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Current Neuropharmacology 2022Pain is a complex phenomenon that is usually unpleasant and aversive. It can range widely in intensity, quality, and duration and has diverse pathophysiologic mechanisms...
Pain is a complex phenomenon that is usually unpleasant and aversive. It can range widely in intensity, quality, and duration and has diverse pathophysiologic mechanisms and meanings. Voltage-gated sodium and calcium channels are essential to transmitting painful stimuli from the periphery until the dorsal horn of the spinal cord. Thus, blocking voltage-gated calcium channels (VGCCs) can effectively control pain refractory to treatments currently used in the clinic, such as cancer and neuropathic pain. VGCCs blockers isolated of cobra Naja naja kaouthia (α-cobratoxin), spider Agelenopsis aperta (ω-Agatoxin IVA), spider Phoneutria nigriventer (PhTx3.3, PhTx3.4, PhTx3.5, PhTx3.6), spider Hysterocrates gigas (SNX-482), cone snails Conus geographus (GVIA), Conus magus (MVIIA or ziconotide), Conus catus (CVID, CVIE and CVIF), Conus striatus (SO- 3), Conus fulmen (FVIA), Conus moncuri (MoVIA and MoVIB), Conus regularis (RsXXIVA), Conus eburneus (Eu1.6), Conus victoriae (Vc1.1.), Conus regius (RgIA), and spider Ornithoctonus huwena (huwentoxin-I and huwentoxin-XVI) venoms caused antinociceptive effects in different acute and chronic pain models. Currently, ziconotide is the only clinical used N-type VGCCs blocker peptide for chronic intractable pain. However, ziconotide causes different adverse effects, and the intrathecal route of administration also impairs its use in a more significant number of patients. In this sense, peptides isolated from animal venoms or their synthetic forms that act by modulating or blocking VGCCs channels seem to be a relevant prototype for developing new analgesics efficacious and well tolerated by patients.
Topics: Analgesics; Animals; Calcium Channel Blockers; Calcium Channels; Neuralgia; Peptides; Spiders
PubMed: 34259147
DOI: 10.2174/1570159X19666210713121217 -
European Journal of Physical and... Mar 2009Seven cases of combination of intrathecal (IT) ziconotide and baclofen therapy in patients with refractory neuropathic pain and spasticity were reviewed. Five of the...
Seven cases of combination of intrathecal (IT) ziconotide and baclofen therapy in patients with refractory neuropathic pain and spasticity were reviewed. Five of the seven adult patients were receiving IT baclofen treatment when ziconotide was initiated. All five patients had experienced at least one previous failed IT treatment regimen. Pain intensity scores improved by a mean of 50.3% with the use of ziconotide-baclofen therapy. Mean time to onset of pain relief was 15 weeks, at a mean ziconotide dose of 3.7 microg/day. Within this group of patients, adverse events were observed in one patient, but they were not considered to be ziconotide related and subsequently resolved. The remaining two patients were receiving ziconotide treatment when baclofen was initiated. Pain intensity scores improved by 75% and 30%, respectively. Pain relief was evident at two weeks and one week, with corresponding ziconotide doses of 2.4 microg/day and 14.4 microg/day, respectively. One patient in this group reported adverse events, but all resolved during continued treatment with the study drugs. Treatment regimens varied between patients in these case series; each regimen used a different titration strategy and different concentrations of ziconotide and baclofen. Combination IT ziconotide and baclofen therapy may be a treatment option for patients with neuropathic pain and spasticity. Future studies are warranted to determine the optimal dosing and titration schedules for ziconotide-baclofen usage.
Topics: Adult; Baclofen; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Muscle Relaxants, Central; Muscle Spasticity; Neuralgia; Neuroprotective Agents; Pain; Pain Measurement; Treatment Outcome; omega-Conotoxins
PubMed: 19156022
DOI: No ID Found -
Toxins Oct 2015Ziconotide (Prialt®), a synthetic version of the peptide ω-conotoxin MVIIA found in the venom of a fish-hunting marine cone snail Conus magnus, is one of very few... (Review)
Review
Ziconotide (Prialt®), a synthetic version of the peptide ω-conotoxin MVIIA found in the venom of a fish-hunting marine cone snail Conus magnus, is one of very few drugs effective in the treatment of intractable chronic pain. However, its intrathecal mode of delivery and narrow therapeutic window cause complications for patients. This review will summarize progress in the development of small molecule, non-peptidic mimics of Conotoxins and a small number of other venom peptides. This will include a description of how some of the initially designed mimics have been modified to improve their drug-like properties.
Topics: Amino Acid Sequence; Animals; Calcium Channel Blockers; Calcium Channels, N-Type; Cell Line, Tumor; Humans; Models, Molecular; Molecular Sequence Data; Molecular Structure; Mollusk Venoms; Patch-Clamp Techniques; Peptidomimetics; omega-Conotoxins
PubMed: 26501323
DOI: 10.3390/toxins7104175 -
Food Research International (Ottawa,... Nov 2020Extensive biodiversity and availability of marine and estuarine molluscs, along with their their wide-range of utilities as food and nutraceutical resources developed... (Review)
Review
Extensive biodiversity and availability of marine and estuarine molluscs, along with their their wide-range of utilities as food and nutraceutical resources developed keen attention of the food technologists and dieticians, particularly during the recent years. The current review comprehensively summarized the nutritional qualities, functional food attributes, and bioactive properties of these organisms. Among the phylum mollusca, Cephalopoda, Bivalvia, and Gastropoda were mostly reported for their nutraceutical applications and bioactive properties. The online search tools, like Scifinder/Science Direct/PubMed/Google Scholar/MarinLit database and marine natural product reports (1984-2019) were used to comprehend the information about the molluscs. More than 1334 secondary metabolites were reported from marine molluscs between the periods from 1984 to 2019. Among various classes of specialized metabolites, terpenes were occupied by 55% in gastropods, whereas sterols occupied 41% in bivalves. The marketed nutraceuticals, such as Cadalmin green mussel extract (Perna viridis) and Lyprinol® (Perna canaliculus) were endowed with potential anti-inflammatory activities, and were used against arthritis. Molluscan-derived therapeutics, for example, ziconotide was used as an analgesic, and elisidepsin was used in the treatment of cancer. Greater numbers of granted patents (30%) during 2016-2019 recognized the increasing importance of bioactive compounds from molluscs. Consumption of molluscs as daily diets could be helpful in the enhancement of immunity, and reduce the risk of several ailments. The present review comprehended the high value compounds and functional food ingredients from marine and estuarine molluscs.
Topics: Animals; Anti-Inflammatory Agents; Bivalvia; Ecosystem; Food Ingredients; Prospective Studies
PubMed: 33233216
DOI: 10.1016/j.foodres.2020.109637 -
Cureus Mar 2022Migraine is one of the most prevalent and debilitating illnesses globally. There are multitudes of treatment options available for migraines. One of the emerging...
Migraine is one of the most prevalent and debilitating illnesses globally. There are multitudes of treatment options available for migraines. One of the emerging treatment options for migraine, refractory to conventional treatment modalities, is the intrathecal Ziconotide. Ziconotide (Prialt, Jazz Pharmaceuticals, Dublin, Ireland) enforces selective block of N-type calcium channels, which control neurotransmission at many synapses. Ziconotide is proposed to have efficacy for chronic neuropathic pain, with a favorable lack of tolerance and chemical dependency. Few studies in the literature report the successful resolution of migraine headaches with Ziconotide. The authors report the successful use of intrathecal Ziconotide therapy for chronic refractory migraines.
PubMed: 35505713
DOI: 10.7759/cureus.23714 -
Neuromodulation : Journal of the... 2012Ziconotide is a peptide that blocks N-type calcium channels and is antihyperalgesic after intrathecal (IT) delivery. We here characterize the spinal kinetics of IT...
BACKGROUND AND PURPOSE
Ziconotide is a peptide that blocks N-type calcium channels and is antihyperalgesic after intrathecal (IT) delivery. We here characterize the spinal kinetics of IT bolus and infused ziconotide in dog.
EXPERIMENTAL APPROACH
Male beagle dogs (N= 5) were prepared with chronic IT lumbar injection and cerebrospinal fluid (LCSF) sampling catheters connected to vest-mounted pumps. Each dog received the following: 1) IT bolus ziconotide (10 µg + 1 µCi (3) H-inulin); 2) IT infusion for 48 hours of ziconotide (1 µg/100 µL/hour); 3) IT infusion for 48 hours of ziconotide (5 µg/100 µL/hour); and 4) intravenous injection of ziconotide (0.1 mg/kg). After IT bolus, LCSF ziconotide and inulin showed an initial peak and biphasic (distribution/elimination) clearance (ziconotide T(1/2-α/β) = 0.14 and 1.77 hours, and inulin T(1/2-α/β) = 0.16 and 3.88 hours, respectively). The LCSF : plasma ziconotide concentration ratio was 20,000:1 at 30 min and 30:1 at eight hours. IT infusion of 1 and then 5 µg/hour resulted in LCSF concentrations that peaked by eight hours and remained stable at 343 and 1380 ng/mL, respectively, to the end of the 48-hour infusions. Terminal elimination T(1/2) after termination of continuous infusion was 2.47 hours. Ziconotide LCSF : cisternal CSF : plasma concentration ratios after infusion of 1 and 5 µg/hour were 1:0.017:0.001 and 1:0.015:0.003, respectively. IT infusion of ziconotide at 1 µg/hour inhibited thermal skin twitch by 24 hours and produced modest trembling, ataxia, and decreased arousal. Effects continued through the 48-hour infusion period, increased in magnitude during the subsequent 5 µg/hour infusion periods, and disappeared after drug clearance.
CONCLUSIONS AND IMPLICATIONS
After IT bolus or infusion, ziconotide displays linear kinetics that are consistent with a hydrophilic molecule of approximately 2500 Da that is cleared slightly more rapidly than inulin from the LCSF. Behavioral effects were dose dependent and reversible.
Topics: Animals; Area Under Curve; Arousal; Blood Pressure; Calcium Channel Blockers; Dogs; Dose-Response Relationship, Drug; Heart Rate; Infusions, Parenteral; Injections, Spinal; Male; Motor Activity; Nociception; Pharmacokinetics; Skin; Time Factors; omega-Conotoxins
PubMed: 22748108
DOI: 10.1111/j.1525-1403.2012.00479.x -
Pharmacological Research Feb 2024Chronic pain is a complex and challenging medical condition that affects millions of people worldwide. Understanding the underlying mechanisms of chronic pain is a key... (Review)
Review
Chronic pain is a complex and challenging medical condition that affects millions of people worldwide. Understanding the underlying mechanisms of chronic pain is a key goal of preclinical pain research so that more effective treatment strategies can be developed. In this review, we explore nociception, pain, and the multifaceted factors that lead to chronic pain by focusing on preclinical models. We provide a detailed look into inflammatory and neuropathic pain models and discuss the most used animal models for studying the mechanisms behind these conditions. Additionally, we emphasize the vital role of these preclinical models in developing new pain-relief drugs, focusing on biologics and the therapeutic potential of NMDA and cannabinoid receptor antagonists. We also discuss the challenges of TRPV1 modulation for pain treatment, the clinical failures of neurokinin (NK)- 1 receptor antagonists, and the partial success story of Ziconotide to provide valuable lessons for preclinical pain models. Finally, we highlight the overall success and limitations of current treatments for chronic pain while providing critical insights into the development of more effective therapies to alleviate the burden of chronic pain.
Topics: Animals; Humans; Chronic Pain; Neuralgia; Pain Management; Models, Animal; Research
PubMed: 38232910
DOI: 10.1016/j.phrs.2024.107073 -
Marine Drugs Feb 2023The venom of marine cone snails is mainly composed of peptide toxins called conopeptides, among which conotoxins represent those that are disulfide-rich. Publications on... (Review)
Review
The venom of marine cone snails is mainly composed of peptide toxins called conopeptides, among which conotoxins represent those that are disulfide-rich. Publications on conopeptides frequently state that conopeptides attract considerable interest for their potent and selective activity, but there has been no analysis yet that formally quantifies the popularity of the field. We fill this gap here by providing a bibliometric analysis of the literature on cone snail toxins from 2000 to 2022. Our analysis of 3028 research articles and 393 reviews revealed that research in the conopeptide field is indeed prolific, with an average of 130 research articles per year. The data show that the research is typically carried out collaboratively and worldwide, and that discoveries are truly a community-based effort. An analysis of the keywords provided with each article revealed research trends, their evolution over the studied period, and important milestones. The most employed keywords are related to pharmacology and medicinal chemistry. In 2004, the trend in keywords changed, with the pivotal event of that year being the approval by the FDA of the first peptide toxin drug, ziconotide, a conopeptide, for the treatment of intractable pain. The corresponding research article is among the top ten most cited articles in the conopeptide literature. From the time of that article, medicinal chemistry aiming at engineering conopeptides to treat neuropathic pain ramped up, as seen by an increased focus on topological modifications (e.g., cyclization), electrophysiology, and structural biology.
Topics: Animals; Conus Snail; Conotoxins; Peptides; Snails
PubMed: 36976203
DOI: 10.3390/md21030154 -
Pain Physician 2015Use of intrathecal admixtures is widespread, but compounding these is sometimes challenging and may result in errors and complications causing super-potency or sub... (Observational Study)
Observational Study
Rationale for Prospective Assays of Intrathecal Mixtures Including Morphine, Ropivacaine and Ziconotide: Prevention of Adverse Events and Feasibility in Clinical Practice.
BACKGROUND
Use of intrathecal admixtures is widespread, but compounding these is sometimes challenging and may result in errors and complications causing super-potency or sub potency adverse events in patients or malfunctions in the pump itself.
OBJECTIVE
The purpose of this study is to evaluate the accuracy of compounding of intrathecal admixtures through a prospective, systematic quantitative analysis of each component of the mixture before delivery to patients.
STUDY DESIGN
Observational follow up prospective study of intrathecal mixtures components concentrations before refills.
SETTINGS
Assays were performed on all intrathecal admixtures produced by the ICO-Paul Papin compounding pharmacy between January 2013 and October 2014 using Ultra High Performance Liquid Chromatography (U.H.P.L.C.). In addition, pH levels of admixtures have been measured since June 2014. When measured concentrations were 15% above or below the required concentrations, the mixture was excluded and compounded again.
RESULTS
1729 mixtures were analyzed. Mean deviation from theoretical values was -1.17% ± 0.28% for morphine, -0.95% ± 1.07% for ropivacaine, and 4.82% ± 0.6% for ziconotide. Exclusion rates were 8.33% overall, but fell from 11.67% in 2013 to 4.97% in 2014. Most exclusions were caused by inaccuracy in the dose of ziconotide. Average mixture pH of the 603 tested admixtures was 4.83 ± 0.6%.
LIMITATIONS
This study is monocentric and limitations include also its non-randomized nature with no clinical comparison of the rate of adverse events with a refill process without control of each component concentrations.
CONCLUSION
Prospective assays provide benefits in ensuring accuracy of intrathecal mixture compounding and in preventing overdosing or sub dosing, most notably concerning Ziconotide.
Topics: Adult; Aged; Amides; Analgesics, Non-Narcotic; Analgesics, Opioid; Anesthetics, Local; Chemistry, Pharmaceutical; Feasibility Studies; Female; Follow-Up Studies; Humans; Injections, Spinal; Middle Aged; Morphine; Pain Measurement; Prospective Studies; Ropivacaine; omega-Conotoxins
PubMed: 26218938
DOI: No ID Found -
Therapeutics and Clinical Risk... Jun 2009Ziconotide is a conopeptide intrathecal (IT) analgesic which is approved by the US Food and Drug Administration (FDA) for the management of severe chronic pain. It is a...
Ziconotide is a conopeptide intrathecal (IT) analgesic which is approved by the US Food and Drug Administration (FDA) for the management of severe chronic pain. It is a synthetic equivalent of a naturally occurring conopeptide found in the venom of the fish-eating marine cone snail and provides analgesia via binding to N-type voltage-sensitive calcium channels in the spinal cord. As ziconotide is a peptide, it is expected to be completely degraded by endopeptidases and exopeptidases (Phase I hydrolytic enzymes) widely located throughout the body, and not by other Phase I biotransformation processes (including the cytochrome P450 system) or by Phase II conjugation reactions. Thus, IT administration, low plasma ziconotide concentrations, and metabolism by ubiquitous peptidases make metabolic interactions of other drugs with ziconotide unlikely. Side effects of ziconotide which tend to occur more commonly at higher doses may include: nausea, vomiting, confusion, postural hypotension, abnormal gait, urinary retention, nystagmus/amblyopia, drowsiness/somnolence (reduced level of consciousness), dizziness or lightheadedness, weakness, visual problems (eg, double vision), elevation of serum creatine kinase, or vestibular side effects. Initially, when ziconotide was first administered to human subjects, titration schedules were overly aggressive and led to an abundance of adverse effects. Subsequently, clinicians have gained appreciation for ziconotide's relatively narrow therapeutic window. With appropriate usage multiple studies have shown ziconotide to be a safe and effective intrathecal analgesic alone or in combination with other intrathecal analgesics.
PubMed: 19707262
DOI: 10.2147/tcrm.s4438