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BMC Musculoskeletal Disorders Jun 2022Fibrodysplasia Ossificans Progressiva (FOP) is a genetic, progressive and devastating disease characterized by severe heterotopic ossification (HO), loss of mobility and...
Protocol paper: a multi-center, double-blinded, randomized, 6-month, placebo-controlled study followed by 12-month open label extension to evaluate the safety and efficacy of Saracatinib in Fibrodysplasia Ossificans Progressiva (STOPFOP).
BACKGROUND
Fibrodysplasia Ossificans Progressiva (FOP) is a genetic, progressive and devastating disease characterized by severe heterotopic ossification (HO), loss of mobility and early death. There are no FDA approved medications. The STOPFOP team identified AZD0530 (saracatinib) as a potent inhibitor of the ALK2/ACVR1-kinase which is the causative gene for this rare bone disease. AZD0530 was proven to prevent HO formation in FOP mouse models. The STOPFOP trial investigates the repositioning of AZD0530, originally developed for ovarian cancer treatment, to treat patients with FOP.
METHODS
The STOPFOP trial is a phase 2a study. It is designed as a European, multicentre, 6-month double blind randomized controlled trial of AZD0530 versus placebo, followed by a 12-month trial comparing open-label extended AZD0530 treatment with natural history data as a control. Enrollment will include 20 FOP patients, aged 18-65 years, with the classic FOP mutation (ALK2 R206H). The primary endpoint is objective change in heterotopic bone volume measured by low-dose whole-body computer tomography (CT) in the RCT phase. Secondary endpoints include F NaF PET activity and patient reported outcome measures.
DISCUSSION
Clinical trials in rare diseases with limited study populations pose unique challenges. An ideal solution for limiting risks in early clinical studies is drug repositioning - using existing clinical molecules for new disease indications. Using existing assets may also allow a more fluid transition into clinical practice. With positive study outcome, AZD0530 may provide a therapy for FOP that can be rapidly progressed due to the availability of existing safety data from 28 registered clinical trials with AZD0530 involving over 600 patients.
TRIAL REGISTRATION
EudraCT, 2019-003324-20. Registered 16 October 2019, https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-003324-20/NL .
CLINICALTRIALS
gov , NCT04307953 . Registered 13 March 2020.
Topics: Adolescent; Adult; Aged; Benzodioxoles; Double-Blind Method; Humans; Middle Aged; Multicenter Studies as Topic; Mutation; Myositis Ossificans; Ossification, Heterotopic; Quinazolines; Randomized Controlled Trials as Topic; Young Adult
PubMed: 35650602
DOI: 10.1186/s12891-022-05471-x -
Neurodegenerative Disease Management Aug 2022Tweetable abstract An overview of the active clinical trials for Parkinson's disease psychosis. In this article, we review the drugs currently undergoing clinical... (Review)
Review
Tweetable abstract An overview of the active clinical trials for Parkinson's disease psychosis. In this article, we review the drugs currently undergoing clinical testing for Parkinson's disease psychosis and offer some perspectives on the treatment of the condition.
Topics: Clinical Trials as Topic; Humans; Parkinson Disease; Psychotic Disorders
PubMed: 35592949
DOI: 10.2217/nmt-2022-0020 -
Chronic Stress (Thousand Oaks, Calif.) 2022Trauma and chronic stress are believed to induce and exacerbate psychopathology by disrupting glutamate synaptic strength. However, in human methods to estimate...
BACKGROUND
Trauma and chronic stress are believed to induce and exacerbate psychopathology by disrupting glutamate synaptic strength. However, in human methods to estimate synaptic strength are limited. In this study, we established a novel putative biomarker of glutamatergic synaptic strength, termed energy-per-cycle (EPC). Then, we used EPC to investigate the role of prefrontal neurotransmission in trauma-related psychopathology.
METHODS
Healthy controls (n = 18) and patients with posttraumatic stress (PTSD; n = 16) completed C-acetate magnetic resonance spectroscopy (MRS) scans to estimate prefrontal EPC, which is the ratio of neuronal energetic needs per glutamate neurotransmission cycle (V/V).
RESULTS
Patients with PTSD were found to have 28% reduction in prefrontal EPC ( = 3.0; = 32, = .005). There was no effect of sex on EPC, but age was negatively associated with prefrontal EPC across groups ( = -0.46, n = 34, = .006). Controlling for age did not affect the study results.
CONCLUSION
The feasibility and utility of estimating prefrontal EPC using C-acetate MRS were established. Patients with PTSD were found to have reduced prefrontal glutamatergic synaptic strength. These findings suggest that reduced glutamatergic synaptic strength may contribute to the pathophysiology of PTSD and could be targeted by new treatments.
PubMed: 35434443
DOI: 10.1177/24705470221092734 -
Molecular Psychiatry May 2022N-methyl-D-aspartate receptor (NMDAR) hypofunction is a leading pathophysiological model of schizophrenia. Resting-state functional magnetic resonance imaging (rsfMRI)... (Randomized Controlled Trial)
Randomized Controlled Trial
N-methyl-D-aspartate receptor (NMDAR) hypofunction is a leading pathophysiological model of schizophrenia. Resting-state functional magnetic resonance imaging (rsfMRI) studies demonstrate a thalamic dysconnectivity pattern in schizophrenia involving excessive connectivity with sensory regions and deficient connectivity with frontal, cerebellar, and thalamic regions. The NMDAR antagonist ketamine, when administered at sub-anesthetic doses to healthy volunteers, induces transient schizophrenia-like symptoms and alters rsfMRI thalamic connectivity. However, the extent to which ketamine-induced thalamic dysconnectivity resembles schizophrenia thalamic dysconnectivity has not been directly tested. The current double-blind, placebo-controlled study derived an NMDAR hypofunction model of thalamic dysconnectivity from healthy volunteers undergoing ketamine infusions during rsfMRI. To assess whether ketamine-induced thalamic dysconnectivity was mediated by excess glutamate release, we tested whether pre-treatment with lamotrigine, a glutamate release inhibitor, attenuated ketamine's effects. Ketamine produced robust thalamo-cortical hyper-connectivity with sensory and motor regions that was not reduced by lamotrigine pre-treatment. To test whether the ketamine thalamic dysconnectivity pattern resembled the schizophrenia pattern, a whole-brain template representing ketamine's thalamic dysconnectivity effect was correlated with individual participant rsfMRI thalamic dysconnectivity maps, generating "ketamine similarity coefficients" for people with chronic (SZ) and early illness (ESZ) schizophrenia, individuals at clinical high-risk for psychosis (CHR-P), and healthy controls (HC). Similarity coefficients were higher in SZ and ESZ than in HC, with CHR-P showing an intermediate trend. Higher ketamine similarity coefficients correlated with greater hallucination severity in SZ. Thus, NMDAR hypofunction, modeled with ketamine, reproduces the thalamic hyper-connectivity observed in schizophrenia across its illness course, including the CHR-P period preceding psychosis onset, and may contribute to hallucination severity.
Topics: Glutamates; Hallucinations; Humans; Ketamine; Lamotrigine; Magnetic Resonance Imaging; Receptors, N-Methyl-D-Aspartate; Schizophrenia
PubMed: 35422467
DOI: 10.1038/s41380-022-01502-0 -
Antioxidants (Basel, Switzerland) Dec 2021Diisopropylfluorophosphate (DFP), an organophosphate nerve agent (OPNA), exposure causes status epilepticus (SE) and epileptogenesis. In this study, we tested the...
Saracatinib, a Src Tyrosine Kinase Inhibitor, as a Disease Modifier in the Rat DFP Model: Sex Differences, Neurobehavior, Gliosis, Neurodegeneration, and Nitro-Oxidative Stress.
Diisopropylfluorophosphate (DFP), an organophosphate nerve agent (OPNA), exposure causes status epilepticus (SE) and epileptogenesis. In this study, we tested the protective effects of saracatinib (AZD0530), a Src kinase inhibitor, in mixed-sex or male-only Sprague Dawley rats exposed to 4-5 mg/kg DFP followed by 2 mg/kg atropine and 25 mg/kg 2-pralidoxime. Midazolam (3 mg/kg) was given to the mixed-sex cohort (1 h post-DFP) and male-only cohort (~30 min post-DFP). Saracatinib (20 mg/kg, oral, daily for 7 days) or vehicle was given two hours later and euthanized eight days or ten weeks post-DFP. Brain immunohistochemistry (IHC) showed increased microgliosis, astrogliosis, and neurodegeneration in DFP-treated animals. In the 10-week post-DFP male-only group, there were no significant differences between groups in the novel object recognition, Morris water maze, rotarod, or forced swim test. Brain IHC revealed significant mitigation by saracatinib in contrast to vehicle-treated DFP animals in microgliosis, astrogliosis, neurodegeneration, and nitro-oxidative stressors, such as inducible nitric oxide synthase, GP91, and 3-Nitrotyrosine. These findings suggest the protective effects of saracatinib on brain pathology seem to depend on the initial SE severity. Further studies on dose optimization, including extended treatment regimen depending on the SE severity, are required to determine its disease-modifying potential in OPNA models.
PubMed: 35052568
DOI: 10.3390/antiox11010061 -
Neuropsychopharmacology : Official... Jul 2022This study tested the efficacy of repeated intravenous ketamine doses to reduce symptoms of posttraumatic stress disorder (PTSD). Veterans and service members with PTSD... (Randomized Controlled Trial)
Randomized Controlled Trial
Dose-related effects of ketamine for antidepressant-resistant symptoms of posttraumatic stress disorder in veterans and active duty military: a double-blind, randomized, placebo-controlled multi-center clinical trial.
This study tested the efficacy of repeated intravenous ketamine doses to reduce symptoms of posttraumatic stress disorder (PTSD). Veterans and service members with PTSD (n = 158) who failed previous antidepressant treatment were randomized to 8 infusions administered twice weekly of intravenous placebo (n = 54), low dose (0.2 mg/kg; n = 53) or standard dose (0.5 mg/kg; n = 51) ketamine. Participants were assessed at baseline, during treatment, and for 4 weeks after their last infusion. Primary analyses used mixed effects models. The primary outcome measure was the self-report PTSD Checklist for DSM-5 (PCL-5), and secondary outcome measures were the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and the Montgomery Åsberg Depression Rating Scale (MADRS). There were no significant group-by-time interactions for PTSD symptoms measured by the PCL-5 or CAPS-5. The standard ketamine dose ameliorated depression measured by the MADRS significantly more than placebo. Ketamine produced dose-related dissociative and psychotomimetic effects, which returned to baseline within 2 h and were less pronounced with repeated administration. There was no evidence of differential treatment discontinuation by ketamine dose, consistent with good tolerability. This clinical trial failed to find a significant dose-related effect of ketamine on PTSD symptoms. Secondary analyses suggested that the standard dose exerted rapid antidepressant effects. Further studies are needed to determine the role of ketamine in PTSD treatment. ClinicalTrials.gov identifier: NCT02655692.
Topics: Antidepressive Agents; Double-Blind Method; Humans; Ketamine; Military Personnel; Stress Disorders, Post-Traumatic; Treatment Outcome; Veterans
PubMed: 35046508
DOI: 10.1038/s41386-022-01266-9 -
Bioengineered Feb 2022The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can target cardiomyocytes (CMs) to directly invade the heart resulting in high mortality. This study...
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can target cardiomyocytes (CMs) to directly invade the heart resulting in high mortality. This study aims to explore the biological characteristics of SARS-CoV-2 infected myocardium based on omics by collecting transcriptome data and analyzing them with a series of bioinformatics tools. Totally, 86 differentially expressed genes (DEGs) were discovered in SARS-CoV-2 infected CMs, and 15 miRNAs were discovered to target 60 genes. Functional enrichment analysis indicated that these DEGs were mainly enriched in the inflammatory signaling pathway. After the protein-protein interaction (PPI) network was constructed, several genes including CCL2 and CXCL8 were regarded as the hub genes. SRC inhibitor saracatinib was predicted to potentially act against the cardiac dysfunction induced by SARS-CoV-2. Among the 86 DEGs, 28 were validated to be dysregulated in SARS-CoV-2 infected hearts. Gene Set Enrichment Analysis (GSEA) analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that malaria, IL-17 signaling pathway, and complement and coagulation cascades were significantly enriched. Immune infiltration analysis indicated that 'naive B cells' was significantly increased in the SARS-CoV-2 infected heart. The above results may help to improve the prognosis of patients with COVID-19.
Topics: Blood Coagulation; COVID-19; Chemokine CCL2; Complement System Proteins; Computational Biology; Gene Expression Profiling; Gene Expression Regulation, Viral; Genome, Human; Heart; Humans; Inflammation; Interleukin-17; Interleukin-8; MicroRNAs; Myocardium; Prognosis; Protein Interaction Mapping; SARS-CoV-2; Signal Transduction
PubMed: 35037831
DOI: 10.1080/21655979.2021.2014621 -
Frontiers in Microbiomes 2022Organophosphate nerve agents (OPNAs) act as irreversible inhibitors of acetylcholinesterase and can lead to cholinergic crisis including salivation, lacrimation,...
Organophosphate nerve agents (OPNAs) act as irreversible inhibitors of acetylcholinesterase and can lead to cholinergic crisis including salivation, lacrimation, urination, defecation, gastrointestinal distress, respiratory distress, and seizures. Although the OPNAs have been studied in the past few decades, little is known about the impact on the gut microbiome which has become of increasing interest across fields. In this study, we challenged animals with the OPNA, diisopropylfluorophosphate (DFP, 4mg/kg, s.c.) followed immediately by 2mg/kg atropine sulfate (i.m.) and 25mg/kg 2-pralidoxime (i.m.) and 30 minutes later by 3mg/kg midazolam (i.m.). One hour after midazolam, animals were treated with a dosing regimen of saracatinib (SAR, 20mg/kg, oral), a src family kinase inhibitor, to mitigate DFP-induced neurotoxicity. We collected fecal samples 48 hours, 7 days, and 5 weeks post DFP intoxication. 16S rRNA genes (V4) were amplified to identify the bacterial composition. At 48 hours, a significant increase in the abundance of and decrease in the abundance of were observed in DFP treated animals. At 7 days there was a significant reduction in and , but a significant increase in in the DFP groups compared to controls. The taxonomic changes at 5 weeks were negligible. There was no impact of SAR administration on microbial composition. There was a significant DFP-induced reduction in alpha diversity at 48 hours but not at 7 days and 5 weeks. There appeared to be an impact of DFP on beta diversity at 48 hours and 7 days but not at 5 weeks. In conclusion, acute doses of DFP lead to short-term gut dysbiosis and SAR had no effect. Understanding the role of gut dysbiosis in long-term toxicity may reveal therapeutic targets.
PubMed: 37304619
DOI: 10.3389/frmbi.2022.1006078 -
Biomedicine & Pharmacotherapy =... Feb 2022Age-related meibomian gland dysfunction (MGD) is the main cause of evaporative dry eye disease in an aging population. Decreased meibocyte cell renewal and lipid...
Age-related meibomian gland dysfunction (MGD) is the main cause of evaporative dry eye disease in an aging population. Decreased meibocyte cell renewal and lipid synthesis are associated with age-related MGD. Here, we found an obvious decline of Ki67, ΔNp63, and Na/K ATPase expression in aged meibomian glands. Potential Na/K ATPase agonist periplocin, a naturally occurring compound extracted from the traditional herbal medicine cortex periplocae, could promote the proliferation and stem cell activity of meibocyte cells in vitro. Moreover, we observed that periplocin treatment effectively increased the expression of Na+ /K+ ATPase, accompanied with the enhanced expression of Ki67 and ΔNp63 in aged meibomian glands, indicating that periplocin may accelerate meibocyte cell renewal in aged mice. LipidTox staining showed increased lipid accumulation after periplocin treatment in cultured meibomian gland cells and aged meibomian glands. Furthermore, we demonstrated that the SRC pathway was inhibited in aged meibomian glands; however, it was activated by periplocin. Accordingly, the inhibition of the SRC signaling pathway by saracatinib blocked periplocin-induced proliferation and lipid accumulation in meibomian gland cells. In sum, we suggest periplocin-ameliorated meibocyte cell renewal and lipid synthesis in aged meibomian glands via the SRC pathway, which could be a promising candidate for age-related MGD.
Topics: Aging; Animals; Cell Proliferation; Cells, Cultured; Epithelial Cells; Ki-67 Antigen; Male; Meibomian Gland Dysfunction; Meibomian Glands; Mice, Inbred C57BL; Saponins; Signal Transduction; Sodium-Potassium-Exchanging ATPase; Up-Regulation; src-Family Kinases; Mice
PubMed: 34883449
DOI: 10.1016/j.biopha.2021.112487 -
The Journal of Headache and Pain Dec 2021Purinergic P2X7 receptor plays an important role in migraine pathophysiology. Yet precise molecular mechanism underlying P2X7R signaling in migraine remains unclear....
BACKGROUND
Purinergic P2X7 receptor plays an important role in migraine pathophysiology. Yet precise molecular mechanism underlying P2X7R signaling in migraine remains unclear. This study explores the hypothesis that P2X7 receptor transmits signaling to Src family kinases (SFKs) during cortical spreading depression (CSD) and neuroinflammation after CSD.
METHODS
CSD was recorded using electrophysiology in rats and intrinsic optical imaging in mouse brain slices. Cortical IL-1β and TNFα mRNA levels were detected using qPCR. Glutamate release from mouse brain slices was detected using glutamate assay.
RESULTS
The data showed that deactivation of SFKs by systemic injection of PP2 reduced cortical susceptibility to CSD in rats and CSD-induced IL-1β and TNF-α gene expression in rat ipsilateral cortices. Consistently, in mouse brain slices, inhibition of SFKs activity by saracatinib and P2X7 receptor by A740003 similarly reduced cortical susceptibility to CSD. When the interaction of P2X7 receptor and SFKs was disrupted by TAT-P2X7, a marked reduction of cortical susceptibility to CSD, IL-1β gene expression and glutamate release after CSD induction were observed in mouse brain slices. The reduced cortical susceptibility to CSD by TAT-P2X7 was restored by NMDA, and disrupting the Fyn-NMDA interaction using TAT-Fyn (39-57) but not disrupting Src-NMDA receptor interaction using TAT-Src (40-49) reduced cortical susceptibility to CSD. Furthermore, activation of P2X7 receptor by BzATP restored the TAT-Fyn (39-57)-reduced cortical susceptibility to CSD.
CONCLUSION
This study reveals that SFKs activity transmits P2X7 receptor signaling to facilitate CSD propagation via glutamatergic pathway and promote neuroinflammation, which is of particular relevance to migraine.
Topics: Animals; Cortical Spreading Depression; Mice; Neuroinflammatory Diseases; Rats; Receptors, Purinergic P2X7; Signal Transduction; src-Family Kinases
PubMed: 34863113
DOI: 10.1186/s10194-021-01359-8