Since ziconotide only partially decreases high-voltage activation in differentiated human neuroblastoma IMR32 cells, rat superior cervical ganglion neurons, and rat hippocampus neurons, this is because most native cells carry numerous distinct calcium channels. calcium flow. Moreover, ziconomide lessens the calcium currents that HEK cells, tsa-201 cells, and Xenopus laevis oocytes produce when the α1B subunit is expressed [1]. By lowering the release of pronociceptive neurotransmitters in the spinal cord's dorsal horn, ziconotide blocks pain signals and has antinociceptive effects [1].

In an experimental autoimmune mouse model of encephalomyelitis (EAE), IL-17 was produced in the spleen 25 days after EAE was triggered by MOG35-55 [2]. Ziconotide (it; 25-100 pmol/site; 5 μL; days 4, 10, 15, 20, and 24) similarly decreases IL-1β and IL-23 levels in the CNS.

Animal/Disease Models: Female C57BL/6 mice (18-22 g, 6-8 weeks old) injected with myelin oligodendrocyte glycoprotein [2]
Doses: 25 pmol/site, 50 pmol/site, 100 pmol /site
Route of Administration: intrathecal injection; results on days 4, 10, 15, 20 and 24: Dramatically diminished mechanical hypersensitivity in EAE animals.

Absorption, Distribution and Excretion
Ziconotide administered intrathecally over one hour in doses between 1 and 10 mcg produced calculated AUC values between 83.6-608 ng\*h/mL and Cmax between 16.4-132 ng/mL; these values are approximately dose-proportional. Given the intrathecal administration and low membrane permeability due to its size, ziconotide is expected to remain primarily in the CSF; plasma levels, where detected, remain constant up to nine months following administration.
A small fraction of intravenous ziconotide (< 1%) is recovered in urine.
In patients administered 1-10 mcg intrathecal ziconotide over one hour, the apparent volume of distribution was calculated as 155 ± 263 mL; this value is roughly equivalent to the expected CSF volume. Although intravenous administration is not indicated, intravenous administration of between 0.3-10 mcg/kg/day ziconotide resulted in an apparent volume of distribution of 30,460 ± 6366 mL.
Ziconotide CSF clearance is 0.38 ± 0.56 mL/min while plasma clearance is 270 ± 44 mL/min.
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 hr. ... The peptide was 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 hr. ... 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.
The pharmacokinetics and pharmacodynamics of ziconotide were assessed over a 48-hour period following intrathecal (i.t.) administration (1, 5, 7.5, or 10 ug) to 22 patients with chronic, nonmalignant pain. Plasma and cerebrospinal fluid samples were obtained over a 24-hour period. Analgesic efficacy was monitored using Visual Analog Scale of Pain Intensity (VASPI) and Category Pain Relief Scores (CPRS) measurements. Pharmacokinetic (PK) parameters were calculated by noncompartmental methods. Plasma ziconotide data were insufficient for pharmacokinetic calculations. In cerebrospinal fluid, the median half-life of ziconotide was 4.5 hours. The median cerebrospinal fluid clearance and volume of distribution were 0.26 mL/min and 99 mL, respectively. Cerebrospinal fluid pharmacokinetics of ziconotide were linear, based on cumulative exposure and peak cerebrospinal fluid concentrations. A dose-related analgesia was observed. ...
Intrathecal administration of ziconotide results in little systemic exposure. Following passage from the CSF into the systemic circulation, ziconotide is expected to be degraded to peptide fragments and their constituent amino acids by endopeptidases and exopeptidases present in most organs.
Ziconotide is about 50% bound to human plasma proteins. The mean cerebrospinal fluid (CSF) volume of distribution (Vd) of ziconotide following intrathecal administration approximates the estimated total CSF volume (140 mL).
For more Absorption, Distribution and Excretion (Complete) data for ZICONOTIDE (6 total), please visit the HSDB record page.

---

Metabolism / Metabolites
Ziconotide is expected to be processed by various peptidases upon entering systemic circulation; no detailed information on ziconotide metabolism has been reported.
Ziconotide is rapidly distributed and/or metabolized in spinal cerebrospinal fluid (CSF) after intrathecal administration, followed by relatively rapid mass transport of the product from the CSF into the plasma. The relative contributions of mass transport, within and outside the spinal cord, and metabolism within it, are unclear. There is certainly evidence for rapid transport into the blood and metabolism within the spinal cord is likely to have a significant role. Following entry into the blood, the compound is quickly metabolized by normal proteolytic mechanisms, eventually to its constituent amino acids; it can be assumed that these will be further metabolized or incorporated into proteins by normal processes.
Ziconotide is cleaved by endopeptidases and exopeptidases at multiple sites on the peptide. Following passage from the cerebrospinal fluid (CSF) into the systemic circulation during continuous IT administration, ziconotide is expected to be susceptible to proteolytic cleavage by various ubiquitous peptidases/proteases present in most organs (e.g., kidney, liver, lung, muscle, etc.), and thus readily degraded to peptide fragments and their individual constituent free amino acids. Human and animal CSF and blood exhibit minimal hydrolytic activity toward ziconotide in vitro. The biological activity of the various expected proteolytic degradation products of ziconotide has not been assessed.

---

Biological Half-Life
In patients administered 1-10 mcg intrathecal ziconotide over one hour, the elimination half-life was calculated as 4.6 ± 0.9 hr. Although intravenous administration is not indicated, intravenous administration of between 0.3-10 mcg/kg/day ziconotide resulted in an elimination half-life of 1.3 ± 0.3 hr.
The terminal half-life of ziconotide in cerebrospinal fluid after an intrathecal administration was around 4.6 hours (range 2.9-6.5 hours).

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of ziconotide during breastfeeding. Ziconotide is usually not detectable or barely detectable in plasma after intrathecal administration, and because it is a peptide with a molecular weight of 2639 Daltons, the amount in milk is likely to be very low. It is also likely to be partially destroyed in the infant's gastrointestinal tract and absorption by the infant is probably minimal. If ziconotide is required by the mother, it is not a reason to discontinue breastfeeding. Breastfed infants should be monitored for sedation, which may result in respiratory depression or feeding problems.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

---

Protein Binding
Ziconotide is roughly 50% bound to human plasma proteins.

---

Interactions
Ziconotide is a selective, potent and reversible blocker of neuronal N-type voltage-sensitive calcium channels (VSCCs). Morphine is an agonist of mu-opioid receptors and inhibits N-type VSCC channels via a G-protein coupling mechanism. Both agents are antinociceptive when they are administered intrathecally (spinally). The present study investigated the acute and chronic (7-day) interactions of intrathecally administered ziconotide and morphine on nociception in several animal models of pain. In the acute study, intrathecal bolus injections of morphine and ziconotide alone produced dose-dependent inhibition of formalin-induced tonic flinch responses and withdrawal responses to paw pressure. The combination of ziconotide and morphine produced an additive inhibition of formalin-induced tonic flinch responses and a significant leftward shift of the morphine dose-response curve in the paw pressure test. After chronic (7-day) intrathecal infusion, ziconotide enhanced morphine analgesia in the formalin test. In contrast, chronic intrathecal morphine infusion produced tolerance to analgesia, but did not affect ziconotide antinociception. Antinociception produced by ziconotide alone was the same as that observed when the compound was co-administered with morphine to morphine-tolerant rats. In the hot-plate and tail immersion tests, chronic intrathecal infusion of morphine lead to rapid tolerance whereas ziconotide produced sustained analgesia with no loss of potency throughout the infusion period. Although ziconotide in combination with morphine produced an apparent synergistic analgesic effects during the initial phase of continuous infusion, it did not prevent morphine tolerance to analgesia. These results demonstrate that (1) acute intrathecal administrations of ziconotide and morphine produce additive or synergistic analgesic effects; (2) chronic intrathecal morphine infusion results in tolerance to analgesia but does not produce cross-tolerance to ziconotide; (3) chronic intrathecal ziconotide administration produces neither tolerance nor cross-tolerance to morphine analgesia; (4) intrathecal ziconotide does not prevent or reverse morphine tolerance.
Used concomitantly with anticonvulsants, antidepressants, antipsychotics, anxiolytics, and sedatives in clinical studies. Potential interaction with CNS depressants (increased incidence of adverse CNS effects [e.g., dizziness, confusion, reduced levels of consciousness]). Dosage adjustment or discontinuance of ziconotide or the concomitant CNS depressant may be needed. Potential interaction with antidepressants or anticonvulsants (elevated serum creatine kinase [CK, creatine phosphokinase, CPK]).

[1]. Ziconotide: a review of its pharmacology and use in the treatment of pain. Neuropsychiatr Dis Treat. 2007 Feb;3(1):69-85.

[2]. Beneficial Effects of the Calcium Channel Blocker CTK 01512-2 in a Mouse Model of Multiple Sclerosis. Mol Neurobiol. 2018 Dec;55(12):9307-9327.

Ziconotide (also known as SNX-111) is a neurotoxic peptide derived from the cone snail Conus magus comprising 25 amino acids with three disulphide bonds. Other such peptides, collectively termed conotoxins, exist, and some have shown efficacy in binding specific subsets of calcium channels; ziconotide is used in part because it can be synthesized without loss of proper bond formation or structural elements. Ziconotide is used to manage severe chronic pain refractory to other methods, through its ability to inhibit N-type calcium channels involved in nociceptive signalling. Ziconotide was granted FDA approval on December 28, 2004 for marketing by TerSera therapeutics LLC. under the name Prialt. To date, ziconotide is the only calcium channel blocking peptide approved for use by the FDA.
Ziconotide is a synthetic, nonopiod, twenty-five amino acid polybasic peptide analogue of an omega-conotoxin derived from the marine snail Conus magus with analgesic activity. Ziconotide appears to block neuronal N-type voltage-sensitive calcium channels (NCCB), inhibiting transmission from pain-sensing primary nociceptors. This agent may exhibit significant analgesic activity in refractory pain.
See also: Ziconotide Acetate (has salt form).

---

Drug Indication
Ziconotide is indicated for the management of severe chronic pain in patients refractory to other treatments, and for whom intrathecal therapy is warranted.
Ziconotide is indicated for the treatment of severe, chronic pain in patients who require intrathecal (IT) analgesia.

---

Mechanism of Action
Nociceptive pain signalling is a complex processing pathway involving peripheral nociceptors, primary afferent nerve fibres, and downstream CNS neurons located in the spinal cord. Voltage-gated calcium channels (VGCCs) are important regulatory components of neural signalling and include the N-type (Cav2.2) heteromultimeric high-voltage type calcium channels. Chronic pain conditions, including inflammatory and neuropathic pain, often involve the aberrant upregulation of VGCC activity through various cellular mechanisms, which can lead to allodynia and hyperalgesia. Specifically, N-type channel activation in lightly myelinated Aδ- and C-fibres is known to mediate the release of neurotransmitters substance P (SP), calcitonin gene-related peptide (CGRP), and glutamate, which influence downstream neural activation and pain perception. In addition, SP and CGRP induce inflammation, potentially exacerbating pre-existing inflammatory chronic pain. Ziconotide belongs to the ω-conotoxin class of neurotoxic peptides derived from the cone snail _Conus magus_ which are capable of inhibiting N-type VGCCs. Although the exact mechanism is yet to be elucidated, it is thought that ω-conotoxins function through direct occlusion of the ion pore to prevent calcium translocation across the membrane. Additional studies involving expression of chimeric subunits and molecular modelling suggest that insertion of the ziconotide Met¹² residue into a hydrophobic pocket formed by Ile³⁰⁰, Phe³⁰², and Leu³⁰⁵ of Cav2.2 increases binding and may be associated with toxic adverse effects.
/Ziconotide/ is a N-type calcium channel blocker (NCCB). Voltage-sensitive calcium channel (VSCC) conduction plays a major role in the transmission of pain. The N-type VSCC's are found in high concentrations in the dorsal root ganglion cells responsible for the spinal processing of pain. Ziconotide selectively and reversibly binds to and blocks these channels without interacting with other ion channels or cholinergic, monoaminergic or mu and delta-opioid receptors. Ziconotide thus inhibits the spinal signalling of pain.

---

Therapeutic Uses
Ziconotide is used intrathecally for the management of severe chronic pain in patients who are intolerant of or do not obtain adequate pain relief from other therapies (e.g., systemic analgesics, adjunctive therapies, intrathecal morphine therapy) when intrathecal therapy is warranted.

---

Drug Warnings
/BOXED WARNING/ WARNING: NEUROPSYCHIATRIC ADVERSE REACTIONS. Prialt is contraindicated in patients with a preexisting history of psychosis. Severe psychiatric symptoms and neurological impairment may occur during treatment with Prialt. Monitor all patients frequently for evidence of cognitive impairment, hallucinations, or changes in mood or consciousness. Discontinue Prialt therapy in the event of serious neurological or psychiatric signs or symptoms.
Meningitis has occurred in patients receiving ziconotide, principally in individuals receiving therapy via an external microinfusion device and catheter. Meningitis may occur secondary to inadvertent contamination of the microinfusion device or as a result of CSF seeding caused by hematogenous or direct spread from an infected pump pocket or catheter tract. Patients should be monitored for signs and symptoms of meningitis (e.g., fever, headache, stiff neck, altered mental status, nausea or vomiting, seizures). Preparation of ziconotide solution and filling of the drug reservoir should be performed under aseptic conditions by trained and qualified personnel. If meningitis is suspected (especially in immunocompromised patients) or is confirmed, appropriate measures (CSF culture, anti-infective therapy, removal of the microinfusion device and catheter) should be initiated.
Use of Prialt has been associated with CNS-related adverse events, including psychiatric symptoms, cognitive impairment, and decreased alertness/unresponsiveness. For the 1254 patients treated /in clinical trials/, the following cognitive adverse event rates were reported: confusion (33%), memory impairment (22%), speech disorder (14%), aphasia (12%), thinking abnormal (8%), and amnesia (1%). Cognitive impairment may appear gradually after several weeks of treatment. The PRIALT dose should be reduced or discontinued if signs or symptoms of cognitive impairment develop, but other contributing causes should also be considered. The various cognitive effects of Prialt are generally reversible within 2 weeks after drug discontinuation. The medians for time to reversal of the individual cognitive effects ranged from 3 to 15 days. The elderly (> or = 65 years of age) are at higher risk for confusion.
Cognitive impairment (e.g., confusion, memory impairment, speech disorder, aphasia, abnormal thinking, amnesia) has been reported in patients receiving ziconotide. Cognitive impairment may appear gradually over several weeks and generally is reversible following discontinuance of the drug. If cognitive impairment develops, the dose of ziconotide should be reduced or the drug discontinued; other causes that could contribute to cognitive impairment should be considered.
For more Drug Warnings (Complete) data for ZICONOTIDE (17 total), please visit the HSDB record page.

---

Pharmacodynamics
Ziconotide inhibits N-type calcium channels involved in nociceptive signalling, primarily in the dorsal horn of the spinal cord. Although binding is reversible, careful dosing is required to ensure therapeutic effects while minimizing adverse effects, and ziconotide has been described as possessing a narrow therapeutic window. Patients taking ziconontide may experience cognitive and neuropsychiatric symptoms, reduced levels of consciousness, and elevated serum creatine kinase levels. In addition, ziconotide may increase the risk of infection, including serious cases of meningitis. Patients who withdraw from opiates for ziconotide initiation are advised to taper off the dose.

C102H172N36O32S7

2639.13408

2637.098

107452-89-1

Ziconotide acetate;914454-03-8;Ziconotide TFA

16135415

Typically exists as solid at room temperature

1.6±0.1 g/cm3

1.710

-17.05

42

46

40

177

5480

22

NCCCCC1NC(=O)CNC(=O)C(CCCCN)NC(=O)C(N)CSSCC2C(NC(C(NCC(NC(C(NC3C(NC(C(NC(C(NCC(NC(C(NC(C(=O)N)CSSCC(C(N2)=O)NC(=O)C(CC(=O)O)NC(=O)C(CC2=CC=C(O)C=C2)NC(=O)C(CCSC)NC(=O)C(CC(C)C)NC(=O)C(CCCNC(=N)N)NC(=O)C(CO)NC(=O)C(CSSC3)NC(=O)C(CCCCN)NC(=O)C(C)NC(=O)CNC1=O)=O)CCCCN)=O)=O)CO)=O)CCCNC(=N)N)=O)=O)CO)=O)=O)C(O)C)=O

BPKIMPVREBSLAJ-QTBYCLKRSA-N

InChI=1S/C102H172N36O32S7/c1-50(2)34-63-91(161)127-62(26-33-171-5)90(160)129-64(35-53-22-24-54(143)25-23-53)92(162)130-65(36-78(148)149)93(163)135-72-48-175-173-45-69(80(108)150)133-86(156)58(18-8-12-29-105)121-76(146)39-117-85(155)66(41-139)131-88(158)61(21-15-32-114-102(111)112)126-96(166)70-46-176-177-47-71(97(167)132-68(43-141)95(165)125-60(87(157)128-63)20-14-31-113-101(109)110)134-89(159)59(19-9-13-30-106)123-81(151)51(3)119-74(144)37-115-83(153)56(16-6-10-27-103)120-75(145)38-116-84(154)57(17-7-11-28-104)124-82(152)55(107)44-172-174-49-73(137-98(72)168)99(169)138-79(52(4)142)100(170)118-40-77(147)122-67(42-140)94(164)136-70/h22-25,50-52,55-73,79,139-143H,6-21,26-49,103-107H2,1-5H3,(H2,108,150)(H,115,153)(H,116,154)(H,117,155)(H,118,170)(H,119,144)(H,120,145)(H,121,146)(H,122,147)(H,123,151)(H,124,152)(H,125,165)(H,126,166)(H,127,161)(H,128,157)(H,129,160)(H,130,162)(H,131,158)(H,132,167)(H,133,156)(H,134,159)(H,135,163)(H,136,164)(H,137,168)(H,138,169)(H,148,149)(H4,109,110,113)(H4,111,112,114)/t51-,52+,55-,56-,57-,58-,59-,60-,61-,62-,63-,64-,65-,66-,67-,68-,69-,70-,71-,72-,73-,79-/m0/s1

2-[(1R,4S,7S,13S,16R,21R,24S,27S,30S,33S,36S,39S,42R,45S,48S,54S,60S,63R,68R,71S,77S)-63-amino-13,45,54,60-tetrakis(4-aminobutyl)-4,36-bis(3-carbamimidamidopropyl)-16-carbamoyl-71-[(1R)-1-hydroxyethyl]-7,39,77-tris(hydroxymethyl)-27-[(4-hydroxyphenyl)methyl]-48-methyl-33-(2-methylpropyl)-30-(2-methylsulfanylethyl)-2,5,8,11,14,23,26,29,32,35,38,41,44,47,50,53,56,59,62,69,72,75,78,85-tetracosaoxo-18,19,65,66,81,82-hexathia-3,6,9,12,15,22,25,28,31,34,37,40,43,46,49,52,55,58,61,70,73,76,79,84-tetracosazatricyclo[40.37.4.221,68]pentaoctacontan-24-yl]acetic acid

Zicontide Acetate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

---

Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

View More

Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

---

Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

View More

Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

---

Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

---

 (Please use freshly prepared in vivo formulations for optimal results.)