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| Clinical data | |
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| Pronunciation | /zaɪˈkɒnoʊtaɪd/ zy-KON-oh-tyd |
| Trade names | Prialt |
| Other names | SNX–111 |
| AHFS/Drugs.com | Monograph |
| License data | |
| Routes of administration | Intrathecal |
| ATC code | |
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| Pharmacokinetic data | |
| Bioavailability | 50% |
| Eliminationhalf-life | 2.9–6.5 hours |
| Excretion | <1% urine |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.212.174 |
| Chemical and physical data | |
| Formula | C102H172N36O32S7 |
| Molar mass | 2639.14 g·mol−1 |
| 3D model (JSmol) | |
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Ziconotide, sold under the brand namePrialt, also calledintrathecal ziconotide (ITZ) because of its administration route, is an atypicalanalgesic agent for the amelioration of severe andchronic pain. Derived fromConus magus, a cone snail, it is thesynthetic form of an ω-conotoxinpeptide.[2]
In December 2004 the USFood and Drug Administration (FDA) approved ziconotidewhen delivered as an infusion into thecerebrospinal fluid using anintrathecalpump system.[citation needed]
Due to the profound side effects or lack of efficacy when delivered through more common routes, such as orally or intravenously, ziconotide must be administeredintrathecally (i.e., directly into the spinal fluid). As this is the most expensive and invasive method of drug delivery and involves additional risks of its own,[3] ziconotide therapy is generally considered appropriate (as evidenced by the range of use approved by the FDA in the US) only for "management of severe chronic pain in patients for whom intrathecal (IT) therapy is warranted and who are intolerant of or refractory to other treatment, such as systemicanalgesics, adjunctive therapies or ITmorphine".[4] Research is ongoing to determine whether ziconotide can be formulated in a way that would allow it to be administered by less invasive means.[5][6]
However, this must be weighed against the high level ofpain management, both in terms of degree and length, and the apparent lack oftolerance[7] and other signs ofdependence[8] even after extended treatment along with the need for alternatives to other therapies that have not worked for the patient. Ziconotide is also contraindicated for patients with certain preexistingmental disorders (e.g.,psychosis) due to evidence that they are more susceptible to certain severe side effects.[9]
The most common side effects are dizziness,nausea, confusion,nystagmus, and headache. Others may include weakness,hypertonia,ataxia, abnormal vision,anorexia,somnolence, unsteadiness on feet,vertigo, urinary retention, pruritus, increased sweating,diarrhea,nausea, vomiting,asthenia,fever, rigors,sinusitis, muscle spasms, myalgia,insomnia,anxiety, amnesia,tremor, memory impairment, and induced psychiatric disorders. Other side effects which are less frequent but still clinically significant include auditory and visualhallucinations, thoughts of suicide, acute kidney failure,atrial fibrillation, cardiovascular accident,sepsis, new or worsening depression, paranoia, disorientation,meningitis, andseizures. Therefore, it is contraindicated in people with a history ofpsychosis,schizophrenia, clinical depression, andbipolar disorder. Recent incidents suggesting a link between intrathecal ziconotide treatment and increased risk of suicide have led to calls for strict and ongoing psychiatric monitoring of patients to avoid suicide occurring in vulnerable individuals.[10]
Ziconotide is a hydrophilic molecule that is freely soluble in water and is practically insoluble inmethyl t-butyl ether. Ziconotide acts as a selectiveN-type voltage-gated calcium channelblocker.[11][12] This action inhibits the release of pro-nociceptiveneurochemicals likeglutamate,calcitonin gene-related peptide (CGRP), andsubstance P in the brain andspinal cord, resulting in pain relief.[12]
Ziconotide is apeptide with theamino acid sequenceH-Cys-Lys-Gly-Lys-Gly-Ala-Lys-Cys-Ser-Arg-Leu-Met-Tyr-Asp-Cys-Cys-Thr-Gly-Ser-Cys-Arg-Ser-Gly-Lys-Cys-NH2 (CKGKGAKCSRLMYDCCTGSCRSGKC-NH2) and contains 3disulfide bonds (Cys1-Cys16, Cys8-Cys20, and Cys15-Cys25).
Ziconotide is derived from the toxin of thecone snail speciesConus magus. Scientists have been intrigued by the effects of the thousands of chemicals in marine snail toxins since the initial investigations in the late 1960s byBaldomero Olivera. Olivera, now a professor of biology in theUniversity of Utah, was inspired by accounts of the deadly effects of these toxins from his childhood in the Philippines. Ziconotide was discovered in the early 1980s by University of Utah research scientist Michael McIntosh,[13] when he was barely out of high school and working with Baldomero Olivera.[14]
Ziconotide was developed into an artificially manufactured drug by Elan Corporation. It was approved for sale under the name Prialt by the U.S. Food and Drug Administration on December 28, 2004, and by theEuropean Commission on February 22, 2005. Azur Pharma acquired worldwide rights (except Europe) to Prialt in 2010.[citation needed]
