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Ryan Patel, Carlota Montagut-Bordas, Anthony H Dickenson
Neuropathic pain remains poorly treated for large numbers of patients and little progress has been made in developing novel classes of analgesics. To redress this issue, ziconotide (Prialt(TM) ) was developed and approved as a first in class synthetic version of ω-conotoxin MVIIA, a Cav 2.2 peptide blocker. Unfortunately, the impracticalities of intrathecal delivery, low therapeutic index and severe neurological side effects associated with ziconotide has restricted its use to exceptional circumstances. Ziconotide exhibits no state or use dependent block of Cav 2...
March 20, 2017: British Journal of Pharmacology
J Gorson, M Holford
Venomous organisms used in research were historically chosen based on size and availability. This opportunity-driven strategy created a species bias in which snakes, scorpions, and spiders became the primary subjects of venom research. Increasing technological advancements have enabled interdisciplinary studies using genomics, transcriptomics, and proteomics to expand venom investigation to animals that produce small amounts of venom or lack traditional venom producing organs. One group of non-traditional venomous organisms that have benefitted from the rise of -omic technologies is the Conoideans...
November 2016: Integrative and Comparative Biology
Seyed Sahand Eisapoor, Shahla Jamili, Delavar Shahbazzadeh, Pargol Ghavam Mostafavi, Kamran Pooshang Bagheri
Almost all conopeptides purified from Conus venoms are cysteine-rich peptides. Among them, omega-conotoxin MVIIA, FDA approved peptide drug (Prialt(®)), selected as a cysteine-rich model that its protection from oxidation is critical during solid phase synthesis. Deprotection of cysteines is a crucial step after peptide synthesis. The current study aimed to set up a new highly efficient deprotection protocol for omega-conotoxin MVIIA. Deprotection was performed based on mercury acetate with significant major modification...
May 2016: Chemical Biology & Drug Design
Prachi Anand, Alison O'Neil, Emily Lin, Trevor Douglas, Mandë Holford
The blood brain barrier (BBB) is often an insurmountable obstacle for a large number of candidate drugs, including peptides, antibiotics, and chemotherapeutic agents. Devising an adroit delivery method to cross the BBB is essential to unlocking widespread application of peptide therapeutics. Presented here is an engineered nanocontainer for delivering peptidic drugs across the BBB encapsulating the analgesic marine snail peptide ziconotide (Prialt®). We developed a bi-functional viral nanocontainer based on the Salmonella typhimurium bacteriophage P22 capsid, genetically incorporating ziconotide in the interior cavity, and chemically attaching cell penetrating HIV-Tat peptide on the exterior of the capsid...
August 3, 2015: Scientific Reports
R Patel, K Rutten, M Valdor, K Schiene, S Wigge, S Schunk, N Damann, T Christoph, A H Dickenson
Prialt, a synthetic version of Ca(v)2.2 antagonist ω-conotoxin MVIIA derived from Conus magus, is the first clinically approved voltage-gated calcium channel blocker for refractory chronic pain. However, due to the narrow therapeutic window and considerable side effects associated with systemic dosing, Prialt is only administered intrathecally. N-triazole oxindole (TROX-1) is a novel use-dependent and activation state-selective small-molecule inhibitor of Ca(v)2.1, 2.2 and 2.3 calcium channels designed to overcome the limitations of Prialt...
June 25, 2015: Neuroscience
Uta Baddack, Silke Frahm, Beatriz Antolin-Fontes, Jenny Grobe, Martin Lipp, Gerd Müller, Ines Ibañez-Tallon
OBJECTIVE: A hallmark of rheumatoid arthritis (RA) is the chronic pain that accompanies inflammation and joint deformation. Patients with RA rate pain relief as the highest priority; however, few studies have addressed the efficacy and safety of therapies directed specifically toward pain pathways. The ω-conotoxin MVIIA (ziconotide) is used in humans to alleviate persistent pain syndromes, because it specifically blocks the voltage-gated calcium 2.2 (CaV 2.2) channel, which mediates the release of neurotransmitters and proinflammatory mediators from peripheral nociceptor nerve terminals...
June 2015: Arthritis & Rheumatology
Mark Sanford
Ziconotide (Prialt(®)) is a synthetic conopeptide analgesic that acts by selectively antagonizing N-type voltage-gated calcium channels. Intrathecal ziconotide is the only non-opioid intrathecal analgesic that is FDA-approved for use in patients with treatment-refractory, chronic pain. The efficacy of intrathecal ziconotide was demonstrated in randomized, double-blind, placebo-controlled trials in patients with treatment-refractory noncancer-related pain or cancer- or AIDS-related pain. Across trials, ziconotide recipients had significantly greater reductions in pain intensity during ziconotide treatment than those receiving placebo (primary endpoint)...
November 2013: CNS Drugs
Salma I Mohammed, Sam Eldabe, Karen H Simpson, Morag Brookes, Grace Madzinga, Ashish Gulve, Ganesan Baranidharan, Helen Radford, Tracey Crowther, Eric Buchser, Christophe Perruchoud, Alan Mark Batterham
OBJECTIVES: This study evaluated efficacy and safety of bolus doses of ziconotide (Prialt®, Eisai Limited, Hertfordshire, UK) to assess the option of continuous administration of this drug via an implanted intrathecal drug delivery system. MATERIALS AND METHODS: Twenty adults with severe chronic pain who were under consideration for intrathecal (IT) therapy were enrolled in this open label, nonrandomized, pilot study. Informed consent was obtained. Demographics, medical/pain history, pain scores, and concomitant medications were recorded...
November 2013: Neuromodulation: Journal of the International Neuromodulation Society
Irina Vetter, Richard J Lewis
Cone snails have evolved many 1000s of small, structurally stable venom peptides (conopeptides) for prey capture and defense. Whilst < 0.1% have been pharmacologically characterised, those with known function typically target membrane proteins of therapeutic importance, including ion channels, transporters and GPCRs. Several conopeptides reduce pain in animals models, with one in clinical development (χ-conopeptide analogue Xen2174) and one marketed (ω- conotoxin MVIIA or Prialt) for the treatment of severe pain...
2012: Current Topics in Medicinal Chemistry
Magbubah Essack, Vladimir B Bajic, John A C Archer
Cone snails produce a distinctive repertoire of venom peptides that are used both as a defense mechanism and also to facilitate the immobilization and digestion of prey. These peptides target a wide variety of voltage- and ligand-gated ion channels, which make them an invaluable resource for studying the properties of these ion channels in normal and diseased states, as well as being a collection of compounds of potential pharmacological use in their own right. Examples include the United States Food and Drug Administration (FDA) approved pharmaceutical drug, Ziconotide (Prialt(®); Elan Pharmaceuticals, Inc...
June 2012: Marine Drugs
Christina I Schroeder, David J Craik
Conopeptides from the venoms of marine snails have attracted much interest as leads in drug design. Currently, one drug, Prialt(®), is on the market as a treatment for chronic neuropathic pain. Conopeptides target a range of ion channels, receptors and transporters, and are typically small, relatively stable peptides that are generally amenable to production using solid-phase peptide synthesis. With only a small fraction of the predicted diversity of conopeptides examined so far, these peptides represent an exciting and largely untapped resource for drug discovery...
June 2012: Future Medicinal Chemistry
Nalin L Subasinghe, Mark J Wall, Michael P Winters, Ning Qin, Mary Lou Lubin, Michael F A Finley, Michael R Brandt, Michael P Neeper, Craig R Schneider, Raymond W Colburn, Christopher M Flores, Zhihua Sui
Selective blockers of the N-type calcium channel have proven to be effective in animal models of chronic pain. However, even though intrathecally delivered synthetic ω-conotoxin MVIIA from Conus magnus (ziconotide [Prialt®]) has been approved for the treatment of chronic pain in humans, its mode of delivery and narrow therapeutic window have limited its usefulness. Therefore, the identification of orally active, small-molecule N-type calcium channel blockers would represent a significant advancement in the treatment of chronic pain...
June 15, 2012: Bioorganic & Medicinal Chemistry Letters
Richard J Lewis, Sébastien Dutertre, Irina Vetter, MacDonald J Christie
Conopeptides are a diverse group of recently evolved venom peptides used for prey capture and/or defense. Each species of cone snails produces in excess of 1000 conopeptides, with those pharmacologically characterized (≈ 0.1%) targeting a diverse range of membrane proteins typically with high potency and specificity. The majority of conopeptides inhibit voltage- or ligand-gated ion channels, providing valuable research tools for the dissection of the role played by specific ion channels in excitable cells...
April 2012: Pharmacological Reviews
Robert Fisher, Sam Hassenbusch, Elliot Krames, Michael Leong, Michael Minehart, Joshua Prager, Peter Staats, Lynn Webster, K Dean Willis
No abstract text is available yet for this article.
July 2005: Neuromodulation: Journal of the International Neuromodulation Society
David J Adams, Brid Callaghan, Géza Berecki
Conotoxins (conopeptides) are small disulfide bonded peptides from the venom of marine cone snails. These peptides target a wide variety of membrane receptors, ion channels and transporters, and have enormous potential for a range of pharmaceutical applications. Structurally related ω-conotoxins bind directly to and selectively inhibit neuronal (N)-type voltage-gated calcium channels (VGCCs) of nociceptive primary afferent neurones. Among these, ω-conotoxin MVIIA (Prialt) is approved by the Food and Drug Administration (FDA) as an alternative intrathecal analgesic for the management of chronic intractable pain, particularly in patients refractory to opioids...
May 2012: British Journal of Pharmacology
Marijke Stevens, Steve Peigneur, Jan Tytgat
Voltage-gated sodium channels (VGSCs) are large transmembrane proteins that conduct sodium ions across the membrane and by doing so they generate signals of communication between many kinds of tissues. They are responsible for the generation and propagation of action potentials in excitable cells, in close collaboration with other channels like potassium channels. Therefore, genetic defects in sodium channel genes can cause a wide variety of diseases, generally called "channelopathies." The first insights into the mechanism of action potentials and the involvement of sodium channels originated from Hodgkin and Huxley for which they were awarded the Nobel Prize in 1963...
2011: Frontiers in Pharmacology
S S Ebada, P Proksch
Natural Guanidines from marine invertebrates represent a group of bioactive secondary metabolites that revealed prominent pharmacological activities such as antimicrobial, antiproliferative, analgesic, and anti-coagulant properties. Acyclovir (Zovirax(®)), the first guanidine-derived pharmaceutical for the treatment of herpes infections since late 1970s, was synthesized based on a marine arabinosyl nucleoside, spongosine. Recently, ziconotide (Prialt(®)), a synthetic form of the marine-derived peptide (ω-conotoxin MVIIA) comprising a guanidine moiety, has been approved for the treatment of chronic pain...
March 2011: Mini Reviews in Medicinal Chemistry
Whitney B Michiels, Gail L McGlthlen, Benjamin J Platt, Eric J Grigsby
OBJECTIVE: We report a case of a 59-year-old female with severe TN who experienced satisfactory symptom relief from a single-shot trial of intrathecal ziconotide. METHOD: Performed a 1 μg single-shot trial of Prialt. RESULTS: Report of satisfaction, no side effects, and complete face and back relief briefly but most notably relief from the TN. DISCUSSION: Ziconotide should be considered for treatment of TN, although further investigation is recommended...
May 2011: Clinical Journal of Pain
Francesco Belardetti
Clinical exploitation of the therapeutic potential of calcium channels has long been limited to L-type blockers for cardiovascular diseases. Recently, N-type blockers have been fully validated for the treatment of chronic pain, following approval of the intrathecally active ziconotide (Prialt(®)). This review describes the successful efforts to broaden the therapeutic scope of this mechanism to other major CNS indications, based on the discovery of N-type blockers orally active against pain. In animal models, the N-type blocker and pain-reducing NP078585 is efficacious against key elements of ethanol dependency, including self-administration and relapse...
May 2010: Future Medicinal Chemistry
Russell W Teichert, Baldomero M Olivera
An accelerated rate of natural-product discovery is critical for the future of ion channel pharmacology. For the full potential of natural products to be realized, an interdisciplinary initiative is required that combines chemical ecology and ion channel physiology. A prime source of future drug leads targeted to ion channels is the vast assortment of compounds that mediate biotic interactions in the marine environment. Many animals have evolved a chemical strategy to change the behavior of their prey, predators or competitors, which appears to require a large set of ion channel-targeted compounds acting in concert...
May 2010: Future Medicinal Chemistry
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