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Discovery Medicine Jan 2019NSAIDs may prevent Alzheimer's disease (AD) but have failed as a treatment, possibly because only 1-2% of an oral NSAID dose reaches the brain. This minuscule dose is... (Review)
Review
NSAIDs may prevent Alzheimer's disease (AD) but have failed as a treatment, possibly because only 1-2% of an oral NSAID dose reaches the brain. This minuscule dose is enough to have a preventative effect on Alzheimer's disease but not to treat it. We propose a new route of administration for drugs to treat AD: transspinal delivery by transdermal patch over the back-of-neck/cervical spine. The drug would diffuse from the patch through the intervertebral spaces, penetrate the dura, enter the CSF, and reach the brain. For example, diclofenac from a transdermal patch over the back of neck should readily penetrate the dura mater to reach the CSF and brain; since the analgesic ziconotide, and antisense molecules for treating spinal muscular atrophy in children and Huntington's disease, are delivered intrathecally and readily enter the brain. In addition to NSAIDs, an anticancer drug, paclitaxel, has considerable potential as an AD treatment. Paclitaxel is administered IV. But the blood-brain penetration of paclitaxel is poor and paclitaxel has systemic side effects such as anemia, leukopenia, peripheral neuropathy, etc. A high dose of paclitaxel might be administered to the brain by transdermal patch over the back of the neck/cervical spine while avoiding the systemic side effects. A transdermal patch over the cervical spine could revolutionize the drug therapy of AD, and probably other neurodegenerative/neuropsychiatric diseases as well.
Topics: Administration, Cutaneous; Alzheimer Disease; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Combined Chemotherapy Protocols; Back; Diclofenac; Drug Administration Routes; Drug Delivery Systems; Humans; Neck; Neoplasms; Transdermal Patch
PubMed: 30721650
DOI: No ID Found -
Annals of the Academy of Medicine,... Nov 2009Cancer pain is complex and multifactorial. Most cancer pain can be effectively controlled using analgesics in accordance to the WHO analgesic ladder. However, in a small... (Review)
Review
Cancer pain is complex and multifactorial. Most cancer pain can be effectively controlled using analgesics in accordance to the WHO analgesic ladder. However, in a small but significant percentage of cancer patients, systemic analgesics fail to provide adequate control of cancer pain. These cancer patients can also suffer from intolerable adverse effects of drug therapy or intractable cancer pain in advance disease. Though the prognosis of these cancer patients is often very limited, the pain relief, reduced medical costs and improvement in function and quality of life from a wide variety of available interventional procedures is extremely invaluable. These interventions can be used as sole agents or as useful adjuncts to supplement analgesics. This review will discuss interventional procedures such as epidural and intrathecal drug infusions, intrathecal neurolysis, sympathetic nervous system blockade, nerve blocks, vertebroplasty and the more invasive neurosurgical procedures. Intrathecal medications including opioids, local anaesthetics, clonidine, and ziconotide will also be discussed.
Topics: Analgesics; Humans; Neoplasms; Pain Measurement; Pain, Intractable
PubMed: 19956822
DOI: No ID Found -
Neuropsychiatric Disease and Treatment Feb 2007Ziconotide is a powerful analgesic drug that has a unique mechanism of action involving potent and selective block of N-type calcium channels, which control...
Ziconotide is a powerful analgesic drug that has a unique mechanism of action involving potent and selective block of N-type calcium channels, which control neurotransmission at many synapses. The analgesic efficacy of ziconotide likely results from its ability to interrupt pain signaling at the level of the spinal cord. Ziconotide is a peptidic drug and has been approved for the treatment of severe chronic pain in patients only when administered by the intrathecal route. Importantly, prolonged administration of ziconotide does not lead to the development of addiction or tolerance. The current review discusses the various studies that have addressed the in vitro biochemical and electrophysiological actions of ziconotide as well as the numerous pre-clinical studies that were conducted to elucidate its antinociceptive mechanism of action in animals. In addition, this review considers the pivotal Phase 3 (and other) clinical trials that were conducted in support of ziconotide's approval for the treatment of severe chronic pain and tries to offer some insights regarding the future discovery and development of newer analgesic drugs that would act by a similar mechanism to ziconotide but which might offer improved safety, tolerability and ease of use.
PubMed: 19300539
DOI: 10.2147/nedt.2007.3.1.69 -
Neuro-Chirurgie Feb 2015Neurosurgical treatment of pain used two kind of techniques: 1) Lesional techniques interrupt the transmission of nociceptive neural input by lesionning the nociceptive... (Review)
Review
Neurosurgical treatment of pain used two kind of techniques: 1) Lesional techniques interrupt the transmission of nociceptive neural input by lesionning the nociceptive pathways (drezotomy, cordotomy, tractotomy…). They are indicated to treat morphine-resistant cancer pain and few cases of selected neuropathic pain. 2) Neuromodulation techniques try to decrease pain by reinforcing inhibitory and/or to limit activatory mechanisms. Chronic electrical stimulation of the nervous system (peripheral nerve stimulation, spinal cord stimulation, motor cortex stimulation…) is used to treat chronic neuropathic pain. Intrathecal infusion of analgesics (morphine, ziconotide…), using implantable pumps, allows to increase their efficacy and to reduce their side effects. These techniques can improve, sometimes dramatically, selected patients with severe and chronic pain, refractory to all other treatments. The quality of the analgesic outcome depends on the relevance of the indications.
Topics: Analgesics; Chronic Pain; Drug Resistance; Electric Stimulation Therapy; Humans; Infusion Pumps, Implantable; Neural Pathways; Neurosurgical Procedures; Pain, Intractable
PubMed: 25681114
DOI: 10.1016/j.neuchi.2014.11.008 -
Journal of Pain and Symptom Management Mar 2009This open-label multicenter study evaluated the long-term safety and efficacy of intrathecal ziconotide and included 78 patients with chronic pain who had completed one... (Clinical Trial)
Clinical Trial
This open-label multicenter study evaluated the long-term safety and efficacy of intrathecal ziconotide and included 78 patients with chronic pain who had completed one of two previous ziconotide clinical trials. Each patient's initial ziconotide dose was based on his or her dose from the study of origin and was adjusted as necessary on the basis of adverse events and analgesic effect. The median ziconotide dose was 6.48 mcg/day (range, 0.00-120.00 mcg/day) at the Initial Visit and ranged from 5.52 to 7.20 mcg/day across all study visits. The most commonly reported new adverse events that were considered ziconotide related were memory impairment (11.3%); dizziness, nystagmus, and speech disorder (8.5% each); nervousness and somnolence (7.0% each); and abnormal gait (5.6%). There was no evidence of increased adverse event incidence at higher cumulative ziconotide doses. Elevations in creatine kinase were noted, but the proportion of patients with creatine kinase elevations did not change from the Initial Visit to the Termination Visit (4.1% each). Stable mean Visual Analog Scale of Pain Intensity scores during the three years of the study suggested no evidence of increased pain intensity with increased duration of ziconotide exposure. Long-term treatment with ziconotide appeared to be well tolerated and effective in patients whose response to ziconotide and ability to tolerate the drug had been previously demonstrated.
Topics: Analgesics, Non-Narcotic; Chronic Disease; Female; Humans; Injections, Spinal; Long-Term Care; Male; Middle Aged; Pain; Pain Measurement; omega-Conotoxins
PubMed: 18715748
DOI: 10.1016/j.jpainsymman.2008.02.016 -
Journal of Pain Research 2014Chronic pain continues to pose substantial and growing challenges for patients, caregivers, health care professionals, and health care systems. By the time a patient... (Review)
Review
Chronic pain continues to pose substantial and growing challenges for patients, caregivers, health care professionals, and health care systems. By the time a patient with severe refractory pain sees a pain specialist for evaluation and management, that patient has likely tried and failed several nonpharmacologic and pharmacologic approaches to pain treatment. Although relegated to one of the interventions of "last resort", intrathecal drug delivery can be useful for improving pain control, optimizing patient functionality, and minimizing the use of systemic pain medications in appropriately selected patients. Due to its clinical and logistical requirements, however, intrathecal drug delivery may fit poorly into the classic pain clinic/interventional model and may be perceived as a "critical mass" intervention that is feasible only for large practices that have specialized staff and appropriate office resources. Potentially, intrathecal drug delivery may be more readily adopted into larger practices that can commit the necessary staff and resources to support patients' needs through the trialing, initiation, monitoring, maintenance, and troubleshooting phases of this therapy. Currently, two agents - morphine and ziconotide - are approved by the United States Food and Drug Administration for long-term intrathecal delivery. The efficacy and safety profiles of morphine have been assessed in long-term, open-label, and retrospective studies of >400 patients with chronic cancer and noncancer pain types. The efficacy and safety profiles of ziconotide have been assessed in three double-blind, placebo-controlled trials of 457 patients, and safety has been assessed in 1,254 patients overall, with severe chronic cancer, noncancer, and acquired immunodeficiency syndrome pain types. Both agents are highlighted as first-line intrathecal therapy for the management of neuropathic or nociceptive pain. The purpose of this review is to discuss practical considerations for intrathecal drug delivery, delineate criteria for the identification and selection of candidates for intrathecal drug delivery, and consider which agent may be more appropriate for individual patients.
PubMed: 25419158
DOI: 10.2147/JPR.S65441 -
Marine Drugs Feb 2010Marine ecosystems (>70% of the planet's surface) comprise a continuous resource of immeasurable biological activities and immense chemical entities. This diversity has... (Review)
Review
Marine ecosystems (>70% of the planet's surface) comprise a continuous resource of immeasurable biological activities and immense chemical entities. This diversity has provided a unique source of chemical compounds with potential bioactivities that could lead to potential new drug candidates. Many marine-living organisms are soft bodied and/or sessile. Consequently, they have developed toxic secondary metabolites or obtained them from microorganisms to defend themselves against predators [1]. For the last 30-40 years, marine invertebrates have been an attractive research topic for scientists all over the world. A relatively small number of marine plants, animals and microbes have yielded more than 15,000 natural products including numerous compounds with potential pharmaceutical potential. Some of these have already been launched on the pharmaceutical market such as Prialt (ziconotide; potent analgesic) and Yondelis (trabectedin or ET-743; antitumor) while others have entered clinical trials, e.g., alpidin and kahalalide F. Amongst the vast array of marine natural products, the terpenoids are one of the more commonly reported and discovered to date. Sesterterpenoids (C(25)) and triterpenoids (C(30)) are of frequent occurrence, particularly in marine sponges, and they show prominent bioactivities. In this review, we survey sesterterpenoids and triterpenoids obtained from marine sponges and highlight their bioactivities.
Topics: Animals; Humans; Porifera; Saponins; Sesterterpenes; Terpenes; Triterpenes
PubMed: 20390108
DOI: 10.3390/md8020313 -
Cell Reports Nov 2021N-type voltage-gated calcium (Ca) channels mediate Ca influx at presynaptic terminals in response to action potentials and play vital roles in synaptogenesis, release of...
N-type voltage-gated calcium (Ca) channels mediate Ca influx at presynaptic terminals in response to action potentials and play vital roles in synaptogenesis, release of neurotransmitters, and nociceptive transmission. Here, we elucidate a cryo-electron microscopy (cryo-EM) structure of the human Ca2.2 complex in apo, ziconotide-bound, and two Ca2.2-specific pore blockers-bound states. The second voltage-sensing domain (VSD) is captured in a resting-state conformation, trapped by a phosphatidylinositol 4,5-bisphosphate (PIP) molecule, which is distinct from the other three VSDs of Ca2.2, as well as activated VSDs observed in previous structures of Ca channels. This structure reveals the molecular basis for the unique inactivation process of Ca2.2 channels, in which the intracellular gate formed by S6 helices is closed and a W-helix from the domain II-III linker stabilizes closed-state inactivation. The structures of this inactivated, drug-bound complex lay a solid foundation for developing new state-dependent blockers for treatment of chronic pain.
Topics: Action Potentials; Calcium Channel Blockers; Calcium Channels, N-Type; Calcium Signaling; Cryoelectron Microscopy; Dipeptides; HEK293 Cells; Humans; Ion Channel Gating; Models, Molecular; Phosphatidylinositol 4,5-Diphosphate; Protein Conformation, alpha-Helical; Structure-Activity Relationship; omega-Conotoxins
PubMed: 34731621
DOI: 10.1016/j.celrep.2021.109931 -
Angewandte Chemie (International Ed. in... Jul 2023Ziconotide (ω-conotoxin MVIIA) is an approved analgesic for the treatment of chronic pain. However, the need for intrathecal administration and adverse effects have...
Ziconotide (ω-conotoxin MVIIA) is an approved analgesic for the treatment of chronic pain. However, the need for intrathecal administration and adverse effects have limited its widespread application. Backbone cyclization is one way to improve the pharmaceutical properties of conopeptides, but so far chemical synthesis alone has been unable to produce correctly folded and backbone cyclic analogues of MVIIA. In this study, an asparaginyl endopeptidase (AEP)-mediated cyclization was used to generate backbone cyclic analogues of MVIIA for the first time. Cyclization using six- to nine-residue linkers did not perturb the overall structure of MVIIA, and the cyclic analogues of MVIIA showed inhibition of voltage-gated calcium channels (Ca 2.2) and substantially improved stability in human serum and stimulated intestinal fluid. Our study reveals that AEP transpeptidases are capable of cyclizing structurally complex peptides that chemical synthesis cannot achieve and paves the way for further improving the therapeutic value of conotoxins.
Topics: Humans; omega-Conotoxins; Analgesics; Conotoxins; Calcium Channels; Calcium Channel Blockers
PubMed: 37148162
DOI: 10.1002/anie.202302812 -
The Mental Health Clinician Sep 2018Ziconotide is an intrathecally administered medication indicated for the treatment of severe chronic pain in patients who are intolerant of or refractory to other...
Ziconotide is an intrathecally administered medication indicated for the treatment of severe chronic pain in patients who are intolerant of or refractory to other treatment options. A black box warning is included in the packaging and states ziconotide is contraindicated in patients with a preexisting history of psychosis. Patients taking ziconotide should be monitored for evidence of cognitive impairment, hallucinations, or changes in mood, and ziconotide should be discontinued if neurological or psychiatric signs and symptoms appear. We present a case of a 49-year-old white male with no previous neuropsychiatric history who received ziconotide for several years before he developed command auditory hallucinations within 24 hours of a dose increase. Upon admission to the emergency room, the patient's pain management physician was contacted and the ziconotide dose was decreased and eventually discontinued. Because of a continuation of symptoms, the patient was transferred from the emergency room to an acute care psychiatric hospital where he was started on risperidone 1 mg orally at bedtime. At discharge, the patient was noted to be in good behavioral control without any hallucinations. The patient was encouraged to follow up with his pain management physician to determine if ziconotide should be reconsidered.
PubMed: 30206508
DOI: 10.9740/mhc.2018.09.242