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Nature Aug 2021The neuronal-type (N-type) voltage-gated calcium (Ca) channels, which are designated Ca2.2, have an important role in the release of neurotransmitters. Ziconotide is a...
The neuronal-type (N-type) voltage-gated calcium (Ca) channels, which are designated Ca2.2, have an important role in the release of neurotransmitters. Ziconotide is a Ca2.2-specific peptide pore blocker that has been clinically used for treating intractable pain. Here we present cryo-electron microscopy structures of human Ca2.2 (comprising the core α1 and the ancillary α2δ-1 and β3 subunits) in the presence or absence of ziconotide. Ziconotide is thoroughly coordinated by helices P1 and P2, which support the selectivity filter, and the extracellular loops (ECLs) in repeats II, III and IV of α1. To accommodate ziconotide, the ECL of repeat III and α2δ-1 have to tilt upward concertedly. Three of the voltage-sensing domains (VSDs) are in a depolarized state, whereas the VSD of repeat II exhibits a down conformation that is stabilized by Ca2-unique intracellular segments and a phosphatidylinositol 4,5-bisphosphate molecule. Our studies reveal the molecular basis for Ca2.2-specific pore blocking by ziconotide and establish the framework for investigating electromechanical coupling in Ca channels.
Topics: Analgesics, Non-Narcotic; Calcium Channel Blockers; Calcium Channels, N-Type; Cryoelectron Microscopy; Humans; Models, Molecular; Phosphatidylinositol 4,5-Diphosphate; Protein Conformation; Protein Stability; omega-Conotoxins
PubMed: 34234349
DOI: 10.1038/s41586-021-03699-6 -
European Review For Medical and... Feb 2023The mere glimpse of venomous animals has always terrified humans because of the devastating effects of their venoms. However, researchers across the globe have isolated... (Review)
Review
The mere glimpse of venomous animals has always terrified humans because of the devastating effects of their venoms. However, researchers across the globe have isolated therapeutically active ingredients from these venoms and continue to explore them for drug leads. These efforts lead to the discovery of therapeutic molecules that the US-FDA has approved to treat different diseases, such as hypertension (Captopril), chronic pain (Ziconotide), and diabetes (Exenatide). The main active constituents of most venoms are proteins and peptides, which gained more attention because of advancements in biotechnology and drug delivery. The utilization of newer screening approaches improved our understanding of the pharmacological complexity of venom constituents and facilitated the development of novel therapeutics. Currently, with many venom-derived peptides undergoing different phases of clinical trials, more are in pre-clinical drug development phases. This review highlights the various sources of venoms, their pharmacological actions, and the current developments in venom-based therapeutics.
Topics: United States; Animals; Humans; Venoms; Chronic Pain; Drug Delivery Systems; Hypertension; United States Food and Drug Administration
PubMed: 36876699
DOI: 10.26355/eurrev_202302_31408 -
Marine Drugs Aug 2022Sea snails of the genus produce toxins that have been the subjects of numerous studies, projects, publications, and patents over the years. Since toxins were... (Review)
Review
Sea snails of the genus produce toxins that have been the subjects of numerous studies, projects, publications, and patents over the years. Since toxins were discovered in the 1960s, their biological activity has been thought to have high pharmaceutical potential that could be explored beyond the limits of academic laboratories. We reviewed 224 patent documents related to conotoxins and conopeptides globally to determine the course that innovation and development has taken over the years, their primary applications, the technological trends over the last six years, and the leaders in the field, since the only previous patent review was performed in 2015 and focused in USA valid patents. In addition, we explored which countries/territories protect their inventions and patents and the most relevant collaborations among assignees. We also evaluated whether academia or pharmaceutical companies are the future of conotoxin research. We concluded that the 224 conotoxin patents reviewed in this study have more academic value than industrial value, which was noted by the number of active patents that have not yet been licensed and the contributions to medical research, especially as tools to study neuropathic pain, inflammation, immunology, drug design, receptor binding sites, cancer, neurotransmission, epilepsy, peptide biosynthesis, and depression. The aim of this review is to provide an overview of the current state of conotoxin patents, their main applications, and success based on the number of licensing and products in the market.
Topics: Animals; Conotoxins; Conus Snail; Humans; Industry; Pharmaceutical Preparations
PubMed: 36005534
DOI: 10.3390/md20080531 -
Brain and Behavior Mar 2021This article summarizes recommendations made by six pain specialists who discussed the rationale for ziconotide intrathecal analgesia (ITA) and the requirement for...
This article summarizes recommendations made by six pain specialists who discussed the rationale for ziconotide intrathecal analgesia (ITA) and the requirement for evidence-based guidance on its use, from a European perspective. Riemser Pharma GmbH (Greifswald, Germany), which holds the European marketing authorization for ziconotide, hosted the meeting. The group agreed that ITA is under-used in Europe, adding that ziconotide ITA has potential to be a first-line alternative to morphine; both are already first-line options in the USA. Ziconotide ITA (initiated using a low-dose, slow-titration approach) is suitable for many patients with noncancer- or cancer-related chronic refractory pain and no history of psychosis. Adopting ziconotide as first-line ITA could reduce opioid usage in these patient populations. The group advocated a risk-reduction strategy for all candidate patients, including compulsory prescreening for neuropsychosis, and requested US-European alignment of the licensed starting dose for ziconotide: the low-and-slow approach practiced in the USA has a better tolerability profile than the fixed high starting dose licensed in Europe. Of note, an update to the European Summary of Product Characteristics is anticipated in early 2021. The group acknowledged that the Polyanalgesic Consensus Conference (PACC) treatment algorithms for ziconotide ITA provide useful guidance, but recommendations tailored specifically for European settings are required. Before a consensus process can formally begin, the group called for additional European prospective studies to investigate ziconotide in low-and-slow dosing strategies, in different patient settings. Such data would enable European guidance to have the most appropriate evidence at its core.
Topics: Analgesics, Non-Narcotic; Europe; Germany; Humans; Injections, Spinal; Pain Management; Prospective Studies; omega-Conotoxins
PubMed: 33690987
DOI: 10.1002/brb3.2055 -
Pain Physician Dec 2021Numerous combination intrathecal drug therapy (CIDT) strategies exist and are utilized for varying pain syndromes, typically when monotherapy dose escalation or... (Review)
Review
BACKGROUND
Numerous combination intrathecal drug therapy (CIDT) strategies exist and are utilized for varying pain syndromes, typically when monotherapy dose escalation or medication alternation is deemed untenable or unfeasible. Unfortunately, the supportive evidence basis for the use of these strategies and specific drug combinations is generally lacking and unclear, with many medications being used for off-label indications.
OBJECTIVE
In this manuscript, we provide a robust exploration and analysis of the literature to provide an evidence-based narrative for the use of CIDT strategies in regard to clinical indications, pharmacologic parameters, specific drug combinations, safety profiles, and future directions.
STUDY DESIGN
Narrative review.
METHODS
This was an evidence based narrative performed after extensive review of the literature.
RESULTS
Variances in intrathecal pharmacokinetics and pharmacodynamics are utilized advantageously with CIDT strategies to achieve improved analgesic benefit; however, appropriate use may be limited by increased or compounded risk of adverse effects. The supportive evidence for CIDT use for chronic pain conditions is largely lacking and limited to small, uncontrolled, observational studies, with many having various confounding factors, including a lack of standardized dosing. The most evidenced CIDT strategies include polyanalgesia with morphine-ziconotide, opioid-clonidine, and morphine-bupivacaine. Notably, in addition to pain relief, morphine-bupivacaine has been shown to decrease early opioid escalation requirements.
LIMITATIONS
The supportive evidence for CIDT use for chronic pain conditions is largely lacking and limited to small, uncontrolled, observational studies, with many having various confounding factors including a lack of standardized dosing.
CONCLUSIONS
CIDT strategies and polyanalgesia combinations can be effective for treating various patient populations with chronic pain. The appropriate use of these strategies may be limited by increased or compounded risk of adverse effects, both of which are highly patient and scenario dependent. Therefore, practitioners should maintain a particularly low threshold of suspicion for adverse effects in patients with CIDT such that safety profiles associated with this therapy can be favorably maintained.
Topics: Analgesics, Opioid; Chronic Pain; Drug Therapy, Combination; Humans; Injections, Spinal; Morphine; Pain Management
PubMed: 34793643
DOI: No ID Found -
Proceedings of the National Academy of... Nov 2023Transmembrane Ca2.2 (N-type) voltage-gated calcium channels are genetically and pharmacologically validated, clinically relevant pain targets. Clinical block of Ca2.2...
Transmembrane Ca2.2 (N-type) voltage-gated calcium channels are genetically and pharmacologically validated, clinically relevant pain targets. Clinical block of Ca2.2 (e.g., with Prialt/Ziconotide) or indirect modulation [e.g., with gabapentinoids such as Gabapentin (GBP)] mitigates chronic pain but is encumbered by side effects and abuse liability. The cytosolic auxiliary subunit collapsin response mediator protein 2 (CRMP2) targets Ca2.2 to the sensory neuron membrane and regulates their function via an intrinsically disordered motif. A CRMP2-derived peptide (CBD3) uncouples the Ca2.2-CRMP2 interaction to inhibit calcium influx, transmitter release, and pain. We developed and applied a molecular dynamics approach to identify the dipeptide in CBD3 as the anchoring Ca2.2 motif and designed pharmacophore models to screen 27 million compounds on the open-access server ZincPharmer. Of 200 curated hits, 77 compounds were assessed using depolarization-evoked calcium influx in rat dorsal root ganglion neurons. Nine small molecules were tested electrophysiologically, while one (CBD3063) was also evaluated biochemically and behaviorally. CBD3063 uncoupled Ca2.2 from CRMP2, reduced membrane Ca2.2 expression and Ca currents, decreased neurotransmission, reduced fiber photometry-based calcium responses in response to mechanical stimulation, and reversed neuropathic and inflammatory pain across sexes in two different species without changes in sensory, sedative, depressive, and cognitive behaviors. CBD3063 is a selective, first-in-class, CRMP2-based peptidomimetic small molecule, which allosterically regulates Ca2.2 to achieve analgesia and pain relief without negative side effect profiles. In summary, CBD3063 could potentially be a more effective alternative to GBP for pain relief.
Topics: Rats; Animals; Chronic Pain; Rats, Sprague-Dawley; Peptidomimetics; Calcium; Calcium Channels, N-Type; Sensory Receptor Cells; Ganglia, Spinal
PubMed: 37972067
DOI: 10.1073/pnas.2305215120 -
Journal of Clinical Medicine Mar 2024Ziconotide is an intrathecal drug administered for the treatment of chronic pain. The current literature lacks an exhaustive benefit/risk assessment on this drug. We... (Review)
Review
BACKGROUND
Ziconotide is an intrathecal drug administered for the treatment of chronic pain. The current literature lacks an exhaustive benefit/risk assessment on this drug. We herein focus on Ziconotide's pharmacology and clinical applications.
METHODS
Literature research was conducted to identify studies on Ziconotide administration for the treatment of chronic pain, published between January 1990 and March 2023 and located via PubMed, Embase, Medline, Cinahl, and Web of Science, using the following keywords: Ziconotide, Omega conotoxin, Prialt, SNX-111, intrathecal therapy, and neuropathic pain. Only publications written in English were selected.
RESULTS
Among the 86 selected studies, we found 4 Randomized Controlled Trials (RCTs) and 3 prospective long-term studies concerning the intrathecal use of Ziconotide as a monotherapy in chronic pain. Other studies described the intrathecal infusion of Ziconotide combined with other drugs. Overall, Ziconotide has been proved to have strong efficacy for relieving chronic pain, although patients with co-morbid psychiatric disorders require a careful monitoring when treated with Ziconotide.
CONCLUSIONS
Overall, the use of Ziconotide, as a monotherapy or in conjunction with other therapies for the treatment of chronic pain, was reported to be efficacious. Overall, its use in patients with chronic pain refractory to other pharmacologic agents outweighs the possible adverse consequences, thus resulting in a favorable benefit/risk assessment.
PubMed: 38541869
DOI: 10.3390/jcm13061644 -
Tremor and Other Hyperkinetic Movements... Oct 2020Ziconotide (ZCN), a nonopioid analgesic, is first-line intrathecal therapy for patients with severe chronic pain refractory to other management options. We describe...
BACKGROUND
Ziconotide (ZCN), a nonopioid analgesic, is first-line intrathecal therapy for patients with severe chronic pain refractory to other management options. We describe three cases of ZCN-induced movement disorders.
CASES
Case one is a 64-year-old woman who presented with oro-lingual (OL) dyskinesia with dysesthesias and bilateral upper extremity kinetic tremor. Case two is a 43-year-old man with a 20-month history of ZCN treatment who developed OL dyskinesia with dysesthesias, involuntary left hand and neck movements, hallucinations, dysesthesias on his feet, and gait imbalance. Case three is a 70-year-old man with a 4-month history of ZCN use who developed OL dyskinesia with dysesthesias.
CONCLUSIONS
Intrathecal treatment of pain with ZCN may be complicated by a drug-induced movement disorder where OL dyskinesia is characteristic. The movement disorder is likely to be dose related and reversible with ZCN discontinuation, but a chronic movement disorder is also possible.
Topics: Adult; Aged; Analgesics, Non-Narcotic; Chronic Pain; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; omega-Conotoxins
PubMed: 33101763
DOI: 10.5334/tohm.431