ZICONOTIDE ANALOGUES : Functional studies

George Miljanich has an interesting new paper on a novel Ziconotide-like sequence from Conus textile (synthetic conotoxin TVIA, termed SNX-185) that shows greater persistence than Ziconotide (synthetic conotoxin MVIIA from Conus magus, also termed SNX-111).

This paper also includes information about SNX-194, a close structural analog of Ziconotide that can pass through the blood-brain barrier. These and other studies on structural analogues of Ziconotide (SNX-111) are timely given that Richard Penn and Judith Paice have recently published a clinical report on three patients who experienced serious adverse effects associated with intrathecal Ziconotide (see below).

Newcomb R, Abbruscato TJ, Singh T, Nadasdi L, Davis TP, Miljanich G (2000) "Bioavailability of Ziconotide in brain: influx from blood, stability, and diffusion" Peptides 21(4):491-501.
Abstract: Ziconotide is a selective peptide antagonist of the N-type calcium channel currently in clinical trials for analgesia. Ziconotide reached a maximal brain concentration of between 0.003 and 0.006% of the injected material per gram of tissue at 3-20 min after i.v. injection, and this decayed to below 0.001%/g after 2 h. The structurally distinct conopeptide SNX-185 (synthetic TVIA) was considerably more persistent in brain after i.v. administration, with 0.0035% of the injected material present at 2-4 h after i.v. injection, and 0.0015% present at 24 h. Similar results (i.e. greater persistence of SNX-185) were obtained when the peptides were perfused through in vivo dialysis probes implanted into the hippocampus. Image analysis and serial sectioning showed that diffusion of Ziconotide in the extracellular fluid around the dialysis probe was minimal, with the peptide located within 1 mm of the probe after 2 h. In vitro diffusion through cultured bovine brain microvessel endothelial cells (BBMEC) verified that a close structural analog of Ziconotide (SNX-194) passed through this blood-brain barrier (BBB) model as expected for peptides of similar physical properties (permeability coefficient of 6.5 x 10(-4) cm/g). Passage from blood to brain was also verified by in situ perfusion through the carotid artery. A statistically greater amount of radioactivity was found to cross the BBB after perfusion of radioiodinated Ziconotide compared to [(14)C]inulin. Capillary depletion experiments and HPLC analysis defined the brain location and stability. [Elan Pharmaceuticals Inc., 3760 Haven Ave. 94305, Menlo Park, CA, USA], PMID: 10822104

Richard D. Penn and Judith A. Paice (2000) "Adverse effects associated with the intrathecal administration of ziconotide". Pain 85, (1-2) 291-296.
Abstract: The omega-conopeptide, ziconotide, is an N-type calcium-channel blocker that has been shown to produce antinociception in animals using formalin and hot-plate tests. Initial reports of intrathecal administration of ziconotide in cancer and AIDS patients whose pain was unrelieved with opioids demonstrated analgesic efficacy. Although adverse effects were reported, these appeared to be easily managed through dose reduction or symptomatic treatment. This clinical report describes the experiences of three patients with serious adverse effects associated with intrathecal ziconotide.
Author Keywords: Conopeptide; N-type calcium-channel blocker; Ziconotide; Neuropathic pain; Intrathecal; Side effects