IN VIVO/IN VITRO CORRELATIONS FOR FOUR DIFFERENTLY DISSOLVING KETOROLAC TABLETS

This study assesses whether in vitro immediate release ketorolac tablet dissolution profiles (utilizing the recently proposed USP dissolution test for ketorolac tablets) can be correlated with in vivo plasma pharmacokinetic parameters. Four batches of ketorolac tablets were utilized: a ketorolac tablet batch that demonstrated a rapid dissolution rate during USP in vitro dissolution testing, two tablet batches that were manufactured such that they dissolved at moderate rates, and a tablet batch that was manufactured such that it dissolved at a distinctly slow rate. The single-dose mean pharmacokinetic characteristics and relative bioavailability of the four different 10 mg ketorolac tromethamine tablets were evaluated in 12 healthy volunteers in a randomized study of Latin square design. The amount dissolved of the various tablets at 10, 20, and 30 min was in the order of fast-dissolving tablets > medium-1-dissolving tablets=medium-2-dissolving tablets > slow-dissolving tablets. In general, the profiles of the average plasma concentrations for ketorolac were similar for the fast- and the two medium-dissolving tablet batches (even though a statistically significant difference was found between the t_max of the fast-dissolving tablet and one of the medium-dissolving tablet batches). The mean plasma concentrations for the slow-dissolving tablet, however, reached peak levels much later, with the peak also being significantly smaller. There were no statistically significant differences in the total AUC or in the mean plasma half-lives among the four formulations. Good correlations were obtained for mean t_max versus the percentage dissolved at 20, 30, and 45 min. Correlations were generally weaker for percentage dissolved versus C_max or percentage bioavailability. This indicates that in vitro dissolution testing for immediate release ketorolac tablets can be a useful indicator of in vivo time to maximum plasma concentration when comparing similarly formulated tablets. Further, the proposed USP dissolution test and specification would have appropriately failed the slow-dissolving tablet batch, which demonstrated a significantly slower rate of absorption as per t_max and C_max.     

Comparisons of intellectual performance among children with psychiatric disorders

The intellectual performances of children with a variety of psychiatric disorders were examined and compared with the findings from a similar study by Hodges and Plow (1990). Mean IQ scores were in the average range for both study samples, and no significant differences were found in WISC-R summary scores. Nevertheless, the Hodges and Plow findings were only partially corroborated. They observed, for instance, a relative deficit in verbal abilities for conduct-disordered children and lower IQ scores for children with anxiety disorders vs. children with all other disorders. Our replication study found no significant differences among the disorder groups for any of the scores examined. Possible explanations for the divergence in findings are discussed.     

Interleukin–1 receptor antagonist gene polymorphism as a disease severity factor in systemic lupus erythematosus

Objective. We have previously described associations between an allele of the interleukin–1 receptor antagonist gene (IL1RN) and several inflammatory diseases. In this study we tested the IL1RN gene as a possible marker in patients with systemic lupus erythematosus (SLE). Methods. Eighty–one SLE patients and 261 ethnically matched control subjects were genotyped by polymerase chain reaction. Results. We found an increase in both frequency and carriage rate of IL1RN*2 in the SLE group. This association strengthened with extensive disease and particularly with the presence of photosensitivity and discoid skin lesions. Conclusion. We describe a novel association between IL1RN*2 and SLE. Carriage of the allele seems to influence severity rather than susceptibility to SLE. We postulate that the association of this polymorphism with disease severity is a widespread feature of common inflammatory and autoimmune diseases.     

Liver kinase B1 depletion from astrocytes worsens disease in a mouse model of multiple sclerosis

Liver kinase B1 (LKB1) is a ubiquitously expressed kinase involved in the regulation of cell metabolism, growth, and inflammatory activation. We previously reported that a single nucleotide polymorphism in the gene encoding LKB1 is a risk factor for multiple sclerosis (MS). Since astrocyte activation and metabolic function have important roles in regulating neuroinflammation and neuropathology, we examined the serine/threonine kinase LKB1 in astrocytes in a chronic experimental autoimmune encephalomyelitis mouse model of MS. To reduce LKB1, a heterozygous astrocyte-selective conditional knockout (het-cKO) model was used. While disease incidence was similar, disease severity was worsened in het-cKO mice. RNAseq analysis identified Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enriched in het-cKO mice relating to mitochondrial function, confirmed by alterations in mitochondrial complex proteins and reductions in mRNAs related to astrocyte metabolism. Enriched pathways included major histocompatibility class II genes, confirmed by increases in MHCII protein in spinal cord and cerebellum of het-cKO mice. We observed increased numbers of CD4+ Th17 cells and increased neuronal damage in spinal cords of het-cKO mice, associated with reduced expression of choline acetyltransferase, accumulation of immunoglobulin-γ, and reduced expression of factors involved in motor neuron survival. In vitro, LKB1-deficient astrocytes showed reduced metabolic function and increased inflammatory activation. These data suggest that metabolic dysfunction in astrocytes, in this case due to LKB1 deficiency, can exacerbate demyelinating disease by loss of metabolic support and increase in the inflammatory environment.     

Association between personality and tau-PET binding in cognitively normal older adults

Personality traits such as Neuroticism and Conscientiousness are associated with Alzheimer disease (AD) pathophysiology in cognitively normal (CN) and impaired individuals, and may represent potential risk or resilience factors, respectively. This study examined the cross-sectional relationship between personality traits and regional tau deposition using positron emission tomography (PET) in cognitively normal older adults. A cohort of CN (Clinical Dementia Rating (CDR) 0, n =?128) older adults completed the NEO Five-Factor Inventory to assess traits of Neuroticism, Extroversion, Openness, Agreeableness, and Conscientiousness and underwent tau-PET and β-amyloid (Aβ)-PET imaging. We utilized linear regression models, adjusting for age, sex, geriatric depression score, and Aβ to evaluate the association between each of the personality traits and regional tau-PET accumulation. Elevated Neuroticism scores were associated with higher tau-PET accumulation in the amygdala (p =?.002), entorhinal cortex (p =?.012), and inferior temporal cortex (p =?.016), as well as with a composite tau-PET measure (p =?.002). In contrast, Extroversion, Openness, Agreeableness, and Conscientiousness were not associated with tau deposition in any of these regions (p’s?>?0.160). Our results indicate that increased Neuroticism is associated with higher tau pathophysiology in regions known to be vulnerable to AD pathophysiology in CN participants. High Neuroticism scores may therefore serve as a potential risk factor for tau accumulation. Alternatively, personality can change with the onset of AD, thus increased tau levels may affect Neuroticism scores. While future longitudinal studies are needed to determine directionality, our findings suggest early associations between Neuroticism and tau accumulation in CN adults.

     

IGF-1R pathway activation as putative biomarker for linsitinib therapy to revert tamoxifen resistance in ER-positive breast cancer

Preclinical studies indicate that activated IGF-1R can drive endocrine resistance in ER-positive (ER+) breast cancer, but its clinical relevance is unknown. We studied the effect of IGF-1R signaling on tamoxifen benefit in patients and we searched for approaches to overcome IGF-1R-mediated tamoxifen failure in cell lines. Primary tumor blocks from postmenopausal ER+ breast cancer patients randomized between adjuvant tamoxifen versus nil were recollected. Immunohistochemistry for IGF-1R, p-IGF-1R/InsR, p-ERα(Ser118), p-ERα(Ser167) and PI3K/MAPK pathway proteins was performed. Multivariate Cox models were employed to assess tamoxifen efficacy. The association between p-IGF-1R/InsR and PI3K/MAPK pathway activation in MCF-7 and T47D cells was analyzed with Western blots. Cell proliferation experiments were performed under various growth-stimulating and -inhibiting conditions. Patients with ER+, IGF-1R-positive breast cancer without p-IGF-1R/InsR staining (n = 242) had tamoxifen benefit (HR 0.41, p = 0.0038), while the results for p-IGF-1R/InsR-positive patients (n = 125) were not significant (HR 0.95, p = 0.3). High p-ERα(Ser118) or p-ERα(Ser167) expression was associated with less tamoxifen benefit. In MCF-7 cells, IGF-1R stimulation increased phosphorylation of PI3K/MAPK proteins and ERα(Ser167) regardless of IGF-1R overexpression. This could be abrogated by the dual IGF-1R/InsR inhibitor linsitinib, but not by the IGF-IR-selective antibody 1H7. In MCF-7 and T47D cells, stimulation of the IGF-1R/InsR pathway resulted in cell proliferation regardless of tamoxifen. Abrogation of cell growth was regained by addition of linsitinib. In conclusion, p-IGF-1R/InsR positivity in ER+ breast cancer is associated with reduced benefit from adjuvant tamoxifen in postmenopausal patients. In cell lines, stimulation rather than overexpression of IGF-1R is driving tamoxifen resistance to be abrogated by linsitinib.     

Biperiden and mepazine effectively inhibit MALT1 activity and tumor growth in pancreatic cancer

MALT1 is a key mediator of NF-κB signaling and a main driver of B-cell lymphomas. Remarkably, MALT1 is expressed in the majority of pancreatic ductal adenocarcinomas (PDACs) as well, but absent from normal exocrine pancreatic tissue. Following, MALT1 shows off to be a specific target in cancer cells of PDAC without affecting regular pancreatic cells. Therefore, we studied the impact of pharmacological MALT1 inhibition in pancreatic cancer and showed promising effects on tumor progression. Mepazine (Mep), a phenothiazine derivative, is a known potent MALT1 inhibitor. Newly, we described that biperiden (Bip) is a potent MALT1 inhibitor with even less pharmacological side effects. Thus, Bip is a promising drug leading to reduced proliferation and increased apoptosis in PDAC cells in vitro and in vivo. By compromising MALT1 activity, nuclear translocation of c-Rel is prevented. c-Rel is critical for NF-κB-dependent inhibition of apoptosis. Hence, off-label use of Bip or Mep represents a promising new therapeutic approach to PDAC treatment. Regularly, the Anticholinergicum Bip is used to treat neurological side effects of Phenothiazines, like extrapyramidal symptoms.