Blut-Hirn-Schranke und Placentar-Schranke für H-Thymidin und H-Cytidin bei der Maus / Blood-Brain-Barrier and Placental-Barrier for H-Thymidine and H-Cytidine in the Mouse

1972 ◽  
Vol 27 (5) ◽  
pp. 554-558b ◽  
Author(s):  
B. Schultze ◽  
N. Hörning ◽  
W. Maurer
Keyword(s):  
Blood Brain Barrier ◽  
Intravenous Injection ◽  
Brain Barrier ◽  
Whole Body ◽  
Placental Barrier ◽  
Whole Body Autoradiography ◽  
Blood Brain ◽  
Pregnant Mice ◽  
Distribution In The Organism

The distribution in the organism of the mouse of free 3H-thymidine and 3H-cytidine was studied 1, 2½, 5 and 15 minutes after intravenous injection into normal and pregnant mice (20th day) using whole body autoradiography. The grain density measured over brain and fetus is 10 times smaller as compared to other tissues of the organism. This means that a blood brain barrier and placental barrier for thymidine and cytidine exists.

Blood-brain barrier penetration of [14C]darolutamide compared with [14C]enzalutamide in rats using whole body autoradiography.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 345-345 ◽  
Author(s):  
Christian Zurth ◽  
Steffen Sandmann ◽  
Dagmar Trummel ◽  
Dietrich Seidel ◽  
Hille Gieschen
Keyword(s):  
Blood Brain Barrier ◽  
Early Time ◽  
The Body ◽  
Brain Barrier ◽  
Male Rats ◽  
Whole Body ◽  
Post Dose ◽  
Whole Body Autoradiography ◽  
Blood Brain

345 Background: Darolutamide (ODM-201) (Daro) is an investigational oral and high-affinity androgen receptor antagonist. In preclinical studies, penetration of Daro through the blood–brain barrier (BBB) is negligible and in a retrospective safety analysis of the ARADES database for CNS-related adverse events (AEs), only 1 report of urinary incontinence was linked to Daro (Fizazi K, et al. 2015). Various clinical trials on enzalutamide (Enza) have reported CNS AEs (eg, seizure, falls, fatigue, pain). To understand the differences in CNS outcomes, we report an in vivo tissue distribution study with [14C]-labelled Enza and Daro in a head-to-head study in rats by means of quantitative whole-body autoradiography (QWBA). Methods: Male rats were orally dosed with 10 mg/kg [14C]Daro or [14C]Enza in the same formulation, administration volume, and radioactive dose. The animals were sacrificed at each drug’s specific tmax (time to reach the maximum concentration) in blood and brain and processed for QWBA. Results: At early time points [14C]Daro- and [14C]Enza-derived radioactivity was rapidly absorbed from the gastrointestinal tract and homogenously distributed throughout the body. By 8 h post dose, [14C]Daro was significantly eliminated from almost all organs/tissues, whereas [14C]Enza remained constant within the body. In contrast to [14C]Daro, high and persistent radioactivity was observed in brain for [14C]Enza. At tmax, the brain/blood-ratio of [14C]Enza was ~0.765, while [14C]Daro was about 10-fold lower at ~0.074. Conclusions: Results show that post dose, there was a 10-fold lower BBB penetration of [14C]Daro compared with [14C]Enza. At 8 h, [14C]Daro was rapidly eliminated and almost undetectable in all tissues, including brain, in contrast to [14C]Enza that remained constant. These data suggest that Daro might have a lower risk of inducing CNS-related AEs than Enza. Further clinical studies are ongoing.

Higher blood–brain barrier penetration of [14C]apalutamide and [14C]enzalutamide compared to [14C]darolutamide in rats using whole-body autoradiography.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 156-156 ◽  
Author(s):  
Christian Zurth ◽  
Steffen Sandman ◽  
Dagmar Trummel ◽  
Dietrich Seidel ◽  
Reinhard Nubbemeyer ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
The Body ◽  
Brain Barrier ◽  
Male Rats ◽  
Whole Body ◽  
Homogeneous Distribution ◽  
Distribution Data ◽  
Post Dose ◽  
Whole Body Autoradiography ◽  
Blood Brain

156 Background: Darolutamide ([14C]Daro) is an investigational oral androgen receptor antagonist, structurally distinct from enzalutamide ([14C]Enza) and apalutamide ([14C]Apa). In a retrospective analysis of the ARADES database, central nervous system (CNS)-related adverse events (AEs) were not linked with Daro (Fizazi, et al. 2015). CNS-related AEs have been observed with Enza and Apa, eg, fatigue, mental impairment, and seizure (Hussain et al, 2018; Smith et al, 2018). In preclinical studies, low blood–brain barrier (BBB) penetration of Daro was observed, suggesting low impact on the CNS. To understand the different CNS effects, we report in vivo tissue distribution data in rats with [14C]-labeled Apa compared to previously presented [14C]Enza and [14C]Daro distribution data (Zurth, ASCO GU 2018) using quantitative whole-body autoradiography (QWBA). Methods: Male rats were orally dosed with 10 mg/kg [14C]Apa under similar experimental conditions as previously reported for [14C]Daro or [14C]Enza, prior to QWBA. One animal was sacrificed at each timepoint: (tmax) 3h, 8h, and 24h post-dose. Timepoint selection was based on a single oral Apa dose pharmacokinetic study in rats. Results: Apa displayed good absorption and homogeneous distribution throughout the body early post-dose, comparable to previous observations for Enza and Daro. As observed for [14C]Enza, [14C]Apa remained constant in the body (t1/2 ~4h vs ~3h) up to 8h post-dose, whereas [14C]Daro was eliminated from all tissues (t1/2 ~1h). High concentrations of [14C]Apa persisted in the brain for up to 8h, although concentrations were ~2-fold lower than previously reported for [14C]Enza. [14C]Daro brain concentrations were near the lower limit of quantification, and ~26x and 46x lower than [14C]Apa and [14C]Enza brain concentrations, respectively. Conclusions: The current preclinical study demonstrated moderate BBB penetration for Apa, similar to the previous Enza data, whereas Daro displayed > 25-fold lower BBB penetration, suggesting that Daro may be less likely to induce CNS-related AEs, which is expected to be confirmed by data from the ARAMIS study.

Assay of Blood Brain Barrier and Placental Barrier Permeability

BIO-PROTOCOL ◽  
2013 ◽  
Vol 3 (15) ◽  
Author(s):  
Saurabh Agnihotri ◽  
Poonam Singh ◽  
Balawant Kumar ◽  
Pankaj Singh ◽  
Swatantra Jain ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Placental Barrier ◽  
Barrier Permeability ◽  
Blood Brain

scholarly journals Intravenous injection of cyclophilin A realizes the transient and reversible opening of barrier of neural vasculature through basigin in endothelial cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Narumi Nakada-Honda ◽  
Dan Cui ◽  
Satoshi Matsuda ◽  
Eiji Ikeda
Keyword(s):  
Endothelial Cells ◽  
Single Dose ◽  
Blood Brain Barrier ◽  
Intravenous Injection ◽  
Cyclophilin A ◽  
Brain Barrier ◽  
Blood Brain ◽  
Neural Tissues ◽  
Neural Diseases

AbstractNeural vasculature forms the blood–brain barrier against the delivery of systemically administered therapeutic drugs into parenchyma of neural tissues. Therefore, procedures to open the blood–brain barrier with minimal damage to tissues would lead to the great progress in therapeutic strategy for intractable neural diseases. In this study, through analyses with mouse in vitro brain microvascular endothelial cells and in vivo neural vasculature, we demonstrate that the administration of cyclophilin A (CypA), a ligand of basigin which is expressed in barrier-forming endothelial cells, realizes the artificial opening of blood–brain barrier. Monolayers of endothelial cells lost their barrier properties through the disappearance of claudin-5, an integral tight junction molecule, from cell membranes in a transient and reversible manner. Furthermore, the intravenous injection of a single dose of CypA into mice resulted in the opening of blood–brain barrier for a certain period which enabled the enhanced delivery of systemically administered doxorubicin into the parenchyma of neural tissues. These findings that the pre-injection of a single dose of CypA realizes an artificial, transient as well as reversible opening of blood–brain barrier are considered to be a great step toward the establishment of therapeutic protocols to overcome the intractability of neural diseases.

scholarly journals Safe long-term repeated disruption of the blood-brain barrier using an implantable ultrasound device: a multiparametric study in a primate model

2017 ◽  
Vol 126 (4) ◽  
pp. 1351-1361 ◽  
Author(s):  
Catherine Horodyckid ◽  
Michael Canney ◽  
Alexandre Vignot ◽  
Raphael Boisgard ◽  
Aurélie Drier ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Intravenous Injection ◽  
Cerebral Metabolism ◽  
Brain Barrier ◽  
Histopathological Analysis ◽  
Large Animal ◽  
Papio Anubis ◽  
Primate Model ◽  
Blood Brain ◽  
Bbb Opening

OBJECTIVE The main limitation to the efficacy of chemotherapy for brain tumors is the restricted access to the brain because of the limited permeability of the blood-brain barrier (BBB). Previous animal studies have shown that the application of pulsed ultrasound (US), in combination with the intravenous injection of microbubbles, can temporarily disrupt the BBB to deliver drugs that normally cannot reach brain tissue. Although many previous studies have been performed with external focused US transducers, the device described in the current work emits US energy using an unfocused transducer implanted in the skull thickness. This method avoids distortion of the US energy by the skull bone and allows for simple, repetitive, and broad disruption of the BBB without the need for MRI monitoring. The purpose of the present study was to determine if the BBB can be safely and repeatedly disrupted using such an implantable unfocused US device in a primate model. METHODS An 11.5-mm-diameter, 1-MHz, planar US device was implanted via a bur hole into the skull of 3 primates (2 Papio anubis [olive] baboons and 1 Macaca fascicularis [macaque]) for 4 months. Pulsed US sonications were applied together with the simultaneous intravenous injection of sulfur hexafluoride microbubbles (SonoVue) every 2 weeks to temporarily disrupt the BBB. In each primate, a total of 7 sonications were performed with a 23.2-msec burst length (25,000 cycles) and a 1-Hz pulse repetition frequency at acoustic pressure levels of 0.6–0.8 MPa. Potential toxicity induced by repeated BBB opening was analyzed using MRI, PET, electroencephalography (EEG), somatosensory evoked potential (SSEP) monitoring, behavioral scales, and histopathological analysis. RESULTS The T1-weighted contrast-enhanced MR images acquired after each sonication exhibited a zone of hypersignal underneath the transducer that persisted for more than 4 hours, indicating a broad region of BBB opening in the acoustic field of the implant. Positron emission tomography images with fluorine-18–labeled fluorodeoxyglucose (FDG) did not indicate any changes in the cerebral metabolism of glucose. Neither epileptic signs nor pathological central nerve conduction was observed on EEG and SSEP recordings, respectively. Behavior in all animals remained normal. Histological analysis showed no hemorrhagic processes, no petechia, and extravasation of only a few erythrocytes. CONCLUSIONS The studies performed confirm that an implantable, 1-MHz US device can be used to repeatedly open the BBB broadly in a large-animal model without inducing any acute, subacute, or chronic lesions.

Role of dopamine and arterial chemoreceptors in thermal tachypnea in conscious cats

1990 ◽  
Vol 69 (4) ◽  
pp. 1429-1434 ◽  
Author(s):  
M. Bonora ◽  
H. Gautier
Keyword(s):  
Heat Loss ◽  
Blood Brain Barrier ◽  
Intravenous Injection ◽  
Respiratory Frequency ◽  
Brain Barrier ◽  
Intracerebral Injection ◽  
Principal Mechanism ◽  
Warm Environment ◽  
Blood Brain ◽  
Loss Mechanisms

In mammals submitted to a warm environment, intracerebral injection of dopamine (DA) produces no change or an increase in body temperature accompanied by an increase in metabolic heat production, but its effect on heat loss mechanisms such as vasodilation and tachypnea is not clear. Because the principal mechanism of heat loss in the conscious cat is thermal tachypnea, we studied the influence of DA on thermal tachypnea in response to heat stress (ambient temperature = 33-36 degrees C) in five conscious cats. We first studied the steady-state response to a DA agonist, apomorphine, which crosses the blood-brain barrier. Intravenous injection of apomorphine greatly reduced thermal tachypnea by decreasing respiratory frequency (from 94.9 to 52.5 breaths/min) and increasing tidal volume (from 13.2 to 20.4 ml). The subsequent injection of the DA antagonist haloperidol, which also crosses the blood-brain barrier, restored the initial tachypnea. To further investigate the mechanism involved in thermal tachypnea, we studied the influence of peripheral chemoreceptors by transiently stimulating or inhibiting carotid body (CB) activity during tachypneic breathing. CB stimulation by intravenous injection of NaCN or domperidone reduced thermal tachypnea mainly by decreasing the respiratory frequency, whereas CB inhibition by DA tended to increase frequency and thus tachypnea. It is concluded that 1) in a warm environment, central DA receptors are also greatly involved in heat loss mechanisms, 2) arterial chemoreceptor input appears to counteract this tachypneic breathing, and 3) thermal and hypoxic tachypnea may be controlled by the same mechanism in which a DA-like system has a key role.

Effects of peripheral CCK receptor blockade on gastric emptying in rats

2003 ◽  
Vol 284 (1) ◽  
pp. R66-R75 ◽  
Author(s):  
Roger D. Reidelberger ◽  
Linda Kelsey ◽  
Dean Heimann ◽  
Martin Hulce
Keyword(s):  
Gastric Emptying ◽  
Blood Brain Barrier ◽  
Intravenous Injection ◽  
Intravenous Infusion ◽  
Brain Barrier ◽  
Receptor Blockade ◽  
Induced Responses ◽  
Barrier Permeability ◽  
Blood Brain ◽  
Brain Barrier Permeability

Type A CCK receptor (CCKAR) antagonists differing in blood-brain barrier permeability [devazepide penetrates; the dicyclohexylammonium salt of Nα-3-quinolinoyl-d-Glu- N,N-dipentylamide (A-70104) does not] were used to test the hypothesis that duodenal nutrient-induced inhibition of gastric emptying is mediated by CCKARs located peripheral to the blood-brain barrier. Rats received A-70104 (700 or 3,000 nmol · kg−1· h−1iv) or devazepide (2.5 μmol/kg iv) and either a 15-min intravenous infusion of CCK-8 (3 nmol · kg−1· h−1) or duodenal infusion of casein, peptone, Intralipid, or maltose. Gastric emptying of saline was measured during the last 5 min of each infusion. A-70104 and devazepide abolished the gastric emptying response to a maximal inhibitory dose of CCK-8. Each of the macronutrients inhibited gastric emptying. A-70104 and devazepide attenuated inhibitory responses to each macronutrient. Intravenous injection of a CCK antibody to immunoneutralize circulating CCK had no effect on peptone or Intralipid-induced responses. Thus endogenous CCK appears to act in part by a paracrine or neurocrine mechanism at CCKARs peripheral to the blood-brain barrier to inhibit gastric emptying.

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