Ziconotide is a foreign made drug with orphan status for opium refractory pain.
The first clinical studies on ziconotide are beginning to appear. See for example, Klotz U.Int J Clin Pharmacol Ther. 2006 Oct;44(10):478-83.”Ziconotide–a novel neuron-specific calcium channel blocker for the intrathecal treatment of severe chronic pain–a short review.”–from Heidelberg.
Ziconotide, taken from a marine toxin in snails, must be injected intrathecally (into the spinal fluid) and each dose runs around 3000 dollars. However, it does appear to block the N type calcium channel, which is what is needed to get the job done to stop pain. It also has side effects; namely, dizziness, nausea, and confusion. The side effects are claimed to be minimized by starting the dose slowly and working up gradually.
What is very encouraging is that it appears to stop neuropathic pain. No specific studies on central pain are yet in the literature. If it were just a little cheaper (it is manufactured in Ireland), we would have larger patient series to have more definite information on central pain. However, it probably works. If Bill Gates or Warren Buffett gets Central Pain, this will ptobably be their drug of choice.
Perhaps the most encouraging aspect is that blocking N type Calcium channels actually works. This validates the theory behind existing data on the behavior of N type channels in causing chronic pain. When the ion channels don’t work, the sodium/calcium exchange channels won’t work and hence the action potentials in pain nerves won’t fire. If Bono shows up to demand drug companies make the stuff affordable, we may be in fat city. Other N type calcium channel blockers are being developed. Someone is going to make a lot of money if they can find an oral one that works. Newron is working on just such a drug.
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Although there are still no published clinical studies on ziconotide and central pain, we have had very limited feedback via the internet from CP subjects. This information unfortunately does not allow us to conclude that ziconotide is the magic cure. However, the Australians have found that the cone snail (Conus Regis) and others are a literal storehouse of medicines against pain, pharmacologic gold rush. There may yet appear other toxins which stop central pain. There are certainly a burgeoning number of snail species found to have neurotoxins which are effective against peripheral nerve injury pain. A very major problem is that the shells of these toxic snails are quite beautiful and a favorite with tourists and collectors. We recommend an immediate ban on catching or selling these snails, since their numbers are dwindling rapidly and the potential for medicines is literally exploding, with some snail varieties having as many as four hundred chemicals in their injectate which are active against pain. This is valuable not only for direct pain relief, but tagging the toxins as they interact in the pain chemical pathway will tell us what the pathway really is. We know parts of the chemical pain cascade, but we have not yet mastered all of it. Scientists have quit killing the snails, and have begun the rather dangerous approach of milking them. Of course, should the snail manage to harpoon them with its proboscis, the researcher might die.
November 1st, 2006 at 8:49 am #jrueus
Very interesting pathway here, in the Oct 2006 journal of neurochem on PIP(2)-TRPM8 channel interaction, implications are profound vis-a-vis the interrelation between TRP thermoreceptor ion channels and N type calcium channels, could this pathway be keeping the cell actional potential depolarized (as a gatekeeper) to pain:
Ethanol inhibits cold-menthol receptor TRPM8 by modulating its interaction with membrane phosphatidylinositol 4,5-bisphosphate.
* Benedikt J,
* Teisinger J,
* Vyklicky L,
* Vlachova V.
Department of Cellular Neurophysiology, Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
“Ethanol has opposite effects on two members of the transient receptor potential (TRP) family of ion channels: it inhibits the cold-menthol receptor TRPM8, whereas it potentiates the activity of the heat- and capsaicin-gated vanilloid receptor TRPV1. Both thermosensitive cation channels are critically regulated by the membrane lipid, phosphatidylinositol 4,5-bisphosphate (PIP(2)). The effects of this phospholipid on TRPM8 and TRPV1 are also functionally opposite: PIP(2) is necessary for the activation of TRPM8 but it constitutively inhibits TRPV1….” ethanol burns, causing “burning pain”
Taking that information and relating it to
FEBS Lett. 2006 Oct 16;580(24):5733-8. Epub 2006 Sep 22.
A single amino acid mutation attenuates rundown of voltage-gated calcium channels.
* Zhen XG, et all.
“The activity of voltage-gated calcium channels (VGCCs) decreases with time in whole-cell and inside-out patch-clamp recordings. In this study we found that substituting a single amino acid (I1520) at the intracellular end of IIIS6 in the alpha(1) subunit of P/Q-type Ca(2+) channels with histidine or aspartate greatly attenuated channel rundown in inside-out patch-clamp recordings. The homologous mutations also slowed rundown of N- and L-type Ca(2+) channels, albeit to a lesser degree. In P/Q-type channels, the attenuation of rundown is accompanied by an increased apparent affinity for phosphatidylinositol-4,5-bisphosphate, which has been shown to be critical for maintaining Ca(2+) channel activity [L. Wu, C.S. Bauer, X.-G. Zhen, C. Xie, J. Yang, Dual regulation of voltage-gated calcium channels by PtdIns(4,5)P2. Nature 419 (2002) 947-952]. Furthermore, the histidine mutation significantly stabilized the open state, making the channels easier to open, slower to close, harder to inactivate and faster to recover from inactivation”
PMID: 17010345 [PubMed - in process]
The recent eludication at Oregon State Univ’s exercise and physiology laboratory. “They found that desensitization of the NK-1 receptor pathway before body heating significantly reduced the rise in skin blood flow during subsequent heating. They also concluded that NK-1 receptor desensitization combined with the nitric-oxide inhibition caused additional reductions of blood flow” medicalnewstodayid=55359 (Substance P May Pre-empt Vasoactive Intestinal Polypeptide In Regulating Temperature)…
Equally interesting, the notion that ankyrin repeats, might serve as a mechanical spring(a superhelix of around 20 ankyrin repeats) that exists in relation to TRP channels…and could be targeted in nanopharmacy RX, one such company is attempting to target this.
Nanospring behaviour of ankyrin repeats.
* Lee G,
* Abdi K,
* Jiang Y,
* Michaely P,
* Bennett V,
* Marszalek PE.
Department of Mechanical Engineering and Materials Science and Center for Biologically Inspired Materials and Material Systems, Duke University, Durham, North Carolina 27708, USA.
PMID: 16415852 [PubMed - indexed for MEDLINE]
Brilliant stuff