α4ß7 monoclonal antibody, for treating inflammatory bowel diseases.

AIMS: AMG 181 pharmacokinetics/pharmacodynamics (PK/PD), safety, tolerability and effects after single subcutaneous (s.c.) or intravenous (i.v.) administration were evaluated in a randomized, double-blind, placebo-controlled study. METHODS: Healthy male subjects (n= 68) received a single dose of AMG 181 or placebo at 0.7, 2.1, 7, 21, 70 mg s.c. (or i.v.), 210 mg s.c. (or i.v.), 420 mg i.v. or placebo. Four ulcerative colitis (UC) subjects (n= 4, male : female 2:2) received 210 mg AMG 181 or placebo s.c. (3:1). AMG 181 concentration, anti-AMG 181-antibody (ADA), α4 ß7 receptor occupancy (RO), target cell counts, serum C-reactive protein, fecal biomarkers and Mayo score were measured. Subjects were followed 3-9 months after dose. RESULTS: Following s.c. dosing, AMG 181 was absorbed with a median tmax ranging between 2-10 days and a bioavailability between 82% and 99%. Cmax and AUC increased dose-proportionally and approximately dose-proportionally, respectively, within the 70-210 mg s.c. and 70-420 mg i.v. ranges. The linear ß-phase t1/2 was 31 (range 20-48) days. Target-mediated disposition occurred at serum AMG 181 concentrations of less than 1 µg ml(-1) . The PD effect on α4 ß7 RO showed an EC50 of 0.01 µg ml(-1) . Lymphocytes, eosinophils, CD4+ T cells and subset counts were unchanged. AMG 181-treated UC subjects were in remission with mucosal healing at weeks 6, 12 and/or 28. The placebo-treated UC subject experienced colitis flare at week 6. No ADA or AMG 181 treatment-related serious adverse events were observed. CONCLUSIONS: AMG 181 has PK/PD, safety, and effect profiles suitable for further testing in subjects with inflammatory bowel diseases.

Unsymmetrical oxovanadium complexes derived from salicylaldehyde and phenanthroline: synthesis, DNA interactions, and antitumor activities.

Two unsymmetrical oxovanadium complexes incorporating salicylaldehyde derivate and phenanthroline [VO(DESAA)(phen)] (1), (DESAA = 4-(diethylamino)salicylaldehyde anthranilic acid, phen = phenanthroline) and [VO(CLSAA)(phen)] (2), (CLSAA = 5-chlorosalicylaldehyde anthranilic acid)] have been synthesized and characterized. The interactions of the complexes with CT-DNA were studied using different techniques. Complexes 1 and 2 interact with CT-DNA by intercalative modes and can efficiently cleave pBR322 DNA after light irradiation. The two complexes showed high cytotoxic activities against myeloma cell (Ag8.653) and gliomas cell (U251) lines. Interestingly, complex 1 exhibited greater antitumor efficiency, larger binding affinity with CT-DNA, and better cleaving ability than those of complex 2. In addition, their antitumor mechanism has been analyzed by using cell cycle analysis, apoptosis, and Annexin V-FITC/PI assay. The results showed that complex 1 can cause G2/M-phase arrest of the cell cycle, exhibit a significantly induced apoptosis in Ag8.653 cells, and display typical morphological apoptotic characteristics. These complexes induced proliferative suppression of Ag8.653 cells via the induction of apoptosis.

Homeostasis of human NK cells is not IL-15 dependent.

IL-15 is a proinflammatory cytokine that plays an important role in the development and activation of NK cells and is a potential target for inflammatory disease therapy. Studies conducted in IL-15- and IL-15R knockout mice identified IL-15 as an important cytokine for NK cell homeostasis. Consistent with this information derived from genetically modified mice, we demonstrated that neutralizing IL-15 with a mouse anti-mouse IL-15 mAb (M96) depletes C57BL/6 mouse NK cells. An mAb directed against macaque IL-15 (Hu714MuXHu) was manufactured and demonstrated to block IL-15-induced activation of nonhuman primate (NHP) NK cells in vitro. Neutralization of macaque IL-15 by parenteral administration of Hu714MuXHu reduces (>95%) circulating NK cell counts in NHPs. A blocking mAb directed against human IL-15 (huIL-15; AMG 714) was manufactured. Unexpectedly, when human subjects were treated with the blocking anti-IL-15 Ab AMG 714 in clinical trials, no reductions in circulating NK cell counts were observed despite achieving significantly higher exposures than the levels of Hu714MuXHu needed to cause NK cell count reductions in NHPs in vivo. Both AMG 714 and Hu714MuXHu are able to block huIL-15 activity in a human T cell blast proliferation and IFN-γ production assay. Both Abs block huIL-15-mediated Stat5 activation and CD69 expression in human NK cells. Collectively, these results demonstrate that NK cell homeostasis is obligatorily dependent upon IL-15 in both mice and NHPs, but that IL-15 is dispensable for maintenance of circulating human NK cells.

Off-target platelet activation in macaques unique to a therapeutic monoclonal antibody.

AMG X, a human neutralizing monoclonal antibody (mAb) against a soluble human protein, caused thrombocytopenia, platelet activation, reduced mean arterial pressure, and transient loss of consciousness in cynomolgus monkeys after first intravenous administration. In vitro, AMG X induced activation in platelets from macaque species but not from humans or baboons. Other similar mAbs against the same pharmacological target failed to induce these in vivo and in vitro effects. In addition, the target protein was known to not be expressed on platelets, suggesting that platelet activation occurred through an off-target mechanism. AMG X bound directly to cynomolgus platelets and required both the Fab and Fc portion of the mAb for platelet activation. Binding to platelets was inhibited by preincubation of AMG X with its pharmacological target or with anti-human Fc antibodies or by preincubation of platelets with AMG X F(ab')(2) or human immunoglobulin (IVIG). AMG X F(ab')(2) did not activate platelets. Thus, platelet activation required both recognition/binding of a platelet ligand with the Fab domain and interaction of platelet Fc receptors (i.e., FcγRIIa) with the Fc domain. These findings reflect the complexity of the mechanism of action of mAbs and the increasing awareness of potential for unintended effects in preclinical species.

Pharmacokinetics/pharmacodynamics model-supported early drug development.

Pharmacokinetic/pharmacodynamic (PK/PD) modeling & simulation (M&S) provides quantitative assessment of dose/exposure-response relationships with extensive applications at the late stage drug development as well as during regulatory decision making. However, at preclinical and early phase clinical drug development, the importance of PK/PD M&S has not been as widely recognized. We reviewed selected PK/PD M&S literatures in order to convey importance of M&S in these early development phases. We focused on the application of M&S to select and optimize lead candidates, the use of preclinical PK/PD data to project the range of clinical doses, and the development of comprehensive dose/exposure-response models that can be used to forecast the probability of achieving a target response based on Phase 1 safety, PK and biomarker information. We also reviewed several other M&S approaches that are often used in early drug development such as physiologically-based pharmacokinetic (PBPK) modeling, meta-analysis, PK-pharmacogenomics modeling, and etc. Our aims were to provide expert opinions on the practical utility of PK/PD model-based approaches that have positive impact on early decision-making with the goal of improving the success rate of early to late stage drug development.

In vitro and in vivo pharmacokinetic characterizations of AMG 900, an orally bioavailable small molecule inhibitor of aurora kinases.

AMG 900 is a small molecule being developed as an orally administered, highly potent, and selective pan-aurora kinase inhibitor. The aim of the investigations was to characterize in vitro and in vivo pharmacokinetic (PK) properties of AMG 900 in preclinical species. AMG 900 was rapidly metabolized in liver microsomes and highly bound to plasma proteins in the species tested. It was a weak Pgp substrate with good passive permeability. AMG 900 exhibited a low-to-moderate clearance and a small volume of distribution. Its terminal elimination half-life ranged from 0.6 to 2.4 h. AMG 900 was well-absorbed in fasted animals with an oral bioavailability of 31% to 107%. Food intake had an effect on rate (rats) or extent (dogs) of AMG 900 oral absorption. The clearance and volume of distribution at steady state in humans were predicted to be 27.3 mL/h/kg and 93.9 mL/kg, respectively. AMG 900 exhibited acceptable PK properties in preclinical species and was predicted to have low clearance in humans. AMG 900 is currently in Phase I clinical testing as a treatment for solid tumours. Preliminary human PK results appear to be consistent with the predictions.

Embossing of chalcogenide glasses: monomode rib optical waveguides in evaporated thin films.

Single-mode optical rib waveguides operating at telecommunication wavelengths are successfully patterned via a hot embossing technique in a thermally evaporated chalcogenide glass thin film on a chalcogenide glass substrate. Ellipsometry is used to measure the refractive index dispersion of the pressed film (As(40)Se(60)) and substrate (Ge(17)As(18)Se(65)).

Pharmacokinetics of murine p75-Fc fusion protein and MP6-XT22 anti-murine TNF-alpha mAb in mice.

Immunologic limitations make it difficult to study the pharmacokinetic effects of human tumor necrosis factor (TNF) blockers in murine models. To counter this, we have studied the pharmacokinetics in mice of two murine analogs of human TNF blockers, a murine p75-FC fusion protein (analogous to etanercept), and the rat MP6-XT22 anti-murine TNF mAb (analogous to infliximab). We analyzed the pharmacokinetics of the murine p75-Fc protein and MP6-XT22 antibody in mice that were uninfected and in mice with disseminated candidiasis in order to confirm dosing strategies and interpret future studies evaluating the efficacy and tolerability of these agents in mice. We propose that, while conducting safety or efficacy studies in murine disease models, it is reasonable to administer the murine p75-Fc protein to mice at <10 mg/kg every 4-5 days, and the MP6-XT22 antibody at 10-20 mg/kg every 4-5 days.