ziconotide and Inflammation

Targeted intrathecal (IT) drug delivery systems (IDDS) are an option in algorithms for the treatment of patients with moderate to severe chronic refractory pain when more conservative options fail. This therapy is well established and supported by several publications. It has shown efficacy and is an important tool for the treatment of spasticity, and both cancer and nonmalignant pain. Recent technological advances, new therapeutic applications, reported complications, and the costs as well as maintenance required for this therapy require the need to stay up-to-date about new recommendations that may improve outcomes. This chapter reviews all technological issues regarding IDDS implantation with follow-up, and pharmacological recommendations published during recent years that provide evidence-based decision making process in the management of chronic pain and spasticity in patients.

Topics: Analgesics, Opioid; Baclofen; Bupivacaine; Catheters, Indwelling; Chronic Pain; Clonidine; Drug Delivery Systems; Humans; Inflammation; Infusion Pumps, Implantable; Injections, Spinal; Neoplasms; omega-Conotoxins; Psychiatric Status Rating Scales; Spine

Voltage-gated calcium channels (VGCCs) play a critical role in neuroinflammatory diseases, such as multiple sclerosis (MS). CTK 01512-2 is a recombinant version of the peptide Phα1β derived from the spider Phoneutria nigriventer, which inhibits N-type VGCC/TRPA1-mediated calcium influx. We investigated the effects of this molecule in the mouse model of experimental autoimmune encephalomyelitis (EAE). The effects of CTK 01512-2 were compared to those displayed by ziconotide-a selective N-type VGCC blocker clinically used for chronic pain-and fingolimod-a drug employed for MS treatment. The intrathecal (i.t.) treatment with CTK 01512-2 displayed beneficial effects, by preventing nociception, body weight loss, splenomegaly, MS-like clinical and neurological scores, impaired motor coordination, and memory deficits, with an efficacy comparable to that observed for ziconotide and fingolimod. This molecule displayed a favorable profile on EAE-induced neuroinflammatory changes, including inflammatory infiltrate, demyelination, pro-inflammatory cytokine production, glial activation, and glucose metabolism in the brain and spinal cord. The recovery of spatial memory, besides a reduction of serum leptin levels, allied to central and peripheral elevation of the anti-inflammatory cytokine IL-10, was solely modulated by CTK 01512-2, dosed intrathecally. The intravenous (i.v.) administration of CTK 01512-2 also reduced the EAE-elicited MS-like symptoms, similarly to that seen in animals that received fingolimod orally. Ziconotide lacked any significant effect when dosed by i.v. route. Our results indicate that CTK 01512-2 greatly improved the neuroinflammatory responses in a mouse model of MS, with a higher efficacy when compared to ziconotide, pointing out this molecule as a promising adjuvant for MS management.

Topics: Animals; Anti-Inflammatory Agents; Calcium Channel Blockers; Chemokines; Cognition Disorders; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Fingolimod Hydrochloride; Hyperalgesia; Inflammation; Inflammation Mediators; Injections, Spinal; Mice, Inbred C57BL; Motor Activity; Multiple Sclerosis; Myelin Sheath; Myelin-Oligodendrocyte Glycoprotein; Nociception; omega-Conotoxins; Peptide Fragments