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