The matched triplicate approach to lead optimisation offers a means of generating more robust quantitative structure activity relationship data and this rigour leads to better quality decision making ...and greater ability to predict optimal compounds within a series. One of the ultimate aims of this approach is to use the data generated to build more accurate predictive models to identify the best compounds within the exemplified chemical space in an efficient manner. This paper describes the continued application of this approach to the optimisation of a series of glucokinase activators. This second phase focussed primarily on the rational solution to plasma instability observed with the previous compounds and, hence, achieved acceptable oral exposure in the series. The campaign was completed by using the predictive power of Free-Wilson analysis based on the matched triplicate datasets to enable a focussed, matrix based endgame culminating in the identification of two development candidates, AZD3651 and AZD9485.
Using "matched triplicate design sets" the
in vivo
stability of lead glucokinase activators was optimised to deliver two development candidates.
Thresholds for detection of both pressure and thermal pain are elevated in patients with bulimia nervosa. The present study was aimed at determining (1) if pressure pain detection thresholds (PDT) ...varied dynamically with the primary disease symptoms of binge eating and vomiting and (2) if the elevation in PDT was effected by treatment with ondansetron (ONDAN), a 5-HT3 receptor antagonist. PDT was defined as the mean of the minimal amount of pressure (measured in g) perceived as painful when exerted by a 1 mm2 blunted point onto the center of the ventral surface of the ungual phalanx of digits 2-5 of the non-dominant hand. Fourteen female patients with severe bulimia nervosa (currently >seven binge/vomit episodes per week; > 2 years illness duration) served as participants. PDT were evaluated at weekly intervals during the course of ongoing treatment studies (double-blind and 'open' label) investigating the therapeutic effects of ONDAN. Data were analyzed by random regression analyses, allowing for the repeated-measures and non-orthogonal design. Data collected from 14 patients under the no-drug condition indicated that PDT increased over the interval between binge/vomit episodes, with significant elevations occurring at times when patients had naturally exceeded their average inter-binge interval. Eleven of these 14 patients underwent 4 weeks of ONDAN treatment. Under this drug condition, the time since the last binge/vomit episode was no longer a significant predictor of PDT. These patients also experienced a significant reduction in the frequency of bulimic behaviors, a finding reported in detail elsewhere. The above finding from untreated patients support the involvement of a common underlying mechanism driving both the increase in pain detection thresholds and the occurrence of the next bulimic episode. This possibility is further supported by the findings that ONDAN treatment is associated with a significant moderation of both variables. The effect of ONDAN may be mediated by blockade of afferent vagal neurotransmission, although other mechanisms must be considered.
Temporal and spatial changes in the enzootic activity of western equine encephalomyelitis (WEE) and St. Louis encephalitis (SLE) viruses were monitored at representative wetland study sites in the ...Coachella, San Joaquin, and Sacramento valleys of California from 1996 to 1998 using three methods: (1) virus isolation from pools of 50 host-seekingCulex tarsalisCoquillett females, (2) seroconversions in flocks of 10 sentinel chickens, and (3) seroprevalence in wild birds collected by mist nets and grain baited traps. Overall, 74 WEE and one SLE isolates were obtained from 222,455Cx. tarsalisfemales tested in 4,988 pools. In addition, 133 and 40 seroconversions were detected in 28 chicken flocks, and 143 and 27 of 20,192 sera tested from 149 species of wild birds were positive for antibodies to WEE and SLE, respectively. WEE was active in all three valleys, whereas SLE only was detected in Coachella Valley. Seroconversions in sentinel chickens provided the most sensitive indication of enzootic activity and were correlated with seroprevalence rates in wild birds. Avian seroprevalence rates did not provide an early warning of pending enzootic activity in chickens, because positive sera from after hatching year birds collected during spring most probably were the result of infections acquired during the previous season. Few seroconversions were detected among banded recaptured birds collected during spring and early summer. Age and resident status, but not sex, were significant risk factors for wild bird infection, with the highest seroprevalence rates among after hatching year individuals of permanent resident species. Migrants (with the exception of mourning doves) and winter resident species rarely were positive. House finches, house sparrows, Gambel’s quail, California quail, common ground doves, and mourning doves were most frequently positive for antibodies. The initial detection of enzootic activity each summer coincided closely with the appearance of hatching year birds of these species in our study areas, perhaps indicating their role in virus amplification. Bird species most frequently positive roosted or nested in elevated upland vegetation, sites whereCx. tarsalishost-seeking females hunt most frequently. These serosurveys provided important background information for planned host competence and chronic infection studies.
The in vitro actions were investigated of LY293111, a potent and selective leukotriene B4 (LTB4) receptor antagonist, on human neutrophils, human blood fractions, guinea pig lung membranes, and ...guinea pig parenchymal and tracheal strips. The IC50 for inhibiting 3HLTB4 binding to human neutrophils was 17.6 +/- 4.8 nM. LY293111 inhibited LTB4-induced human neutrophil aggregation (IC50 = 32 +/- 5 nM), luminol-dependent chemiluminescence (IC50 = 20 +/- 2 nM), chemotaxis (IC50 = 6.3 +/- 1.7 nM), and superoxide production by adherent cells (IC50 = 0.5 nM). Corresponding responses induced by N-formyl-L-methionyl-L-leucyl-L-phenylalanine were inhibited by 100-fold higher concentrations of LY293111. LTB4 binding to guinea pig tissues and subsequent activation were also inhibited. The Ki for inhibition of 3HLTB4 binding to lung membranes was 7.1 +/- 0.8 nM; IC50 for preventing binding of 3HLTB4 to spleen membranes was 65 nM. The compound inhibited LTB4-induced contraction of guinea pig lung parenchyma. At 10 nM, LY293111 caused a parallel rightward shift of the LTB4 concentration-response curve. At higher concentrations, plots were shifted in a nonparallel manner, and maximum responses were depressed. LY293111 did not prevent antigen-stimulated contraction of sensitized trachea strips. At micromolar concentrations, LY293111 inhibited production of LTB4 and thromboxane B2 by plasma-depleted human blood stimulated with N-formyl-L-methionyl-L-leucyl-L-phenylalanine and thrombin. In addition, at these higher concentrations, formation of LTB4 by A23187-activated whole blood and conversion of arachidonic acid to LTB4 by a human neutrophil cytosolic fraction were inhibited. In summary, LY293111 is a second-generation LTB4 receptor antagonist with much improved potency in a variety of functional assay systems.
A rule-based, weight-of-evidence approach for assessing contaminated sediment on a site-by-site basis in the Laurentian Great Lakes is described. Information from four lines of evidence-surficial ...sediment chemistry, laboratory toxicity, invertebrate community structure and invertebrate tissue biomagnification-is integrated within each line to produce a pass ('−') or fail ('+') conclusion, then combined across lines resulting in one of 16 outcome scenarios. For each scenario, the current status of the site, interpretation, and management recommendations are given. Management recommendation(s) can range from no action to risk management required (9 of the 16 scenarios). Within each line of evidence, the strength of each response can also be ranked (e.g., score of 1 to 4), providing managers with more information to aid decision options. Other issues that influence scientific management recommendations include site stability, subsurface contamination and spatial extent of effects. The decision framework is intended to be transparent, comprehensive (incorporating exposure, effect, weight-of-evidence, and risk), and minimally uncertain.
The aim of this prospective study was to define the patterns of recovery of mandibular mobility following three commonly performed orthognathic surgical procedures. Twenty-two consecutive patients ...undergoing either isolated Le Fort I osteotomy (LE FORT; n = 7), sagittal split ramus osteotomies (SSRO; n = 7), or intraoral vertical ramus osteotomies (IVRO; n = 9) were studied. LE FORT and SSRO patients had no mandibular immobilization, whereas IVRO patients were immobilized by dental fixation for 3 weeks. Mandibular mobility was assessed by measurement of maximal mandibular opening (MMO) and lateral and protrusive excursions. No significant difference in MMO was observed between groups prior to surgery (LE FORT, 47.0 mm; SSRO, 50.7 mm; IVRO, 54.5 mm). A significant reduction in MMO occurred immediately after surgery in the LE FORT and SSRO groups and at release of fixation in the IVRO group. Each group returned to presurgical levels of mandibular mobility at a different rate following surgery. LE FORT patients recovered quickly, regaining 83% (mean, 38.7 mm) of MMO by 1 month and exceeded preoperative levels (mean, 49.6 mm) by 6 months. SSRO patients showed hypomobility (mean, 23.5 mm) after 1 month, with significant improvement in MMO (mean, 38.0 mm) at 2 months, and nearly complete recovery (96.2%; mean, 48.8 mm) at 6 months. IVRO patients recovered rapidly after release of dental fixation, achieving 78% (mean, 39.8 mm) of preoperative MMO at 2 months. This study shows that significant differences in recovery patterns of mandibular mobility exist between surgical procedures. The clinician should be aware of these differences in recovery patterns in defining goals for individual patient rehabilitation.
Structure-guided drug design led to the identification of a class of spirocyclic ureas which potently inhibit human 11b-HSD1 in vitro. Lead compound 10j was shown to be orally bioavailable in three ...species, distributed into adipose tissue in the mouse, and its (R) isomer 10j2 was efficacious in a primate pharmacodynamic model.
Medullary thymic epithelial cells (mTEC) play an important and unique role in central tolerance, expressing tissue-restricted Ags (TRA) which delete thymocytes autoreactive to peripheral organs. ...Since deficiencies in this cell type or activity can lead to devastating autoimmune diseases, it is important to understand the factors which regulate mTEC differentiation and function. Lymphotoxin (LT) ligands and the LT
β
R have been recently shown to be important regulators of mTEC biology; however, the precise role of this pathway in the thymus is not clear. In this study, we have investigated the impact of this signaling pathway in greater detail, focusing not only on mTEC but also on other thymic stromal cell subsets. LT
β
R expression was found in all TEC subsets, but the highest levels were detected in MTS-15
+
thymic fibroblasts. Rather than directing the expression of the autoimmune regulator Aire in mTEC, we found LT
β
R signals were important for TRA expression in a distinct population of mTEC characterized by low levels of MHC class II (mTEC
low
), as well as maintenance of MTS-15
+
fibroblasts. In addition, thymic stromal cell subsets from LT-deficient mice exhibit defects in chemokine production similar to that found in peripheral lymphoid organs of
Lta
−/−
and
Ltbr
−/−
mice. Thus, we propose a broader role for LT
α
1
β
2-LT
β
R signaling in the maintenance of the thymic microenvironments, specifically by regulating TRA and chemokine expression in mTEC
low
for efficient induction of central tolerance.
The purpose of this study was to prospectively define the recovery of touch discrimination following four commonly performed surgical procedures in 22 consecutive patients with no previous ...maxillofacial surgery. The surgical groups studied were Le Fort I osteotomy (LEFORT; n = 13), sagittal split ramus osteotomy (SSRO; n = 6), intraoral vertical ramus osteotomy (IVRO; n = 9), and isolated genioplasty (GENIO; n = 5). Neurosensory function was assessed by three different testing modalities which included static light touch (SLT), moving touch discrimination (MTD), and two-point discrimination (TPD). Cutaneous sensation of the lower lip and chin were examined for the mandibular procedures, whereas the infraorbital and upper lip regions were evaluated following maxillary surgery. Immediately following surgery, each group varied in both the incidence and magnitude of neurosensory deficits (NSD). The SSRO group had the highest percentage of sites with immediate postsurgical NSD to both SLT (72%) and MTD (67%), followed by the LEFORT (SLT = 50%, MDT = 58%), GENIO (SLT = 27%, MTD = 6%), and IVRO groups (SLT = 11%, MTD = 18%), respectively. Each group also varied in the severity of the initial postoperative deficit as measured by SLT, with the SSRO group showing the greatest deficit followed by the LEFORT, GENIO, and IVRO groups. During the 6-month recovery period each group approached preoperative levels of sensation at a different rate. The LEFORT group recovered most rapidly, with few anatomic sites showing NSD (SLT = 20%, MTD = 5%) at the 1-month postoperative examination, and the majority of the group (96%) returned to preoperative sensation by 3 months following surgery. The SSRO group recovered more slowly, with approximately half of the group demonstrating a deficit (SLT = 50%, MTD = 59%) at 1 month, which diminished to about one fourth of the sites (SLT = 25%, MTD = 5%) by 3 months. Most of the SSRO group (90%) exhibited no residual deficit 6 months following surgery. The IVRO group had few sites with immediate NSD (SLT = 11%, MTD = 15%). In none of the surgical groups was a statistically significant correlation found between the severity of the initial NSD and length of time to complete recovery.
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