A Practical Perspective on the Evaluation of Small Molecule CNS Penetration in Drug Discovery

The separation of the brain from blood by the blood-brain barrier and the bloodcerebrospinal fluid (CSF) barrier poses unique challenges for the discovery and development of drugs targeting the central nervous system (CNS). This review will describe the role of transporters in CNS penetration and examine the relationship between unbound brain (Cu-brain) and unbound plasma (Cu-plasma) or CSF (CCSF) concentration. Published data demonstrate that the relationship between Cu-brain and Cu-plasma or CCSF can be affected by transporter status and passive permeability of a drug and CCSF may not be a reliable surrogate for CNS penetration. Indeed, CCSF usually over-estimates Cu-brain for efflux substrates and it provides no additional value over Cu-plasma as the surrogate of Cu-brain for highly permeable non-efflux substrates. A strategy described here for the evaluation of CNS penetration is to use in vitro permeability, P-glycoprotein (Pgp) and breast cancer resistance protein efflux assays and Cu-brain/Cu-plasma in preclinical species. Cu-plasma should be used as the surrogate of Cu-brain for highly permeable non-efflux substrates with no evidence of impaired distribution into the brain. When drug penetration into the brain is impaired, we recommend using (total brain concentration * unbound fraction in the brain) as Cu-brain in preclinical species or Cu-plasma/in vitro Pgp efflux ratio if Pgp is the major limiting mechanism for brain penetration.
Source: Drug Metabolism Letters - Category: Drugs & Pharmacology Source Type: research

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Purpose: Routine brain imaging in asymptomatic metastatic breast cancer (m-BC) patients is not standard of care. However, early diagnosis of brain metastases resulting in early intervention with stereotactic radiosurgery/radiotherapy could reduce the need for significant interventional procedures, such as whole-brain radiotherapy (WBRT) or extensive surgical resection, improve quality of life and delay neurological deaths. The aim of this study is to identify the clinicopathological characteristics of breast cancer patients who are at high risk of developing brain metastases and may benefit from early brain screening.
Source: Clinical Oncology - Category: Radiology Authors: Source Type: research
Conclusions: Benefits and risks for both the patient and the offspring especially in the long term regarding marijuana use should be carefully weighed for each specific case. Standardized dosing and duration of treatment need to be determined. Recommendations should be made by physicians with expert training and after careful patient evaluation for fully informed patients, whose preference should be respected. Legislations should encourage more active basic, translational, and clinical studies. PMID: 32627638 [PubMed - as supplied by publisher]
Source: Substance Use and Misuse - Category: Addiction Tags: Subst Use Misuse Source Type: research
Randomized controlled trials have failed to report any survival advantage for WBRT combined with SRS in the management of brain metastases, despite the enhanced local and distant control in comparison to each treatment alone. Literature review have revealed important role of primary histology of the tumor when dealing with brain metastases. NSCLC responds better to combined approach even when there was only single brain metastasis present while breast cancer has registered better survival with SRS alone probably due to better response of primary tumor to advancement in surgical and chemotherapeutic agents. Furthermore, mut...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
n Lo Breast cancer is the most frequent malignancy for women in which one in eight women will be diagnosed with the disease in their lifetime. Despite advances made in treating primary breast cancer, there is still no effective treatment for metastatic breast cancer. Consequently, metastatic breast cancer is responsible for 90% of breast cancer-related deaths while only accounting for approximately one third of all breast cancer cases. To help develop effective treatments for metastatic breast cancer, it is important to gain a deeper understanding of the mechanisms by which breast cancer metastasizes, particularly, tho...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
ntaro Semba HER2 is overexpressed in 25–30% of breast cancers, and approximately 30% of HER2-positive breast cancers metastasize to the brain. Although the incidence of brain metastasis in HER2-positive breast cancer is high, previous studies have been mainly based on cell lines of the triple-negative subtype, and the molecular mechanisms of brain metastasis in HER2-positive breast cancer are unclear. In the present study, we performed intracranial injection using nine HER2-positive breast cancer cell lines to evaluate their proliferative activity in brain tissue. Our results show that UACC-893 and MDA-MB-453...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
We describe the case of a 58-year-old woman with a previous history of breast cancer that developed progressive neurological decline due to a large mass located in the left lateral ventricle of the brain. Histology revealed a mesenchymal tumour with multinodular growth, variable cellularity, prominent myxoid stroma and numerous amianthoid fibres. No evidence of pseudo-capsule or lymphoid cuffing was identified. RNA sequencing disclosed EWSR1 –CREB1 gene fusion. Only 20 cases of intracranial mesenchymal tumours harbouring these translocations have been described, mostly in adolescents and young adults and with dural a...
Source: Virchows Archiv - Category: Pathology Source Type: research
Conclusions: Our data provide a strong rationale for a clinical evaluation of marizomib in primary and metastatic TNBC patients.
Source: Theranostics - Category: Molecular Biology Authors: Tags: Research Paper Source Type: research
PMID: 32631621 [PubMed - as supplied by publisher]
Source: Asian Journal of Surgery - Category: Surgery Authors: Tags: Asian J Surg Source Type: research
In conclusion, our results would provide more information for clinical decision and future studies.
Source: Journal of Cancer - Category: Cancer & Oncology Authors: Tags: Research Paper Source Type: research
AbstractThis systematic review explored the neurobiological mechanisms underlying the clinical time course of cancer-related cognitive impairment (CRCI) in breast cancer patients through the review of longitudinal neuroimaging studies. Before chemotherapy, results reported no evidence for neuropsychological, structural (gray matter) and brain perfusion changes. However, functional brain alterations were evident and revealed a frontoparietal hyperactivation during working memory tasks. Fatigue and number of days since surgery were the two suggested confounding factors. Acutely after chemotherapy, this review found no eviden...
Source: Neuropsychology Review - Category: Neuroscience Source Type: research
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