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Marine Natural Products for Human Health Care
Published in Hafiz Ansar Rasul Suleria, Megh R. Goyal, Health Benefits of Secondary Phytocompounds from Plant and Marine Sources, 2021
Ziconotide was the first analgesic drug of marine origin to obtain approval from the U.S Food and Drug Administration (USFDA) to treat the pain. The analgesic property of ziconotide is found to have role in blocking of N-type calcium channels on the primary nociceptive nerves of the spinal cord in animal studies [274]. At the end of 2004 after twenty years of research on the toxins from predatory molluscan gastropods of genus Conus, the toxin got approval for making and clinical use in the USA. After few months, its production was started in Europe under the commercial name “prialt.” Elan Pharmaceuticals launched Prialt® (Ziconotide) as a remedy for chronic pain due to its noteworthy anti-nociceptive action even in patients not responsive to morphine.
Intrathecal drug delivery
Published in Harald Breivik, William I Campbell, Michael K Nicholas, Clinical Pain Management, 2008
Common side effects from the intrathecal delivery of ziconotide are dizziness, nausea, nystagmus, gait imbalance, confusion, and urinary retention.20 They can be severe but can be limited by very careful titration of the drug.
Development of palliative medicine in the United Kingdom and Ireland
Published in Eduardo Bruera, Irene Higginson, Charles F von Gunten, Tatsuya Morita, Textbook of Palliative Medicine and Supportive Care, 2015
Because so many channels and receptors are involved in mediating acute pain, it is unlikely that single analgesic targets will significantly relieve acute pain in all patients [12,13]. channels (ASICs), TRPV-2 and TRPV-4 channels. The ASIC channels are found on unmyelinated fibers in bone marrow and trabecular bone and are in part responsible for bone pain, which frequently has an acid environment due to the accumulation of protons and lactate. Certain potassium channels (KCNK) interact with an ingredient in Szechuan peppercorns. These receptors are found in abundance on C-fibers and A-delta fibers and play a role in acute pain [3]. ily, TRPA channels, are chemoreceptors that respond to acrolein, teargas, automobile exhaust, and burning vegetation and are known to elicit acute pain [3]. lated by pathologic processes such as diabetes neuropathy. Gabapentin targets subunits of the calcium channel (alpha 2-delta-1) and reduces membrane expression of calcium channels and hence reduces neuropathic and bone pain [14,15]. Gabapentin blocks neuroplasticity, synaptogenesis and increases spinal noradrenaline levels, suggesting that the early use of gabapentin is better than starting gabapentin when pain is well established [3,16]. Ziconotide, also an N-type calcium channel blocker, relieves cancer pain when given intrathecally. nin gene related protein, bradykinin, protons, inflammatory cytokines, prostaglandins, and proteases) sensitize certain channels, namely, TRPV1, TRPA1, TRPV-2, TRPV-4, and ASIC, reducing neuron membrane potentials to depolariza- acute injury and continue independent of peripheral nerve input, resulting in maladaptive pain. Low levels of stimulus (usually nonnoxious) maintain neuropathic pain as TPRV-1 channels are upregulated and mu receptors downregulated [4,11]. Long-term potentiation leads to "wind-up" as N-methyld-aspartate (NMDA) receptors on wide dynamic range (WDR) neurons in the deeper lamina (V) of the dorsal horn are activated, producing an expanded receptive field and secondary hyperalgesia. The clinical effect of wind-up is not only secondary hyperalgesia but allodynia within the injured [4]. NMDA receptors increase intracellular calcium that in turn activates kinases (protein kinase C and calmodulin-dependent kinase II) to facilitate pain through phosphorylation of ion channels and opioid receptors. A distinct change in somatosensory processing through long-term potentiation and increased membrane excitability can also arise from loss of inhibitory GABA and glycinergic interneurons located in lamina II [17]. Neuroplasticity involving in synapses and dendrites will cause hypersensitization. Activation and proliferation of spinal cord microglia occurs in neuropathic injury and metastatic bone disease [18,19]. Activation occurs over minutes to hours with acute pain [11,17,20-22]. As a result, there are no single defining molecular mechanisms for central sensitization.
Postoperative pain: a review of emerging therapeutic options
Published in Expert Review of Neurotherapeutics, 2021
Abhishek K Gupta, Shayla Mena, Zhaosheng Jin, Tong J Gan, Sergio Bergese
Conotoxins are peptides found in predatory marine nails in the Conidae (‘cone snail’) family. Ziconotide is a synthetic ω-conotoxin peptide approved by the FDA and EMA for intrathecal delivery using a pump system. It selectively binds to N-type voltage-gated calcium channels found in the laminae of the spinal cord’s dorsal horn, blocking neurotransmission and modulation of nociception [151]. Compared to intrathecal morphine, ziconotide is not associated with hyperalgesia, hypogonadal effects, and withdrawal [152]. Side effects include dizziness, nausea, vomiting, nystagmus, confusion, urinary retention, and somnolence [153]. An analysis of three randomized, controlled trials in ziconotide monotherapy suggested benefit in reducing chronic, neuropathic pain [154]. Due to it’s high cost, narrow therapeutic window, and wide array of side effects ziconotide may be most useful in those who develop severe, chronic pain post-operatively.
How can we improve peptide drug discovery? Learning from the past
Published in Expert Opinion on Drug Discovery, 2021
Before constrained macrocycle or template-based approaches became popular, peptide leads were typically discovered by observing the pharmacological activities of endogenous peptides in humans or animals and then deploying that peptide, or a mimic, to deliver those activities in a therapeutic setting. Insulin was the first and still most prominent example of that approach. In another early approach, peptidic extracts from bacteria, plants, or animals were screened for a desired activity that could be developed into a therapeutic. The conotoxins [18] from venomous marine snails being screened for ion channel activity are an example of that approach, which led to the development of the analgesic peptide ziconotide which works by blocking calcium channels in the spinal cord, as is exenatide, a synthetic version of a peptide derived from the saliva of the Gila monster which is used for the treatment of type 2 diabetes [19]. These two examples illustrate one of the challenges of peptide drug development in that neither is orally administered. Ziconotide is delivered via a surgically implanted pump and has achieved only moderate market success whereas exenatide delivered via subcutaneous injection achieved much greater market success. Space limitations in this editorial prevent a detailed discussion of the approaches used for the extraction, isolation and purification of such natural product peptides but these are covered in recent reviews and references therein [15,18,19]. However, we do note that one of the advantages of peptides over other natural products is that the identification of peptides is nowadays greatly facilitated by the availability of transcriptomic or genomic information [20].
Neuronal calcium channels blocker, ziconotide (ɷ-conotoxin MVIIA), reverses morphine withdrawal-induced memory impairments via alteration in hippocampal NMDA receptor expression in rats
Published in Toxin Reviews, 2020
Hooman Bozorgi, Ehsan Motaghi, Melika Zamani, Reza Ghavimi
Direct transcutaneous IT administration of ziconotide (or vehicle) was performed in accordance with the procedure described by Mestre et al. in 1994. The rats were lightly anesthetized with diethyl ether and a 25-gauge needle connected to a 25-µl Hamilton syringe was inserted between L5 and L6, perpendicular to the vertebral column (Mestre et al. 1994). In animals, the correct injection was ensured by viewing of a tail-flick (Mestre et al. 1994). In the same manner in a pilot study, methylene blue was injected IT and the color stuff was detected in cerebral ventricles.