Biochemical and pharmacological characterization of AZD1981, an orally available selective DP2 antagonist in clinical development for asthma

Background and Purpose

The discovery of DP₂ as a second receptor for PGD₂ has prompted the search for antagonists as potential novel therapies based on the associations between PGD₂ and disease. Here we describe the biochemical and pharmacological properties of 4-(acetylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid (AZD1981), a novel DP₂ receptor antagonist.

Experimental Approach

Binding to DP₂, functional receptor pharmacology and selectivity were studied in both human and animal systems.

Key Results

AZD1981 displaced radio-labelled PGD₂ from human recombinant DP₂ with high potency (pIC₅₀ = 8.4). Binding was reversible, non-competitive and highly selective against a panel of more than 340 other enzymes and receptors, including DP₁ (>1000-fold selective). AZD1981 inhibited DP₂-mediated shape change and CD11b up-regulation in human eosinophils, shape change in basophils and chemotaxis of human eosinophils and Th2 cells with similar potency. AZD1981 exhibited good cross-species binding activity against mouse, rat, guinea pig, rabbit and dog DP₂. Evaluation in mouse, rat or rabbit cell systems was not possible as they did not respond to DP₂ agonists. Agonist responses were seen in guinea pig and dog, and AZD1981 blocked DP₂-mediated eosinophil shape change. Such responses were more robust in the guinea pig, where AZD1981 also blocked DP₂-dependent eosinophil emigration from bone marrow.

Conclusions and Implications

AZD1981 is a DP₂ antagonist that blocks functional responses in eosinophils, Th2 cells and basophils. It exhibited similar potency irrespective of the cell type, DP₂ agonist or species used. This selective orally active agent is currently under clinical evaluation as a potential therapeutic agent in respiratory diseases including asthma.     

Structure of Posttraumatic Stress Disorder Symptoms in Pain and Pain-Free Patients Scheduled for Major Surgery

Factor-analytic studies of the structure of posttraumatic stress disorder (PTSD) symptoms have yielded inconsistent results. One of the reasons for the inconsistency may be that PTSD is highly comorbid with other disorders; the observed factor structure might depend on the particular comorbid disorder. One such disorder is chronic pain. The goal of the present study was to investigate whether PTSD symptom structure differs between pain and pain-free patients scheduled to undergo major surgery. Four hundred and forty-seven patients who were approached 7 to 10 days prior to scheduled surgery completed the PTSD Checklist-Civilian (PCL-C) Version and the Current Pain and Pain History Questionnaire; the latter was used to divide patients into pain (N = 175) and pain-free (N = 272) groups. Results showed that in pain-free patients, PTSD symptoms were best expressed as 2 symptom clusters (re-experiencing/avoidance; emotional numbing/hyperarousal) accounting for 52.4% of the variance. In pain patients, PTSD symptoms were best expressed as a single symptom cluster accounting for 51.1% of the variance. These results suggest different interrelationships among PTSD symptoms in these 2 populations. Results reflect the need for (1) controlling for pain in studies looking at PTSD-symptom expression and (2) further research on PTSD-symptom expression in pain populations.

Perspective

These results may have important implications for research on the comorbidity between PTSD and chronic pain, as well as for treatment of PTSD symptoms in patients presenting with pain problems.     

Population attributable fractions of psychiatric disorders and suicide ideation and attempts associated with adverse childhood experiences

Objectives. We sought to determine the fractions of psychiatric disorders and suicide ideation and attempts in a general population sample attributable to childhood physical abuse, sexual abuse, and witnessing domestic violence.Methods. Data were obtained from the US National Comorbidity Survey Replication. Population attributable fractions were calculated to determine the proportion of psychiatric disorders and suicide ideation and attempts attributable to adverse childhood experiences. The analysis was stratified by gender.Results. The estimated attributable fractions for psychiatric disorders attributable to having experienced any adverse childhood event ranged from 22% to 32% among women and 20% to 24% among men. Having experienced any adverse event accounted for a substantial proportion of suicide ideation and attempts among women (16% and 50%, respectively) and men (21% and 33%, respectively). Substantial proportions of poor mental health outcomes were also attributable to increasing number of adverse events.Conclusions. The estimated proportions of poor mental health outcomes attributed to childhood adversity were medium to large for men and women. Prevention efforts that reduce exposure to adverse childhood events could substantially reduce the prevalence of psychopathology and suicidal behavior in the general population.Past research has established a strong association between exposure to childhood adversity and increased likelihood of psychiatric disorders1^–5 and suicidal behavior6^,7 in adulthood. In addition, when one looks at adverse childhood events along a continuum, a dose–response group relationship has been found with increasing severity of childhood adversity corresponding with poorer mental health outcomes.8 Although the relationship between childhood adversity and poor adult mental health is widely accepted, there is little information on what proportion of psychiatric disorders and suicidal behavior is attributable to adverse childhood experiences in the general population.To date, only a few published studies have calculated population attributable fractions to estimate the proportion of psychiatric disorders and suicidality associated with adverse childhood experiences. In a study of a community sample, Scott found that 3.9% of psychiatric cases were attributable to childhood sexual abuse.9 Dube et al. used a clinic sample to assess the relationship between several adverse childhood experiences and illicit drug use and found that 56% of lifetime drug problems, 63% of illicit drug addiction, and 64% of intravenous drug use was attributable to having experienced at least 1 adverse childhood event.10 In a different study, Dube et al., using the same data, found that 67% of lifetime suicide attempts, 80% of child or adolescent suicide attempts, and 64% of adult suicide attempts were attributable to having experienced 1 or more adverse childhood events.11 Finally, Molnar et al. found that after they controlled for the effects of psychiatric disorders and other adverse childhood experiences, 8% to 12% of serious suicide attempts were attributable to childhood sexual abuse in a nationally representative US sample.7The proportion of poor mental health outcomes attributable to adverse childhood experiences varies substantially from one study to another. At least some of this variation can be explained on methodological grounds. The size of the attributable fraction depends on the prevalence of the exposure in the population and the strength of association between the exposure and outcome variable.12 In the 2 studies in which the authors reported high attributable fractions, broad definitions of any childhood events were used, including experiences such as parental divorce, which resulted in more than 60% endorsement of childhood adversity in the clinical sample.10^,11 The high prevalence of adverse childhood events would contribute to the large estimated attributable fractions. Another explanation for the large attributable fractions in the study in which childhood adversity and suicide were examined was that the authors controlled for depressed affect, self-reported alcoholism, and illicit drug use with single items, but did not control for psychiatric disorders.11 Failure to control for psychiatric disorders when assessing the relationship between childhood adversity and suicide attempts would inflate associations and contribute to larger estimates of attributable fractions.Conversely, other studies have shown lower attributable fractions, which are more common in epidemiological studies. The low attributable fraction in Scott’s9 research may be partly because of the suspected underestimation of the prevalence of childhood sexual abuse, which led the author to conclude that the relationship between childhood sexual abuse and psychiatric disorders may be stronger than the results indicated. Lower attributable fractions reported by Molnar et al.7 were likely attributable to the inclusion of important covariates in the models.In addition to the aforementioned methodological discrepancies in previous studies, other methodological limitations of past research have included the calculation of attributable fractions for only 1 type of childhood adversity,7^,9^,13 the assessment of only 1 category of mental health outcome,7^,10^,11^,13 the estimation of attributable fractions for females only13 or males and females combined without the consideration of possible gender differences,10^,11 the failure to evaluate the impact of potentially important covariates,9 and the lack of nationally representative general population samples.9^–11 We addressed the limitations of past research with the inclusion of numerous childhood adversities and mental health outcomes, the stratification of the analyses based on gender, the inclusion of important covariates, and the use of a contemporary nationally representative sample.We sought to estimate the population attributable fractions for each group of psychiatric disorders (any mood disorder, any anxiety disorder, any substance use disorder, and any psychiatric disorder) and suicidal behavior (ideation and attempts) among men and women attributable to childhood physical abuse, childhood sexual abuse, having witnessed domestic violence, and the number of adverse childhood events experienced after adjustment for important covariates.     

A comparison of anatomical pain sites from a tertiary care sample: Evidence of disconnect between functional and perceived disability specific to lower back pain

Heterogeneity has been identified within chronic musculoskeletal pain (CMP) patient samples; however, investigations have typically focused on psychological constructs or coping (e.g., pain‐related anxiety, catastrophizing) in this regard. Furthermore, studies to date have included either samples presenting with a specific anatomical site (e.g., only lower back pain) or a mix of anatomical sites (e.g., lower back, shoulder, or leg pain) as the primary pain complaint, without making comparisons based on the anatomical site of reported pain. For example, patients with chronic lower back pain (CLBP) may differ from those with chronic upper or lower extremity pain (ULEP) in presentation, recovery trajectory, and psychological variables. The current investigation explored whether systematic differences existed between patients participating in a multidisciplinary reconditioning third‐party‐payer program who have CLBP relative to patients with ULEP. Patients included those with CLBP (n=23; 35% women) or ULEP (e.g., arm, shoulder, leg, knee; n=28; 29% women). The ULEP group began and finished the program with more pain‐related anxiety, more catastrophic thoughts, and more fearful cognitions than the CLBP group. There were no significant correlations between functional deficit and perceived levels of disability or associations between group and return to work status; however, there was an unexpected significant interaction between group and perceived disability. Specifically, CLBP patients reported increasing perceived disability despite improvements in functional deficit, whereas ULEP patients did not. These findings suggest a disconnect between perceived disability and function that may be specific to lower back pain. Implications and directions for future research are discussed.     

Strategies for managing symptoms of anxiety

The purpose of this article is to summarize strategies for effectively managing the symptoms of anxiety. The distinction between the cognitive, physiological and behavioral components of fear and anxiety is explained and various treatment targets are outlined. Empirically-supported strategies that are effective in alleviating common symptoms of anxiety are reviewed. These include various forms of psychosocial intervention (i.e., cognitive and behavioral therapies), pharmacotherapy, in addition combined treatment approaches. Expert consensus guidelines, prognostic factors, patient preferences and accessibility issues are discussed with regard to treatment selection in addition to emerging challenges in the field and future research directions.     

Human thrombopoietin levels are high when thrombocytopenia is due to megakaryocyte deficiency and low when due to increased platelet destruction

Thrombopoietin (TPO), the ligand for c-mpl, stimulates proliferation of committed megakaryocytic progenitors and induces maturation of megakaryocytes. To better understand factors regulating TPO levels, we measured blood levels of TPO in patients with impaired platelet production due to aplastic anemia (AA) and with platelet destructive disorders, including idiopathic thrombocytopenic purpura (ITP), posttransfusion purpura (PTP), drug purpura (DP), and X-linked thrombocytopenia (XLTP). The TPO receptor capture enzyme immunoassay (EIA) used had a detection limit of integral of approximately-150 to 200 pg/mL. TPO was undetectable in 88 of 89 normal individuals. Eighteen of 19 patients with AA and a mean platelet count (MPC) of 18,000/microliters (2,000 to 61,000/microliters) had markedly elevated TPO levels (mean, 1,467 pg/mL; range, 597 to 3,834 pg/mL). Eight AA patients who responded to immunosuppressive therapy with their MPC increasing to 140,000/microliters (92,000 to 175,000/microliters) had substantial decreases in TPO (mean, 440 pg/mL; range, 193 to 771 pg/mL). Initial TPO levels did not differ significantly between responders and nonresponders. In contrast, all 21 patients with ITP and an MPC of 16,000/microliters (1,000 to 51,000 /microliters) had undetectable TPO levels, as did 6 patients with acute PTP or DP and 2 patients with XLTP. Megakaryocyte mass, reflected in the rate of platelet production, appears to be the major determinant of TPO levels in thrombocytopenic patients rather than circulating platelet levels per se. Measurement of serum TPO may be useful in differentiating thrombocytopenias due to peripheral destruction from those due to thrombopoietic failure.     

Endovascular management of pseudoaneurysms of the splenic artery: experience with six patients

The purpose of this paper was to describe our experience with the endovascular management of splenic artery pseudoaneurysms (SAPA). Seven patients with documented SAPA on CT and/or angiography were considered for endovascular treatment. The pseudoaneurysms were located in the main splenic artery (n = 4) or its branches (n = 3). In one patient in whom the pseudoaneurysm was located in a hilar branch, selective catheterization of splenic artery failed. Metallic coils (n = 1), gelfoam and hydrogel particles (n = 1), metallic coils and gelfoam (n = 2), metallic coil, gelfoam and acrylic glue (n = 2) were used as embolization material in the remaining six patients. These patients were followed for a mean period of 11.3 months. Transcatheter embolization was successful in five patients with no procedure‐related complications. In one patient, embolization was incomplete and the patient underwent surgery, but died on the 10th postoperative day because of irreversible shock. Another patient, after successful embolization, underwent surgery for management of an associated pseudocyst. Endovascular treatment is a safe and effective method of management of SAPA.     

Mentally retarded adolescents' breadth of attention and short-term memory processes during matching-to-sample discriminations

Twenty-two moderately and severely mentally retarded adolescents and 22 nonretarded children participated in an experiment designed to examine processes contributing to matching-to-sample deficits of low mental age (MA) retarded persons. One-half of the subjects rehearsed color, form, and size cues during delay intervals. Nonretarded subjects performed better than did retarded subjects on immediate and delayed retention tests. There was no difference in rate of forgetting, and rehearsal improved delayed test performance equally for both groups. Although immediate test results indicated that low-MA persons are capable of multiple-looking, these results also suggest that retarded persons attend to fewer dimensions than do nonretarded children.     

Effects of three PTSD treatments on anger and guilt: exposure therapy, eye movement desensitization and reprocessing, and relaxation training

This study sought to investigate the efficacy of prolonged exposure, eye movement desensitization and reprocessing, and relaxation training on trait anger and guilt and on trauma-related anger and guilt within the context of posttraumatic stress disorder (PTSD) treatment. Fifteen PTSD patients completed each treatment and were assessed at posttreatment and at 3-month follow-up. All three treatments were associated with significant reductions in all measures of anger and guilt, with gains maintained at follow-up. There were no significant treatment differences in efficacy or in the proportion of patients who worsened on anger or guilt measures over the course of treatment. Between-treatment effect sizes were generally very small. Results suggest that all three treatments are associated with reductions in anger and guilt, even for patients who initially have high levels of these emotions. However, these PTSD therapies may not be sufficient for treating anger and guilt; additional interventions may be required.