Epidural and Intrathecal Drug Delivery in Rats and Mice for Experimental Research: Fundamental Concepts, Techniques, Precaution, and Application (original) (raw)

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Intrathecal gene transfer by adeno-associated virus for pain

Current opinion in molecular therapeutics, 2005

Chronic pain is among the most prevalent medical problems, affecting more than half of patients with advanced cancer and many with other common diseases. Current analgesics often fail to provide satisfactory symptom relief and frequently cause severe side effects. Intrathecal (IT) gene transfer is an attractive method for pain research in rodent models, because it allows targeting of a wide variety of secretable peptides and proteins to the spinal cord, an important neural center for the processing of nociceptive signals. The potential of IT gene transfer for improving opioid therapy and for validating new analgesic targets, such as cytokines involved in spinal glial activation, is discussed. The IT space has been notoriously resistant to efficient gene transfer, limiting therapeutic gene expression to less than 2 weeks with most vector systems. Recent progress with adeno-associated virus (AAV) technology allowed efficient long-term gene expression, facilitating studies reflective o...

Sustained release formulations for spinal drug delivery

Spinal drug delivery is a field of growing interest since many active drugs are more potent and safer when injected directly in intrathecal or epidural spaces. Most of the drugs injected in the spinal structures are used for the treatment of chronic diseases (pain, spasticity, cancer, etc.). Thus, many formulation strategies have been used these last twenty years in order to enhance the residence time after spinal drug delivery. This review focuses on the formulations sequestering the active drug in a vehicle with the aim of modifying its distribution and elimination and finally its duration of action. After analyzing the specificities of formulations designed for spinal drug delivery, applications referring to diffusion modifiers or depot dosage forms are then overviewed. The relation between performance and safety of these formulations and their interest in clinical practice is discussed.

High cerebrospinal fluid levels of interleukin-10 attained by AAV in dogs

Gene therapy, 2015

Intrathecal (IT) gene transfer using adeno-associated virus (AAV) may be clinically promising as a treatment for chronic pain if it can produce sufficiently high levels of a transgene product in the cerebrospinal fluid (CSF). Although this strategy was developed in rodents, no studies investigating CSF levels of an analgesic or antiallodynic protein delivered by IT AAV have been performed in large animals. Interleukin-10 (IL-10) is an antiallodynic cytokine for which target therapeutic levels have been established in rats. The present study tested IT AAV8 encoding either human IL-10 (hIL-10) or enhanced green fluorescent protein (EGFP) in a dog model of IT drug delivery. AAV8/hIL-10 at a dose of 3.5 × 10(12) genome copies induced high hIL-10 levels in the CSF, exceeding the target concentration previously found to be antiallodynic in rodents by >1000-fold. AAV8/EGFP targeted the primary sensory and motor neurons and the meninges. hIL-10, a xenogeneic protein in dogs, induced anti...

Physiology of Spinal Opioids and its relevance for Pain Management Selection

To use spinal opioids appropriately, it is necessary to understand the pharmacokinetics and clinical pharmacology of these drugs including which opioids produce selective spinal analgesia and which do not. Briefly, spinal selectivity is highest for hydrophilic opioids and lowest for lipophilic opioids. ...

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