On  Tuesday, 10 November 1998 3:03  you wrote
Subject: "CONE SNAIL"
 
>Did anyone see CBS 'Eye on America' last night?  There was a segment about
>chronic pain and a new treatment using the venom of a "sea cone snail".
There
>was a brief view - looked like a Textile Cone.  Anyone know more?
Interesting
>that we are turning to nature for 'new' medicine.  Another reason to
preserve?
 
Dear Ronald,
The excerpt below from Neurex homepage gives more details on the discovery
and clinical uses of ziconotide, as it is now called. This is a peptide
isolated from the venom of Conus magus (Cone of Maggi, or The Magician's
Cone) and also goes by the names SNX-111 and omega conotoxin MVIIA. It is
undergoing Stage III clinical trials for pain management and is likely to
receive FDA approval mid 1999.
 
More information is available at the Neurex homepage http://www.neurex.com
Just follow the links to "Science and Publications", "Articles", "The
Discovery and Development of SNX-111" to read about the discovery and
development of this N-type calcium channel blocker that is between 100-1000
fold more potent than morphine as an analgesic but unlike morphine is not
addictive.
http://neurex.com/publications/snx-11.html
 
Further information about this and a number of other conotoxins is available
at my Cone Shell and Conotoxins HomePage at URL
http://grimwade.biochem.unimelb.edu.au/~bgl/content.htm and at a new site I
am about to release at http://grimwade.biochem.unimelb.edu.au/cone
 
It is certainly an exciting application of molluscan peptides and one
wonders how many other useful new pharmaceuticals will be found among the
host of peptides comprising the different cone shell venoms.
 
Another two recent articles can be found at
http://206.139.182.46/website2/bio_miljanich.html  and at
http://206.139.182.46/website2/bio_olivera.html  which are summaries of the
presentations by Dr. George Miljanich of Neurex and Dr. Baldomero Olivera,
Univeristy of Utah, describing their studies with cone snail toxins given at
 a symposium on "The Value of Plants,Animals and Microbes to Human Health",
held on April 17 and 18,1998 at the American Museum of Natural History.
 
This will get you started.  Enjoy :),  Bruce Livett
 
EXCERPT FROM NEUREX HOME PAGE
http://neurex.com/clinical/ziconotide.html
 
Ziconotide
Ziconotide, formerly known as SNX-111, is a synthetic analog of one of the
chemicals found in the venom used by the Conus sea snail to immobilize its
prey. Neurex scientists discovered beneficial effects of this compound in
animals based on its ability to selectively block only one of several
classes of neuron specific calcium channels. These results have led to the
investigation of the use of ziconotide in man for two different proposed
indications: treatement of pain and prevention of neurodegeneration
following brain ischemia.
 
Analgesia
Over 20.8 million adult Americans reported experiencing pain for 101 days or
more during the preceding year.1 These numbers indicate that chronic pain is
a serious and pervasive problem not only for the affected patient but also
for the clinician and the health care system that works to resolve or
alleviate the persistent pain. Thus, the need for an effective analgesic
with an acceptable side effect profile, that could be administered
long-term, is indeed a relevant one.
 
Spinally-delivered opioids bind to a variety of opioid receptors found in
the substantia gelatinosa of the dorsal horn. The proposed mechanism of
opioid-induced analgesia is attributed to both the inhibition of release of
excitatory neurotransmitters from primary nociceptive afferents and to
suppression of signal conduction by slow hyperpolarization of projection
neurons. Neuronal voltage-sensitive calcium channels (VSCC) play a role in
this process, as they control calcium fluxes necessary for
depolarization-induced neurotransmitter release. N-type VSCCs are found in
highest density within the substantia gelatinosa. Blockade of calcium influx
via blockade of the N-type VSCC has been shown to create analgesia.
 
Ziconotide is a new type of calcium channel blocker. It specifically blocks
N-type neuron-specific, voltage-sensitive calcium channels, which are found
predominantly at presynaptic nerve terminals. This novel therapeutic agent
is the first and only N-type calcium channel blocker to enter clinical
development. Classical calcium channel blockers (such as verapamil and
diltiazem) act on L-type calcium channels, which are found primarily in
cardiac and vascular smooth muscle. Binding studies in rats have shown that
ziconotide binds to the dorsal horn of the spinal cord, the location of
primary afferent nerve inputs. Ziconotide has been shown to be effacious in
animal models of both nociceptive and neuropathic pain. The presumed
mechanism of action is the blockade of N-type calcium channels with
subsequent modulation of neurotransmitter release.
 
Analgesia Clinical Trials - Preliminary Findings
One Phase I/II study evaluating the use of ziconotide administered
intrathecally (directly into the spine) in patients with chronic pain has
been completed. The study was conducted at 6 investigative sites in the
United States. Thirty-one (31) patients with chronic malignant or
nonmalignant pain who failed conventional analgesic regimens were enrolled.
During a 7-day in-hospital period patients were titrated through intrathecal
doses ranging from 0.3 to 300 ng/kg/hr and administered via external fusion
pumps. In deciding wether to change the patient's dose, the investigator
assessed the patient's satisfaction or dissatisfaction with his/her pain
relief, pain scores, and the presence of intolerable adverse events that
were possibly related to study drug administration. After completing the
inpatient phase of the study, the patients had the option of continuing to
receive study drug by enrolling into the long-term extension phase of the
study, with weekly assessments of pain relief and adverse events.
 
Twenty-four (24) of the 31 patients enrolled were evaluated for efficacy. Of
these 24 patients, 19 had favorable responses in terms of partial to
complete pain relief, and an additional two had changes in the quality and
nature of their pain and which were felt by the patients to be an
improvement. The maximal analgesic effect for 18 of the 24 patients was
accompanied by either no change or a decrease in continuous opioid use and
no patients experienced worsening of pain control with an increase in opioid
use. Nine patients elected to continue receiving ziconotide in the long-term
extension portion of the protocol. Ziconotide use in these patients lasted
for up to 257 days.
 
Adverse events most commonly reported in this study were mental status
changes such as confusion (thought to be due to progression of illness or
concurrent opioids, in most cases) or word finding difficulty, lateral
nystagmus, dizziness and lightheadedness, balance and gait disturbances,
nausea and headache. These adverse events tended to resolve after ziconotide
was discontinued, after the dose was decreased, or while dosing was
continued. Five patients developed meningitis (four cases of bacterial
meningitis, one of chemical meningitis) due to external pump and catheter
delivery systems. All cases of bacterial meningitis resolved with antibiotic
therapy; the chemical meningitis resolved after the catheter was removed.
 
Two large multicenter pivotal trails evaluating the use of intrathecal
ziconotide in patients with chronic pain are currently underway. One study
focuses on patients with chronic pain associated with cancer or AIDS
(malignant pain), while the other target patients with nonmalignant sources
of pain, such as phantom limb pain or diabetic neuropathy. Neurex' corporate
partner in the development of ziconotide for chronic pain is Medtronic. In
the pivotal trials currently underway, ziconotide is being delivered
intrathecally using the Medtronic SynchroMed® Implantable Programmable Drug
Administration System. This system has numerous advantages. It can be
programmed to deliver measured amounts of drug into the spine at specific
times and is set for a set duration, providing therapy over a prolonged
period of time. This reduces the need for ongoing clinical support, enabling
patients to be mobile and to continue with their daly lives.
 
http://neurex.com/clinical/ziconotide.html
 
Brain Ischemia
Oxygen deprivation to the brain can occur from head trauma, such as that
experienced in a motorcycle accident, as a result of heart surgery, or from
a stroke of heart attack. The resulting cascade of chemical events that
occurs in a brain nerve cell can cause losses in speech, visual, hearing and
motor function, or more seriously, significant disability or death. There
are currently no medications on the market to stop brain damage following
ischemia, which causes death or impairment of over 1 million people each
year in the United States.
 
Brain Ischemia Clinical Trials
Neurex' corporate partner, Warner-Lambert, is conducting a multicenter
clinical trial to evaluate the safety and efficacy of ziconotide in
preventing brain damage after head trauma. Over 750 patients are expected to
be enrolled in this study which is being conducted in the United States and
Europe. The American Brain Injury Consortium is participating in this trial.
In addition, Warner-Lambert has begun an initial feasibility study to
evaluate the usefulness of ziconotide in patients who have suffered a
stroke.