Dopamine D-2 up-regulation in psychosis patients after antipsychotic drug treatment

Purpose of reviewRecently, it has been questioned whether the re-emergence of psychotic symptoms following antipsychotic discontinuation or dose reduction is attributable to underlying psychotic vulnerability or to rebound effects of chronic use of antipsychotic medication. It was repeatedly shown that relapse rates are high after discontinuation of maintenance treatment. A potential contributing factor could be the increase in density of postsynaptic dopamine D2 receptors in the striatum and the higher affinity of D2 receptors for dopamine after chronic blockade.Recent findingsTo date, little clinical evidence is available for the mechanisms involved in postsynaptic striatal D2 receptor up-regulation after use of antipsychotic medication, and most knowledge comes from animal studies.SummaryFurther research is needed to investigate whether antipsychotic medication causes neuroadaptations leading to a dopamine supersensitive state in humans, how long such hypersensitive states may last and what differences exist between high and low D2 affinity antipsychotic drugs. Further, information is needed on discontinuation schedules that provide optimal protection for relapse during hypersensitive periods

Is cyclooxygenase-1 involved in neuroinflammation?

Purpose: Reactive microglia are an important hallmark of neuroinflammation. Reactive microglia release various inflammatory mediators, such as cytokines, chemokines, and prostaglandins, which are produced by enzymes like cyclooxygenases (COX). The inducible COX‐2 subtype has been associated with inflammation, whereas the constitutively expressed COX‐1 subtype is generally considered as a housekeeping enzyme. However, recent evidence suggests that COX‐1 can also be upregulated and may play a prominent role in the brain during neuroinflammation. In this review, we summarize the evidence that supports this involvement of COX‐1. Methods: Five databases were used to retrieve relevant studies that addressed COX‐1 in the context of neuroinflammation. The search resulted in 32 articles, describing in vitro, in vivo, post mortem, and in vivo imaging studies that specifically investigated the COX‐1 isoform under such conditions. Results: Reviewed literature generally indicated that the overexpression of COX‐1 was induced by an inflammatory stimulus, which resulted in an increased production of prostaglandin E2. The pharmacological inhibition of COX‐1 was shown to suppress the induction of inflammatory mediators like prostaglandin E2. Positron emission tomography (PET) imaging studies in animal models confirmed the overexpression of COX‐1 during neuroinflammation. The same imaging method, however, could not detect any upregulation of COX‐1 in patients with Alzheimer's disease. Conclusion: Taken together, studies in cultured cells and living rodents suggest that COX‐1 is involved in neuroinflammation. Most postmortem studies on human brains indicate that the concentration of COX‐1‐expressing microglial cells is increased near sites of inflammation. However, evidence for the involvement of COX‐1 in neuroinflammation in the living human brain is still largely lacking

The dual hit hypothesis of schizophrenia:evidence from animal models

Schizophrenia is a heterogeneous psychiatric disorder, which can severely impact social and professional functioning. Epidemiological and clinical studies show that schizophrenia has a multifactorial aetiology comprising genetic and environmental risk factors. Although several risk factors have been identified, it is still not clear how they result in schizophrenia. This knowledge gap, however, can be investigated in animal studies. In this review, we summarise animal studies regarding molecular and cellular mechanisms through which genetic and environmental factors may affect brain development, ultimately causing schizophrenia. Preclinical studies suggest that early environmental risk factors can affect the immune, GABAergic, glutamatergic, or dopaminergic system and thus increase the susceptibility to another risk factor later in life. A second insult, like social isolation, stress, or drug abuse, can further disrupt these systems and the interactions between them, leading to behavioural abnormalities. Surprisingly, first insults like maternal infection and early maternal separation can also have protective effects. Single gene mutations associated with schizophrenia did not have a major impact on the susceptibility to subsequent environmental hits

Allosteric Interactions between Adenosine A2A and Dopamine D2 Receptors in Heteromeric Complexes:Biochemical and Pharmacological Characteristics, and Opportunities for PET Imaging

Adenosine and dopamine interact antagonistically in living mammals. These interactions are mediated via adenosine A2A and dopamine D2 receptors (R). Stimulation of A2AR inhibits and blockade of A2AR enhances D2R-mediated locomotor activation and goal-directed behavior in rodents. In striatal membrane preparations, adenosine decreases both the affinity and the signal transduction of D2R via its interaction with A2AR. Reciprocal A2AR/D2R interactions occur mainly in striatopallidal GABAergic medium spiny neurons (MSNs) of the indirect pathway that are involved in motor control, and in striatal astrocytes. In the nucleus accumbens, they also take place in MSNs involved in reward-related behavior. A2AR and D2R co-aggregate, co-internalize, and co-desensitize. They are at very close distance in biomembranes and form heteromers. Antagonistic interactions between adenosine and dopamine are (at least partially) caused by allosteric receptor–receptor interactions within A2AR/D2R heteromeric complexes. Such interactions may be exploited in novel strategies for the treatment of Parkinson’s disease, schizophrenia, substance abuse, and perhaps also attention deficit-hyperactivity disorder. Little is known about shifting A2AR/D2R heteromer/homodimer equilibria in the brain. Positron emission tomography with suitable ligands may provide in vivo information about receptor crosstalk in the living organism. Some experimental approaches, and strategies for the design of novel imaging agents (e.g., heterobivalent ligands) are proposed in this review

Traumatic lingual ulceration in a newborn: Riga-Fede disease

Riga Fede disease is a reactive mucosal disease as a result of repetitive trauma of the tongue by the anterior primary teeth during forward and backward movement. Although the aspect of the lesion might be impressive, its nature is relatively benign. The history and clinical features are most often so typical that there is seldom a need for addititonal histopathological examination. Riga Fede disease can most often be treated with conservative measures only. Beside the presentation of a six-month-old boy with Riga Fede disease, the literature has been reviewed as well. From this review it can be concluded that Riga Fede disease is almost exclusively restricted to the tongue, occurs soon after birth when associated with (neo)natal teeth, has a male predilection, and is in one quarter of the cases associated with neurologic disorders. In the later case, Riga Fede disease develops after the age of 6 months

Pharmacokinetic and Pharmacodynamic Studies of Elacestrant, A Novel Oral Selective Estrogen Receptor Degrader, in Healthy Post-Menopausal Women

BACKGROUND AND OBJECTIVES: Advanced estrogen receptor-positive (ER+) breast cancer is currently treated with endocrine therapy. Elacestrant is a novel, nonsteroidal, selective estrogen receptor degrader with complex dose-related ER agonist/antagonist activity that is being developed as a treatment option for ER+ breast cancer. METHODS: Two first-in-human phase 1 studies of elacestrant in healthy postmenopausal women (Study 001/Study 004) were conducted to determine its pharmacokinetic and pharmacodynamic profile as well as its safety and maximum tolerated dose. RESULTS: In total, 140 postmenopausal subjects received at least one dose of study drug (114 received elacestrant and 26 received placebo). Single-ascending dose and multiple-ascending dose assessments showed that doses up to 1000 mg daily were safe and well tolerated, and the maximum tolerated dose was not reached. Oral administration of elacestrant had an absolute bioavailability of 10% and a mean half-life ranging from 27 to 47 h, reaching steady state after 5-6 days. Mean occupancy of the ER in the uterus after seven daily doses was 83% for 200 mg and 92% for 500 mg daily. The median ratio of elacestrant concentrations in the cerebral spinal fluid vs. plasma was 0.126% (500 mg dose) and 0.205% (200 mg dose). Most adverse events were related to the upper gastrointestinal tract. CONCLUSIONS: These data demonstrate that elacestrant has good bioavailability when administered orally with a half-life that supports once-daily administration. Engagement of the ER and some ability to cross the blood-brain barrier was demonstrated in addition to an acceptable safety profile

Correction to:Pharmacokinetic and Pharmacodynamic Studies of Elacestrant, A Novel Oral Selective Estrogen Receptor Degrader, in Healthy Post-Menopausal Women (European Journal of Drug Metabolism and Pharmacokinetics, (2020), 45, 5, (675-689), 10.1007/s13318-020-00635-3)

Authors would like to correct the errors in table 2

Positron emission tomography of tumour [18F]fluoroestradiol uptake in patients with acquired hormone-resistant metastatic breast cancer prior to oestradiol therapy

Purpose Whereas anti-oestrogen therapy is widely applied to treat oestrogen receptor (ER) positive breast cancer, paradoxically, oestrogens can also induce tumour regression. Upregulation of ER expression is a marker for oestrogen hypersensitivity. We, therefore, performed an exploratory study to evaluate positron emission tomography (PET) with the tracer 16 alpha-[F-18] fluoro-17 beta-oestradiol (F-18-FES) as potential marker to select breast cancer patients for oestradiol therapy. Methods Eligible patients had acquired endocrine-resistant metastatic breast cancer that progressed after >= 2 lines of endocrine therapy. All patients had prior ER-positive histology. Treatment consisted of oestradiol 2 mg, three times daily, orally. Patients underwent F-18-FES-PET/CT imaging at baseline. Tumour F-18-FES-uptake was quantified for a maximum of 20 lesions and expressed as maximum standardised uptake value (SUVmax). CT-scan was repeated every 3 months to evaluate treatment response. Clinical benefit was defined as time to radiologic or clinical progression >= 24 weeks. Results F-18-FES uptake, quantified for 255 lesions in 19 patients, varied greatly between lesions (median 2.8; range 0.6-24.3) and between patients (median 2.5; range 1.1-15.5). Seven (37 %) patients experienced clinical benefit of oestrogen therapy, eight progressed (PD), and four were non-evaluable due to side effects. The positive and negative predictive value PPV/NPV) of F-18-FES-PET for response to treatment were 60 % (95 % CI: 31-83 %) and 80 % (95 % CI: 38-96 %), respectively, using SUVmax >1.5. Conclusion F-18-FES-PET may aid identification of patients with acquired antihormone resistant breast cancer that are unlikely to benefit from oestradiol therapy

Molecular Imaging of PD-L1 Expression and Dynamics with the Adnectin-Based PET Tracer F-18-BMS-986192

F-18-BMS-986192, an adnectin-based human programmed cell death ligand 1 (PD-L1) tracer, was developed to noninvasively determine whole-body PD-L1 expression by PET. We evaluated the usability of F-18-BMS-986192 PET to detect different PD-L1 expression levels and therapy-induced changes in PD-L1 expression in tumors. Methods: In vitro binding assays with F-18-BMS-986192 were performed on human tumor cell lines with different total cellular and membrane PD-L1 protein expression levels. Subsequently, PET imaging was performed on immunodeficient mice xenografted with these cell lines. The mice were treated with interferon gamma (IFN gamma) intraperitoneally for 3 d or with the mitogen-activated protein kinase kinase inhibitor selumetinib by oral gavage for 24 h. Afterward, F-18-BMS-986192 was administered intravenously, followed by a 60-min dynamic PET scan. Tracer uptake was expressed as percentage injected dose per gram of tissue. Tissues were collected to evaluate ex vivo tracer biodistribution and to perform flow cytometric, Western blot, and immunohistochemical tumor analyses. Results: F-18-BMS-986192 uptake reflected PD-L1 membrane levels in tumor cell lines, and tumor tracer uptake in mice was associated with PD-L1 expression measured immunohistochemically. In vitro IFN gamma treatment increased PD-L1 expression in the tumor cell lines and caused up to a 12-fold increase in tracer binding. In vivo, IFN gamma affected neither PD-L1 tumor expression measured immunohistochemically nor F-18-BMS-986192 tumor uptake. In vitro, selumetinib downregulated cellular and membrane levels of PD-L1 in tumor cells by 50% as measured by Western blotting and flow cytometry. In mice, selumetinib lowered cellular, but not membrane, PD-L1 levels of tumors, and consequently, no treatment-induced change in F-18-BMS-986192 tumor uptake was observed. Conclusion: F-18-BMS-986192 PET imaging allows detection of membrane-expressed PD-L1 as soon as 60 min after tracer injection. The tracer can discriminate a range of tumor cell PD-L1 membrane expression levels

Uniqueness Typing for Resource Management in Message-Passing Concurrency

We view channels as the main form of resources in a message-passing programming paradigm. These channels need to be carefully managed in settings where resources are scarce. To study this problem, we extend the pi-calculus with primitives for channel allocation and deallocation and allow channels to be reused to communicate values of different types. Inevitably, the added expressiveness increases the possibilities for runtime errors. We define a substructural type system which combines uniqueness typing and affine typing to reject these ill-behaved programs