Search

Mavorixafor (XOLREMDI™) is an oral, selective C-X-C chemokine receptor 4 (CXCR4) antagonist developed by X4 Pharmaceuticals that blocks the binding of C-X-C chemokine ligand 12 (also known as stromal derived factor-1) to CXCR4. In April 2024, it became the first therapy to be approved for WHIM syndrome (named by an acronym for its observed characteristics of Warts, Hypogammaglobulinaemia, Infections and Myelokathexis) in the USA, where it is indicated for use in patients aged ≥ 12 years with WHIM syndrome to increase the number of circulating mature neutrophils and lymphocytes. Clinical development of mavorixafor is ongoing for chronic neutropenic disorders. This article summarizes the milestones in the development of mavorixafor leading to this first approval for use in patients aged ≥ 12 years with WHIM syndrome to increase the number of circulating mature neutrophils and lymphocytes., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: The clinical importance of eosinophils in asthma has been shown by the observation of frequent exacerbation in patients with high sputum eosinophil counts and a corresponding decrease in exacerbations when anti-inflammatory therapy was adjusted to maintain low sputum eosinophil percentages. However, less is known of the relation between blood eosinophilia and asthma exacerbation., Objective: To examine whether patients with asthma and a higher blood eosinophil count have more asthma attacks than those with a lower count., Methods: The authors analyzed data from the National Health and Nutrition Examination Survey, an annual cross-sectional survey of the US general population. Patients with asthma and asthma attacks were identified based on participants' self-report or parental report. A high blood eosinophil count was defined using 200, 300, or 400 cells/μL as cutoffs. The primary analysis used data from 2001 through 2010 after adjusting for demographic variables, obesity, smoking, neutrophil level, and past treatment for wheezing. A secondary analysis used data from 2007 through 2010 and included recent treatment for asthma and fraction of exhaled nitric oxide level as additional adjustment variables., Results: In survey years 2001 through 2010, 3,162 patients with asthma had blood eosinophil data and approximately half (54% of children and 52% of adults) reported an asthma attack in the previous year. In the primary analysis, higher blood eosinophil counts were associated with more asthma attacks in children but not in adults. The secondary analysis suggested an association in both children and adults., Conclusion: Patients with asthma with higher blood eosinophil counts experienced more asthma attacks than those with lower eosinophil counts., (Copyright © 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Engineered nanomaterials (ENMs) have potential benefits, but they also present safety concerns for human health. Interlaboratory studies in rodents using standardized protocols are needed to assess ENM toxicity., Methods: Four laboratories evaluated lung responses in C57BL/6 mice to ENMs delivered by oropharyngeal aspiration (OPA), and three labs evaluated Sprague-Dawley (SD) or Fisher 344 (F344) rats following intratracheal instillation (IT). ENMs tested included three forms of titanium dioxide (TiO2) [anatase/rutile spheres (TiO2-P25), anatase spheres (TiO2-A), and anatase nanobelts (TiO2-NBs)] and three forms of multiwalled carbon nanotubes (MWCNTs) [original (O), purified (P), and carboxylic acid "functionalized" (F)]. One day after treatment, bronchoalveolar lavage fluid was collected to determine differential cell counts, lactate dehydrogenase (LDH), and protein. Lungs were fixed for histopathology. Responses were also examined at 7 days (TiO2 forms) and 21 days (MWCNTs) after treatment., Results: TiO2-A, TiO2-P25, and TiO2-NB caused significant neutrophilia in mice at 1 day in three of four labs. TiO2-NB caused neutrophilia in rats at 1 day in two of three labs, and TiO2-P25 and TiO2-A had no significant effect in any of the labs. Inflammation induced by TiO2 in mice and rats resolved by day 7. All MWCNT types caused neutrophilia at 1 day in three of four mouse labs and in all rat labs. Three of four labs observed similar histopathology to O-MWCNTs and TiO2-NBs in mice., Conclusions: ENMs produced similar patterns of neutrophilia and pathology in rats and mice. Although interlaboratory variability was found in the degree of neutrophilia caused by the three types of TiO2 nanoparticles, similar findings of relative potency for the three types of MWCNTs were found across all laboratories, thus providing greater confidence in these interlaboratory comparisons.

Introduction: Despite its superior efficacy, clozapine is typically reserved for treatment-refractory schizophrenia due to the risk of agranulocytosis with an occurrence of up to 1% in recipients. The FDA has rigid treatment guidelines for hematologic monitoring for clozapine patients. If the white blood cell (WBC) count or absolute neutrophil count (ANC) falls below predetermined values, clozapine treatment must be held or discontinued. Diurnal and ethnic variations in complete blood count (CBC) values, somewhat dependent upon blood sampling time have been reported, and called pseudoneutropenia, which appears independent of clozapine therapy. Unnecessary treatment interruption or discontinuation is costly and may lead to disease relapse. The purpose of this study was to evaluate the effect of a time change in CBC sampling on WBC and ANC values in a group of clozapine patients in a regional public inpatient psychiatric facility., Methods: Facility CBC sampling for clozapine patients was switched from 0630 to on or after 0830. A retrospective record review was conducted for all patients who were receiving clozapine before and after the time switch, with a minimum of six values pre- and post-change. CBC values sampled on or after 0830 were accepted as applicable post data, as patients are awakened daily at 0630, and a minimum of two hours of wakefulness/mobility had occurred. Patient medical records, automated lab information system, and the Clozapine National Registry were data sources. Data extracted included WBC/ANC values (with date/time of sampling) and demographic information (DOB, sex, weight, height, BMI, and ethnicity). The data were analyzed using repeated measures ANOVA., Results: Ten patients (80% male, 90% Caucasian, mean age=55.7 years) met study criteria. The difference in the pre/post time change WBC values was marginally significant (mean increase=667/mm3, p=.07), with a significant difference (mean increase=1,130/mm3, p=.003) between the pre/post time change ANC values. ANC values were more positively impacted by the sampling time change than WBC values in this sample. The mean sampling time change across all subjects pre/post was 5 hours 24 minutes., Conclusions: All reasonable steps should be considered to safely continue an effective therapy in treatment-refractory schizophrenia. A larger, more ethnically diverse sample is needed to validate the present work; however, changing the timing of CBC sampling for clozapine patients from early morning to after a minimum two-hour period of wakefulness/movement may have potential to improve WBC and ANC values. Marginal improvements in resultant WBC/ANC values could potentially allow clozapine therapy to continue uninterrupted per FDA monitoring guidelines.

Background: With the increasing use of antiretroviral (ARV) drugs to prevent mother-to-child transmission of human immunodeficiency virus (HIV), large numbers of infants are exposed, with possible consequent toxicity., Methods: Hematologic values in 1820 uninfected HIV- and ARV-exposed children were compared with those in 351 ARV-unexposed children from the Women and Infants Transmission Study. Hemoglobin concentrations and platelet, neutrophil, lymphocyte, and CD4+ and CD8+ cell counts were analyzed at birth and ages 2, 6, 12, 18, and 24 months. Multivariate analysis was conducted age 0-2 and 6-24 months, with adjustment for multiple cofactors., Results: Hemoglobin concentrations and neutrophil, lymphocyte, and CD4+ cell counts were significantly lower at age 0-2 months in infants exposed to ARV drugs than in those who were not. At 6-24 months, differences in hemoglobin concentrations and neutrophil counts were no longer significant, whereas differences in platelet, lymphocyte, and CD4+ cell counts persisted and CD8+ cell counts became significantly lower. In comparison with ARV monotherapy, combination therapy was associated with larger decreases in neutrophil, lymphocyte, and CD8+ cell counts at age 0-2 months but with only differences in CD8+ cell counts at age 6-24 months. Clinically significant abnormalities were rare and did not differ by exposure to ARV drugs., Conclusion: Infants exposed to ARV drugs have small but significant differences in several hematologic parameters for the first 24 months of life. These results indicate the need for long-term follow-up of uninfected infants with ARV exposure.