In Vivo Assay for Neuroleptic Receptor Binding in the Striatum

1987 ◽  
Vol 151 (6) ◽  
pp. 824-830 ◽  
Author(s):  
H. Cambon ◽  
J. C. Baron ◽  
J. P. Boulenger ◽  
C. Loc'h ◽  
E. Zarifian ◽  
...  
Keyword(s):  
Corpus Striatum ◽  
Specific Binding ◽  
Receptor Occupancy ◽  
Saturation Curve ◽  
Validity And Reliability ◽  
Neuroleptic Treatment ◽  
Clear Cut ◽  
Therapeutic Doses ◽  
Dose Dependent

Using PET, we investigated the potency in six patients of therapeutic doses of neuroleptic drugs for preventing specific binding of trace doses of intravenously administered 76Br labelled bromospiperone to corpus striatum in vivo. Measured receptor occupancy showed a clear-cut dose-dependent saturation curve with increasing daily oral dose of neuroleptics, indicating the validity and reliability of the method when used as an in vivo radioreceptor assay. Following drug withdrawal in eight patients, recovery to normal or supranormal receptor availability occurred in a matter of days. The results demonstrate an approach that may help resolve controversies about, and design better strategies for, neuroleptic treatment schedules.

scholarly journals The characterization of a humanized rabbit anti-TNFα monoclonal antibody

2019 ◽  
Author(s):  
Chao Wang ◽  
Xianpu Ni ◽  
Ying Liu ◽  
Zheng Jin ◽  
Huanzhang Xia
Keyword(s):  
Specific Binding ◽  
Positive Control ◽  
Negative Control ◽  
Necrosis Factor Alpha ◽  
Neutralizing Activity ◽  
Immune Mediated ◽  
Factor Alpha ◽  
Dose Dependent

Tumor necrosis factor alpha (TNFα) is now regarding as a key role in the pathogenesis of immune-mediated disease such as Rheumatoid arthritis (RA), Crohn's Disease, Psoriatic arthritis and Plaque Psoriasis. HERE we have successfully developed an anti-hTNFα monoclonal rabbit antibody(HZ3M) with high binding and neutralizing activity based on RabMAbs platform. Rabbit hybridomas, immunized subcutanrously with 0.4 mg human TNFα, were generated from the rabbit splenocytes and a total of 142 hybridoma clones with specific binding to human TNFa were obtained. The anti-TNFa RabMAbs showed better neutralizing activity and higher antigen binding affinity compared to Humira and Remicade, the elimination phase half-life 58.2h respectively. In vivo efficay studies, normal mice or human TNF-alpha transgenic mice were injected with 1.0 mg/kg Humira (positive control), HZ3M at 0.33?1.0 or 3.0 mg/kg, or solvent (negative control), showed that HZ3M is able to bind and neutralize hTNFα in transgenic and normal mice as well as normal rabbits.Clearly dose-dependent response can be determined. Compared to marketed anti-TNFa drug Humira, the efficacy of HZ3M is seems to show significant longer holding time.Our observations indicate that the HZ3M derived from RabMAb preclinical safety study, and might have a therapeutic role in RA treatment.

scholarly journals Confirmation of Fenfluramine Effect on 5-HT1B Receptor Binding of [11C]AZ10419369 using an Equilibrium Approach

2011 ◽  
Vol 32 (4) ◽  
pp. 685-695 ◽  
Author(s):  
Sjoerd J Finnema ◽  
Andrea Varrone ◽  
Tzung-Jeng Hwang ◽  
Christer Halldin ◽  
Lars Farde
Keyword(s):  
Specific Binding ◽  
Occipital Cortex ◽  
Serotonin Release ◽  
Binding Potential ◽  
Bolus Administration ◽  
Positron Emission ◽  
Equilibrium Approach ◽  
Induced Changes ◽  
Dose Dependent

Assessment of serotonin release in the living brain with positron emission tomography (PET) may have been hampered by the lack of suitable radioligands. We previously reported that fenfluramine caused a dose-dependent reduction in specific binding in monkeys using a classical displacement paradigm with bolus administration of [11C]AZ10419369. The aim of this study was to confirm our previous findings using an equilibrium approach in monkey. A total of 24 PET measurements were conducted using a bolus infusion protocol of [11C]AZ10419369 in three cynomolgus monkeys. Initial PET measurements were performed to assess suitable Kbol values. The fenfluramine effect on [11C]AZ10419369 binding was evaluated in a displacement and pretreatment paradigm. The effect of fenfluramine on [11C]AZ10419369 binding potential ( BPND) was dose-dependent in the displacement paradigm and confirmed in the pretreatment paradigm. After pretreatment administration of fenfluramine (5.0 mg/kg), the mean BPND of the occipital cortex decreased by 39%, from 1.38 ± 0.04 to 0.84 ± 0.09. This study confirms that the new 5-HT1B receptor radioligand [11C]AZ10419369 is sensitive to fenfluramine-induced changes in endogenous serotonin levels in vivo. The more advanced methodology is suitable for exploring the sensitivity limit to serotonin release as measured using [11C]AZ10419369 and PET.

Characterization by saturation studies of the in vivo binding of [3H]flunitrazepam in mouse brain

1991 ◽  
Vol 69 (2) ◽  
pp. 176-180 ◽  
Author(s):  
Peter T.-H. Wong
Keyword(s):  
Mouse Brain ◽  
Incubation Temperature ◽  
Specific Binding ◽  
Protein A ◽  
Receptor Occupancy ◽  
Acute Tolerance ◽  
Alternative Methods ◽  
In Vivo Binding

The in vivo binding of [3H]flunitrazepam ([3H]Fln) was characterized in seven regions of the mouse brain. The binding showed saturability and linear Scatchard plots. Hill coefficients were close to unity. Data fitting to a hyperbola by least squares yielded consistent Kd values for all regions studied (0.36–0.6 pmol/mg protein). Bmax values ranged from 0.14 to 0.89 pmol/mg protein, a sixfold regional variation. The order of binding is as follows: cortex > hippocampus > midbrain = thalamus/hypothalamus > striatum ≥ cerebellum > brainstem, consistent with that obtained by in vitro binding. The in vivo receptor density and affinity are apparently lower in comparison with in vitro parameters. This is consistent with the observation that the Kd increases and Bmax decreases in vitro when the incubation temperature is increased from 0 °C. Non-specific binding has been estimated by displacement of in vivo binding by unlabelled ligand in vitro as well as by pretreatment with unlabelled ligand. The two alternative methods were compared and evaluated. It is concluded that the displacement method provides more reliable estimates of the nonspecific binding. Diazepam-sensitive mice did not differ from the control mice in the in vivo [3H]Fln binding. However, mice pretreated with diazepam 1 or 2 days before have binding reduced by 70 or 30%, respectively. The reduced binding may be explained by receptor occupancy by residual oxazepam. However, the low concentration of the residual oxazepam is an unlikely cause of the phenomenon of "acute tolerance" observed in these mice.Key words: benzodiazepines, in vivo binding, characterization, diazepam-sensitive mice, acute tolerance.

In vivo occupancy of striatal and temporal cortical D2/D3 dopamine receptors by typical antipsychotic drugs

1999 ◽  
Vol 175 (3) ◽  
pp. 231-238 ◽  
Author(s):  
Valeria Bigliani ◽  
Rachel S. Mulligan ◽  
Paul D. Acton ◽  
Dimitris Visvikis ◽  
Peter J. Ell ◽  
...  
Keyword(s):  
Dopamine Receptors ◽  
Antipsychotic Drugs ◽  
Specific Binding ◽  
Temporal Cortex ◽  
Receptor Occupancy ◽  
Typical Antipsychotic ◽  
Dopamine Hypothesis ◽  
Antipsychotic Drug Treatment ◽  
The Relationship

BackgroundThe dopamine hypothesis proposes that antipsychotic drugs act primarily through limbic cortical D2/D2-like dopamine receptor blockade.AimTo evaluate this hypothesis with the D2/D3-selective SPET probe [123I]-epidepride.Method[123I]-epidepride SPETscans were performed on 12 patients with schizophrenia treated with antipsychotics and 11 age-matched healthy controls. [123I]-epidepride specific binding to D2/D3 dopamine receptors was estimated, and relative percentage D2/D3 receptor occupancy by typical antipsychotic drugs determined.ResultsMean (s.d.) daily dose was 669.12 (516.8) mg chlorpromazine equivalents. Mean percentage D2/D3 receptor occupancy was 81.6 (8.1) and 73.2 (13.9) in the temporal cortex and striatum respectively.ConclusionsTypical antipsychotic drug treatment is associated with substantial temporal cortical D2/D3 receptor occupancy. The relationship between this and efficacy is poor in patients with treatment-resistant schizophrenia.

scholarly journals Resting-state fMRI-based screening of deschloroclozapine in rhesus macaques predicts dosage-dependent behavioral effects

2021 ◽  
Author(s):  
Atsushi Fujimoto ◽  
Catherine Elorette ◽  
J Megan Fredericks ◽  
Satoka H Fujimoto ◽  
Lazar Fleysher ◽  
...  
Keyword(s):  
Functional Connectivity ◽  
Resting State ◽  
Rhesus Macaques ◽  
Reaction Times ◽  
Receptor Occupancy ◽  
Resting State Fmri ◽  
Learning Task ◽  
Affective Responses ◽  
Dose Dependent

Background: Virally-mediated chemogenetic techniques hold the promise of circuit-specific neuromodulation for human brain disorders. Their protracted development in primates and issues related to the specificity of the actuator drugs has significantly slowed their implementation. Here we took a multi-disciplinary approach to assessing the translational appropriateness of a newly identified actuator drug, deschloroclozapine (DCZ). Methods: Resting-state functional MRI (rs-fMRI) data was acquired from seven rhesus macaques (6 males and 1 female) after administration of either vehicle, 0.1 or 0.3 mg/kg DCZ, the latter of which produce 80% and near 100% chemogenetic receptor occupancy, respectively. Seed-based comparative-connectome analysis and independent component analysis assessed dose dependent neural impact. Two subsets of subjects were tested on socio-emotional tasks (N = 4), and a probabilistic learning task (N = 3), assessing DCZ's impact on unconditioned and conditioned affective responses, respectively. Results: Neither vehicle nor 0.1 mg/kg DCZ changed overall functional connectivity, affective responses, or reaction times in the learning task. 0.3 mg/kg DCZ increased functional connectivity, particularly in frontal regions, and increased reaction times in the learning task. Notably, there was a positive correlation between changes in overall functional connectivity and reaction time. Conclusions: These experiments show the utility of rs-fMRI for in-vivo drug screening and benchmarking. We found that low dose DCZ does not alter brain function or affective behavior. However, higher doses of DCZ impacts frontal connectivity and is associated with deficits in task execution. Implementation of these methods will accelerate the development of chemogenetic in primates for research and therapeutic approaches.

scholarly journals Striatal and extra-striatal D2/D3 dopamine receptor occupancy by quetiapine in vivo

2000 ◽  
Vol 177 (5) ◽  
pp. 408-415 ◽  
Author(s):  
C. M. E. Stephenson ◽  
V. Bigliani ◽  
H. M. Jones ◽  
R. S. Mulligan ◽  
P. D. Acton ◽  
...  
Keyword(s):  
Single Photon ◽  
Specific Binding ◽  
Photon Emission ◽  
Temporal Cortex ◽  
Receptor Occupancy ◽  
Typical Antipsychotic ◽  
Relative Percentage ◽  
Daily Dose ◽  
Cortical Regions

BackgroundSelective action at limbic cortical dopamine D2-like receptors could mediate atypical antipsychotic efficacy with few extrapyramidal side-effects.AimsTo test the hypothesis that quetiapine has ‘limbic selective’ D2/D3 receptor occupancy in vivo.MethodThe high-affinity D2/D3 ligand [123I]-epidepride and single photon emission tomography were used to estimate D2/D3 specific binding and an index of relative percentage D2/D3 occupancy in striatal and temporal cortical regions for quetiapine-treated patients (n=6). Quetiapine-, and previously studied typical-antipsychotic- and clozapine-treated patients were compared.ResultsMean (s.d.) relative percentage D2/D3 receptor occupancy by quetiapine was 32.0% (14.6) in striatum and 60.1% (17.2) in temporal cortex (mean daily dose 450 mg: range 300–700 mg/day). Quetiapine treatment resulted in limbic selective D2/D3 blockade similar to clozapine and significantly higher than typical antipsychotics.ConclusionsPreliminary data suggest that limbic selective D2/D3 receptor blockade is important for atypical drug action.

scholarly journals Immunomodulatory Effects of Tigecycline in Balb/C Mice

2018 ◽  
Vol 68 (4) ◽  
pp. 457-469 ◽  
Author(s):  
Shada Y. Elhayek ◽  
Mohammad A. Fararjeh ◽  
Areej M. Assaf ◽  
Eman Y. Abu-Rish ◽  
Yasser Bustanji
Keyword(s):  
Splenocyte Proliferation ◽  
Cellular Infiltration ◽  
Immunomodulatory Effects ◽  
Clear Explanation ◽  
Hemagglutination Titer ◽  
Therapeutic Doses ◽  
Dose Dependent ◽  
Higher Doses

Abstract Tigecycline is a glycylcycline antibiotic approved by the FDA for the treatment of complicated infections. Despite its effectiveness, the FDA announced a warning of increasing mortality associated with its use. There is, however, no clear explanation for this side effect. Previous reports found a possible effect of tigecycline on leukocyte proliferation and proinflammatory cytokine release. We t herefore i nvestigated the effect of tigecycline on the immune components and response in Balb/c mice in vivo and in vitro. It was found that tigecycline enhanced lymphocyte proliferation and significantly increased cellular infiltration within the footpad, as based on DTH testing, but reduced the hemagglutination titer. In splenocyte cultures, tigecycline suppressed splenocyte proliferation with IC50 3-5 mmol L-1, significantly increased IL-2 secretion and reduced IL-17 secretion in a dose dependent mode. In conclusion, tigecycline is safe at therapeutic and sub-therapeutic doses, but it could still have an immunomodulatory effect at higher doses. Use of higher doses of tigecycline requires further investigation.

EEG-β/γ spectral power elevation in rat: a translatable biomarker elicited by GABAAα2/3-positive allosteric modulators at nonsedating anxiolytic doses

2015 ◽  
Vol 113 (1) ◽  
pp. 116-131 ◽  
Author(s):  
Edward P. Christian ◽  
Dean H. Snyder ◽  
Wei Song ◽  
David A. Gurley ◽  
Joanne Smolka ◽  
...  
Keyword(s):  
Spectral Power ◽  
Dose Range ◽  
Receptor Occupancy ◽  
Brain Regions ◽  
Intrinsic Activity ◽  
Conflict Model ◽  
Subtype Selective ◽  
Dose Dependent

Benzodiazepine drugs, through interaction with GABAAα1, GABAAα2,3, and GABAAα5 subunits, modulate cortical network oscillations, as reflected by a complex signature in the EEG power spectrum. Recent drug discovery efforts have developed GABAAα2,3-subunit-selective partial modulators in an effort to dissociate the side effect liabilities from the efficacy imparted by benzodiazepines. Here, we evaluated rat EEG and behavioral end points during dosing of nine chemically distinct compounds that we confirmed statistically to selectively to enhance GABAAα2,3-mediated vs. GABAAα1 or GABAAα5 currents in voltage clamped oocytes transfected with those GABAA subunits. These compounds were shown with in vivo receptor occupancy techniques to competitively displace [3H]flumazenil in multiple brain regions following peripheral administration at increasing doses. Over the same dose range, the compounds all produced dose-dependent EEG spectral power increases in the β- and and γ-bands. Finally, the dose range that increased γ-power coincided with that eliciting punished over unpunished responding in a behavioral conflict model of anxiety, indicative of anxiolysis without sedation. EEG γ-band power increases showed a significant positive correlation to in vitro GABAAα2,3 modulatory intrinsic activity across the compound set, further supporting a hypothesis that this EEG signature was linked specifically to pharmacological modulation of GABAAα2,3 signaling. These findings encourage further evaluation of this EEG signature as a noninvasive clinical translational biomarker that could ultimately facilitate development of GABAAα2,3-subtype-selective drugs for anxiety and potentially other indications.

Involvement of 5-Hydroxytryptamine in Platelet Aggregation In Vivo in Rats and Guinea Pigs

1989 ◽  
Vol 61 (03) ◽  
pp. 463-467 ◽  
Author(s):  
G M Smith
Keyword(s):  
Platelet Count ◽  
Guinea Pigs ◽  
Platelet Adhesion ◽  
Adenosine Diphosphate ◽  
Rate Of Return ◽  
Low Doses ◽  
Dose Dependent ◽  
Higher Doses ◽  
Rat Platelets

SummaryIn this study, 5-hydroxytryptamine (5-HT) caused a dose- dependent fall in the circulating platelet count suggesting that 5-HT receptors are activated in rat platelets to cause platelet adhesion and aggregation. When low doses of adenosine diphosphate (ADP) were simultaneously injected with 5-HT, there was a significant potentiation of the responses to ADR Ketanserin significantly reduced the potentiated responses. When higher doses of ADP were infused with bolus injections of 5-HT there was no potentiation and ketanserin did not reduce these responses. Ketanserin did not inhibit the collagen-induced fall in circulating platelet count, but did significantly increase the rate of return to the basal platelet count compared with control. 5-HT did not cause a fall in platelet count in guinea-pigs

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