scholarly journals Status Quo and Trends of Intra-Arterial Therapy for Brain Tumors: A Bibliometric and Clinical Trials Analysis

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1885
Author(s):  
Julian S. Rechberger ◽  
Frederic Thiele ◽  
David J. Daniels
Keyword(s):  
Drug Delivery ◽  
Clinical Trials ◽  
Brain Tumors ◽  
Phase 1 ◽  
Citation Count ◽  
Tumor Therapy ◽  
The United States ◽  
Blood Brain Barrier Disruption ◽  
Current State ◽  
Brain Barrier Disruption

Intra-arterial drug delivery circumvents the first-pass effect and is believed to increase both efficacy and tolerability of primary and metastatic brain tumor therapy. The aim of this update is to report on pertinent articles and clinical trials to better understand the research landscape to date and future directions. Elsevier’s Scopus and ClinicalTrials.gov databases were reviewed in August 2021 for all possible articles and clinical trials of intra-arterial drug injection as a treatment strategy for brain tumors. Entries were screened against predefined selection criteria and various parameters were summarized. Twenty clinical trials and 271 articles satisfied all inclusion criteria. In terms of articles, 201 (74%) were primarily clinical and 70 (26%) were basic science, published in a total of 120 different journals. Median values were: publication year, 1986 (range, 1962–2021); citation count, 15 (range, 0–607); number of authors, 5 (range, 1–18). Pertaining to clinical trials, 9 (45%) were phase 1 trials, with median expected start and completion years in 2011 (range, 1998–2019) and 2022 (range, 2008–2025), respectively. Only one (5%) trial has reported results to date. Glioma was the most common tumor indication reported in both articles (68%) and trials (75%). There were 215 (79%) articles investigating chemotherapy, while 13 (65%) trials evaluated targeted therapy. Transient blood–brain barrier disruption was the commonest strategy for articles (27%) and trials (60%) to optimize intra-arterial therapy. Articles and trials predominately originated in the United States (50% and 90%, respectively). In this bibliometric and clinical trials analysis, we discuss the current state and trends of intra-arterial therapy for brain tumors. Most articles were clinical, and traditional anti-cancer agents and drug delivery strategies were commonly studied. This was reflected in clinical trials, of which only a single study had reported outcomes. We anticipate future efforts to involve novel therapeutic and procedural strategies based on recent advances in the field.

scholarly journals Clinical neurorestorative cell therapies: Developmental process, current state and future prospective

2020 ◽  
Vol 8 (2) ◽  
pp. 61-82
Author(s):  
Hongyun Huang
Keyword(s):  
Clinical Trials ◽  
Developmental Process ◽  
Phase 1 ◽  
The United States ◽  
Small Sample ◽  
Cellular Damage ◽  
Placebo Control ◽  
Double Blind ◽  
Cell Therapies ◽  
Current State

Clinical cell therapies (CTs) for neurological diseases and cellular damage have been explored for more than 2 decades. According to the United States Food and Drug Administration, there are 2 types of cell categories for therapy, namely stem cell-derived CT products and mature/functionally differentiated cell-derived CT products. However, regardless of the type of CT used, the majority of reports of clinical CTs from either small sample sizes based on single-center phase 1 or 2 unblinded trials or retrospective clinical studies showed effects on neurological improvement and the ability to either partially or temporarily thwart the deteriorating cellular processes of the neurodegenerative diseases. There have been only a few prospective, multicenter, randomized, double- blind placebo-control clinical trials of CTs so far in this developing novel area that have shown negative results, and more clinical trials are needed. This will expand our knowledge in exploring the type of cells that yield promising results and restore damaged neurological structure and functions of the central nervous system based on higher level evidence-based medical data. In this review, we briefly introduce the developmental process, current state, and future prospective for clinical neurorestorative CT.

Chemotherapy Delivery Issues in Central Nervous System Malignancy: A Reality Check

2007 ◽  
Vol 25 (16) ◽  
pp. 2295-2305 ◽  
Author(s):  
Leslie L. Muldoon ◽  
Carole Soussain ◽  
Kristoph Jahnke ◽  
Conrad Johanson ◽  
Tali Siegal ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Brain Tumor ◽  
Brain Tumors ◽  
Tumor Therapy ◽  
Reality Check ◽  
Current State ◽  
Biologic Effect ◽  
Prospective Trials ◽  
Cns Lymphomas ◽  
Alternative Delivery

PurposeThis review assesses the current state of knowledge regarding preclinical and clinical pharmacology for brain tumor chemotherapy and evaluates relevant brain tumor pharmacology studies before October 2006.ResultsChemotherapeutic regimens in brain tumor therapy have often emerged from empirical clinical studies with retrospective pharmacologic explanations, rather than prospective trials of rational chemotherapeutic approaches. Brain tumors are largely composed of CNS metastases of systemic cancers. Primary brain tumors, such as glioblastoma multiforme or primary CNS lymphomas, are less common. Few of these tumors have well-defined optimal treatment. Brain tumors are protected from systemic chemotherapy by the blood-brain barrier (BBB) and by intrinsic properties of the tumors. Pharmacologic studies of delivery of conventional chemotherapeutics and novel therapeutics showing actual tumor concentrations and biologic effect are lacking.ConclusionIn this article, we review drug delivery across the BBB, as well as blood-tumor and –cerebrospinal fluid (CSF) barriers, and mechanisms to increase drug delivery to CNS and CSF tumors. Because of the difficulty in treating CNS tumors, innovative treatments and alternative delivery techniques involving brain/cord capillaries, choroid plexus, and CSF are needed.

scholarly journals The United States’ Regulatory Environment Is Evolving to Accommodate a Coming Boom in Gene Therapy Research

2019 ◽  
Vol 24 (3) ◽  
pp. 147-152 ◽  
Author(s):  
Daniel Eisenman
Keyword(s):  
United States ◽  
Gene Therapy ◽  
Clinical Trials ◽  
The United States ◽  
Regulatory Environment ◽  
Evidence Based ◽  
Regulatory Structure ◽  
Regulatory Changes ◽  
Current State ◽  
Therapy Field

Introduction: A dramatic increase in the number of clinical trials involving gene-modified cell therapy and gene therapy is taking place. The field is on the verge of a boom, and the regulatory environment is evolving to accommodate the growth. Discussion: This commentary summarizes the current state of the field, including an overview of the growth. The United States (US) regulatory structure for gene therapy will be summarized, and the evolution of the oversight structure will be explained. Conclusion: The gene therapy field has recently produced its first FDA-approved therapeutics and has a pipeline of other investigational products in the final stages of clinical trials before they can be evaluated by the FDA as safe and effective therapeutics. As research continues to evolve, so must the oversight structure. Biosafety professionals and IBCs have always played key roles in contributing to the safe, evidence-based advancement of gene therapy research. With the recent regulatory changes and current surge in gene therapy research, the importance of those roles has increased dramatically.

Quantification and pharmacokinetics of blood-brain barrier disruption in humans

1996 ◽  
Vol 85 (6) ◽  
pp. 1056-1065 ◽  
Author(s):  
Bernhard Zünkeler ◽  
Richard E. Carson ◽  
Jeff Olson ◽  
Ronald G. Blasberg ◽  
Hetty Devroom ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Normal Brain ◽  
Content Type ◽  
Barrier Disruption ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Brain Barrier Disruption ◽  
Fine Print

✓ Hyperosmolar blood-brain barrier disruption (HBBBD), produced by infusion of mannitol into the cerebral arteries, has been used in the treatment of brain tumors to increase drug delivery to tumor and adjacent brain. However, the efficacy of HBBBD in brain tumor therapy has been controversial. The goal of this study was to measure changes in vascular permeability after HBBBD in patients with malignant brain tumors. The permeability (K1) of tumor and normal brain blood vessels was measured using rubidium-82 and positron emission tomography before and repeatedly at 8- to 15-minute intervals after HBBBD. Eighteen studies were performed in 13 patients, eight with glioblastoma multiforme and five with anaplastic astrocytoma. The HBBBD increased K1 in all patients. Baseline K1 values were 2.1 ± 1.4 and 34.1 ± 22.1 µl/minute/ml (± standard deviation) for brain and tumor, respectively. The peak absolute increases in K1 following HBBBD were 20.8 ± 11.7 and 19.7 ± 10.7 µl/minute/ml for brain and tumor, corresponding to percentage increases of approximately 1000% in brain and approximately 60% in tumor. The halftimes for return of K1 to near baseline for brain and tumor were 8.1 ± 3.8 and 4.2 ± 1.2 minutes, respectively. Simulations of the effects of HBBBD made using a very simple model with intraarterial methotrexate, which is exemplary of drugs with low permeability, indicate that 1) total exposure of the brain and tumor to methotrexate, as measured by the methotrexate concentration-time integral (or area under the curve), would increase with decreasing infusion duration and would be enhanced by 130% to 200% and by 7% to 16%, respectively, compared to intraarterial infusion of methotrexate alone; and 2) exposure time at concentrations above 1 µM, the minimal concentration required for the effects of methotrexate, would not be enhanced in tumor and would be enhanced by only 10% in brain. Hyperosmolar blood-brain barrier disruption transiently increases delivery of water-soluble compounds to normal brain and brain tumors. Most of the enhancement of exposure results from trapping the drug within the blood-brain barrier, an effect of the very transient alteration of the blood-brain barrier by HBBBD. Delivery is most effective when a drug is administered within 5 to 10 minutes after disruption. However, the increased exposure and exposure time that occur with methotrexate, the permeability of which is among the lowest of the agents currently used clinically, are limited and the disproportionate increase in brain exposure, compared to tumor exposure, may alter the therapeutic index of many drugs.

scholarly journals Obesity-induced Cognitive Impairment in Older Adults: a Microvascular Perspective

2020 ◽  
Author(s):  
Priya Balasubramanian ◽  
Tamas Kiss ◽  
Stefano Tarantini ◽  
Ádám Nyúl-Tóth ◽  
Chetan Ahire ◽  
...  
Keyword(s):  
United States ◽  
Cognitive Impairment ◽  
Molecular Mechanisms ◽  
Epidemiological Data ◽  
The Elderly ◽  
The United States ◽  
Potential Contribution ◽  
Blood Brain Barrier Disruption ◽  
Brain Barrier Disruption ◽  
Microvascular Rarefaction

Over two thirds of individuals aged 65 and older are obese or overweight in the United States. Epidemiological data show an association between the degree of adiposity and cognitive dysfunction in the elderly. In this review, the pathophysiological roles of microvascular mechanisms, including impaired endothelial function and neurovascular coupling responses, microvascular rarefaction and blood-brain barrier disruption in the genesis of cognitive impairment in geriatric obesity are considered. The potential contribution of adipose-derived factors and fundamental cellular and molecular mechanisms of senescence to exacerbated obesity-induced cerebromicrovascular impairment and cognitive decline in aging are discussed.

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