Perispinal Delivery of CNS Drugs

Abstract

Perispinal injection is a novel emerging method of drug delivery to the central nervous system (CNS). Physiological barriers prevent macromolecules from efficiently penetrating into the CNS after systemic administration. Perispinal injection is designed to use the cerebrospinal venous system (CSVS) to enhance delivery of drugs to the CNS. It delivers a substance into the anatomic area posterior to the ligamentum flavum, an anatomic region drained by the external vertebral venous plexus (EVVP), a division of the CSVS. Blood within the EVVP communicates with the deeper venous plexuses of the CSVS. The anatomical basis for this method originates in the detailed studies of the CSVS published in 1819 by the French anatomist Gilbert Breschet. By the turn of the century, Breschet’s findings were nearly forgotten, until rediscovered by American anatomist Oscar Batson in 1940. Batson confirmed the unique, linear, bidirectional and retrograde flow of blood between the spinal and cerebral divisions of the CSVS, made possible by the absence of venous valves. Recently, additional supporting evidence was discovered in the publications of American neurologist Corning. Analysis suggests that Corning’s famous first use of cocaine for spinal anesthesia in 1885 was in fact based on Breschet’s anatomical findings, and accomplished by perispinal injection. The therapeutic potential of perispinal injection for CNS disorders is highlighted by the rapid neurological improvement in patients with otherwise intractable neuroinflammatory disorders that may ensue following perispinal etanercept administration. Perispinal delivery merits intense investigation as a new method of enhanced delivery of macromolecules to the CNS and related structures.Electronic supplementary materialThe online version of this article (doi:10.1007/s40263-016-0339-2) contains supplementary material, which is available to authorized users.

Randomized controlled trial validating the use of perispinal etanercept to reduce post-stroke disability has wide-ranging implications

“…Etanercept acts through potently and specifically neutralizing TNF. Edward Tobinick, whose extensive collection of published observational studies over a decade this trial formally tests, published an extended review on perispinal etanercept delivery to the brain in Expert Review of Neurotherapeutics in 2010 [2] and an update elsewhere six years later [3]. Parenthetically, it should be noted that the term perispinal had sometimes been used in the 1970s as a regional anatomical term [4], which is quite different to its precise usage here [3].…”

“…Edward Tobinick, whose extensive collection of published observational studies over a decade this trial formally tests, published an extended review on perispinal etanercept delivery to the brain in Expert Review of Neurotherapeutics in 2010 [2] and an update elsewhere six years later [3]. Parenthetically, it should be noted that the term perispinal had sometimes been used in the 1970s as a regional anatomical term [4], which is quite different to its precise usage here [3]. With much attention being drawn to this cytokine's roles in chronic degenerative disease in the central nervous system, as well as its central involvement in disease pathogenesis generally (see [5,6] and [7] for reviews), any excess generation of it is an obvious therapeutic target.…”

Therapeutic Antibody‐Based Drugs in the Treatment of Human Inflammatory Disorders

“…Despite the growing body of evidence implicating TNF in neuroinflammation, there is still debate about the effectiveness and strategy of neutralising TNF in neurodegenerative disorders. One of the reasons for this likely surrounds the difficulties in delivering the TNFneutralising mAb-based reagents to the brain, although it appears that this can be successfully achieved by peri-spinal administration [150]. Moreover, the recent discovery of the brain lymphatics [151] provides an avenue for drug removal away from brain tissue.…”

Non-Viral Nucleic Acid Delivery Strategies to the Central Nervous System

“…For example, lateral intraventricular injections allow for close proximity to the subventricular zone, a region of the brain containing neural progenitor cells, and may be an appropriate injection site for neurogenesis applications. In addition, there are excellent access points that are used routinely in the clinic including a lumbar puncture or intraventricular cannulas (Belverud et al, 2008; Tobinick, 2016). Substances directly injected into the CSF circumvent the BBB and distribute in the brain depending on size and charge.…”

“…Each of these compartments represent a potential entry point as well as unique challenges for neuronal targeting. Vehicles for systemic delivery must utilize a mechanism that will facilitate penetration and uptake across the BBB or BSCB (Spencer and Verma, 2007; Tobinick, 2016). Within the brain, paracellular flow of neuro-active cytokines is controlled by pulsation of the blood vessels that mechanically drives a peristaltic movement of extracellular fluid (Johanson et al, 2011; Iliff et al, 2013).…”