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Daniel S. Kohane - One of the best experts on this subject based on the ideXlab platform.
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corneal anesthesia with site 1 Sodium Channel Blockers and dexmedetomidine
Investigative Ophthalmology & Visual Science, 2015Co-Authors: James B Mcalvin, Changyou Zhan, Jenny C Dohlman, Paraskevi E Kolovou, Borja Salvadorculla, Daniel S. KohaneAbstract:Conventional amino-ester and amino-amide local anesthetics are used to reduce ocular pain related to corneal injury and ophthalmic surgery.1,2 They act by binding to an intracellular domain of the Sodium Channel and blocking Sodium influx.3 They produce corneal anesthesia for 15 to 20 minutes when applied topically, with return of normal sensation after 60 minutes4 and so require repeated administration. Brief ophthalmic procedures, such as cataract extraction, are routinely performed under local anesthesia with conventional local anesthetics, which are administered by a variety of techniques, including topical application onto the cornea, injection into or around the muscle cone, and injection under the Tenon's capsule.5 Given frequently, these agents may delay epithelial healing, cause anterior segment inflammation,6 corneal ulceration, and occasionally neurotrophic keratopathy.1 Their short durations of action and the potential for tissue toxicity exclude their use in lengthier ophthalmic procedures, and limit their use for other causes of corneal pain such as traumatic abrasions and recurrent erosions.1,6 An ocular anesthetic formulation with prolonged effect and minimal toxicity is needed. Such a formulation could be used to prevent pain more effectively during longer surgical procedures and for outpatient management of minor corneal injury during the period when ocular pain is most intense. Tetrodotoxin (TTX) and saxitoxin (STX) are potent local anesthetics that act by binding to site 1 on the extracellular part of the Sodium Channel and blocking Sodium influx.7 Tissue toxicity from site 1 Sodium Channel Blockers (S1SCBs) after injection at peripheral nerves is minimal,8 even when delivered for prolonged periods.9 Site 1 Sodium Channel Blockers also produce corneal analgesia with minimal toxicity to the corneal epithelium,2,6,10 although systemic toxicity from ocular application has been reported.11 Coadministration of local anesthetics with adjuvant agents can enhance anesthetic effect and/or (in the case of S1SCBs) prevent potential systemic toxicity by reducing the dose required for a given effect. For example, we have shown that corneal analgesia can be prolonged by combining S1SCBs with conventional local anesthetics.12 Similarly, addition of the α2-adrenergic receptor (α2-AR) agonists clonidine or dexmedetomidine to conventional amino-amide or amino-ester local anesthetics extends the duration of peripheral nerve block13–17 and ocular anesthesia.18 However, in both of those cases, the conventional local anesthetic is believed to be toxic to the cornea, which could limit usefulness. Here, we hypothesize that coadministration of S1SCBs and α2-AR agonists for ocular anesthesia will prolong corneal block. This hypothesis is supported by the fact that clonidine can enhance the duration of sciatic nerve blockade from TTX.19 Moreover, α2-AR agonists are likely to have minimal toxicity to the cornea. In fact, dexmedetomidine has been shown to reduce local tissue inflammation from conventional local anesthetics.17,20 Here, we report prolonged corneal anesthesia from local anesthetic formulations comprised of dexmedetomidine and TTX or STX, and compare them with the widely used amino-ester ocular anesthetic, 0.5% (wt/vol) proparacaine. We also characterize in vitro cytotoxicity to corneal cells and in vivo corneal healing in the setting of repeated drug administration of those compounds.
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Duration and Local Toxicity of Sciatic Nerve Blockade With Coinjected Site 1 Sodium-Channel Blockers and Quaternary Lidocaine Derivatives
Regional Anesthesia and Pain Medicine, 2012Co-Authors: Sahadev A. Shankarappa, Itay Sagie, Jonathan H. Tsui, Homer H. Chiang, Cristina F. Stefanescu, David Zurakowski, Daniel S. KohaneAbstract:Background and Objectives Quaternary lidocaine derivatives (QLDs) have recently received much attention because of their potential application in prolonged or sensory-selective local anesthesia. However, associated tissue toxicity is an impeding factor that makes QLDs unfavorable for clinical use. Based on the proposed intracellular site of action, we hypothesized that nerve blocks obtained from lower concentrations of QLDs would be enhanced by the coapplication of extracellularly acting site 1 Sodium-Channel blocker, resulting in prolonged block duration but with minimal tissue toxicity. Methods Quaternary lidocaine derivatives (QX-314 or QX-222), site 1 Sodium-Channel Blockers (tetrodotoxin [30 μM] or saxitoxin [12.5 μM]), or both were injected in the vicinity of the sciatic nerve. Thermal nociceptive block was assessed using a modified hot plate test; motor block by a weight-bearing test. Tissue from the site of injection was harvested for histological assessment. Results Coapplication of 25 mM QX-314 or 100 mM QX-222 with site 1 Sodium-Channel Blockers produced an 8- to 10- fold increase in the duration of nerve blocks (P Conclusions Coadministration of site 1 Sodium-Channel Blockers and QLDs greatly prolongs the duration of peripheral nerve block without enhancing local tissue injury, but minimal myotoxicity still persists. It is not clear that the risks of QLDs are outweighed by the benefits in providing prolonged nerve blockade.
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Site 1 Sodium Channel Blockers prolong the duration of sciatic nerve blockade from tricyclic antidepressants.
Pain, 2004Co-Authors: Caryn S Barnet, Julie Y Tse, Daniel S. KohaneAbstract:Many recent reports in the literature address the local anesthetics efficacy of tricyclic antidepressants (TCAs). Here we investigated whether nerve block from TCAs is prolonged by site 1 Sodium Channel Blockers such as tetrodotoxin and saxitoxin, which are known to prolong block from conventional local anesthetics. Tetrodotoxin and saxitoxin greatly prolonged block from TCAs. For example, the median duration of thermal nociceptive blocks for 10 mM amitriptyline, nortriptyline and doxepin were 0, 0, and 124 min; co-injection with 20 microM TTX (median block duration=0), yielded blocks lasting 404, 325, and 697 min, respectively. Co-injection of 12 microM saxitoxin (median block duration=0) with 10 mM amitriptyline resulted in a thermal nociceptive block duration of 373 min. Co-injection of 7.7 mM bupivacaine and 7.7 mM amiptriptyline did not result in block prolongation. Systemic (subcutaneous) delivery of tetrodotoxin or amitriptyline did not result in prolongation of block from the other class of drug injected at the sciatic nerve. In TCA-containing formulations, motor blockade was consistently longer than thermal nociceptive block; motor blockade was also prolonged by tetrodotoxin and saxitoxin. In summary site 1 Sodium Channel Blockers prolong the duration of TCAs via a locally mediated mechanism.
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Vanilloid receptor agonists potentiate the in vivo local anesthetic activity of percutaneously injected site 1 Sodium Channel Blockers.
Anesthesiology, 1999Co-Authors: Daniel S. Kohane, Yu Kuang, Robert Langer, Gary R. Strichartz, Charles B. BerdeAbstract:Background Capsaicin, the pungent ingredient in chili peppers, is a vanilloid with noxious and analgesic effects that inhibits tetrodotoxin-resistant Sodium currents. Because tetrodotoxin-resistant currents are found primarily in small-diameter nociceptor afferents of the peripheral nerves, their inhibition may lead to selective analgesia. Therefore, the authors evaluated the interactions between tetrodotoxin, a site 1 Sodium Channel blocker, and capsaicin on nerve blockade in vivo. Methods Percutaneous sciatic nerve injections with 0 to 9.9 mM capsaicin, 0 to 120 microM tetrodotoxin, or both were administered to male Sprague-Dawley rats. Thermal nociceptive and motor blockade were measured. Data were expressed as medians with 25th and 75th percentiles. Results Capsaicin produced a transient increase in thermal latency with no effect on motor strength. Tetrodotoxin reduced motor strength for a longer duration than nociception. The interaction between tetrodotoxin and capsaicin was synergistic, as evidenced by (1) supraadditive prolongation of both nociceptive and motor block, with the effect of capsaicin reversed by the vanilloid antagonist capsazepine, and (2) synergism in the frequency that rats achieved maximal block shown by isobolographic analysis. The combination of tetrodotoxin and capsaicin showed less motor predominance than tetrodotoxin did alone. Similar interactions were found between tetrodotoxin and resiniferatoxin (another vanilloid), and between capsaicin and saxitoxin (another site 1 Sodium Channel blocker), but much less so between bupivacaine and capsaicin. Conclusions Site 1 Sodium Channel Blockers and vanilloids have synergistic effects on nerve blockade in vivo. These interactions may be useful in developing prolonged local anesthetics and elucidating mechanisms of functionally selective nerve blockade.
Birgit T. Priest - One of the best experts on this subject based on the ideXlab platform.
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Discovery of isoxazole voltage gated Sodium Channel Blockers for treatment of chronic pain
Bioorganic & Medicinal Chemistry Letters, 2009Co-Authors: Pengcheng Shao, Ann E. Weber, Kathryn A. Lyons, William H. Parsons, Maria L. Garcia, Birgit T. Priest, Mchardy M. Smith, John P. FelixAbstract:Abstract A series of novel isoxazole voltage gated Sodium Channel Blockers have been synthesized and evaluated. Substitutions on the benzylic position of benzamide were investigated to determine their effect on Na v 1.7 inhibitory potency. The spirocyclobutyl substitution had the most significant enhancement on Na v 1.7 inhibitory activity.
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Future potential and status of selective Sodium Channel Blockers for the treatment of pain.
Current opinion in drug discovery & development, 2009Co-Authors: Birgit T. PriestAbstract:Voltage-gated Sodium (NaV1) Channels in the peripheral nervous system and CNS play a critical role in pain signaling. Nociceptive neurons express several NaV1 Channel subtypes that may contribute to the hyperexcitability characteristic of chronic pain states. The non-subtype selective, state-dependent NaV1 Channel Blockers lidocaine and carbamazepine are efficacious in the treatment of neuropathic pain; however, the target-driven development of novel Sodium Channel blocking analgesics has been generally unsuccessful. Recent human genetic data indicate an important role for the NaV1.7 Channel subtype in pain signaling, and significant preclinical data identifies the NaV1.8 Channel as a promising analgesic target, suggesting that the selective blockade of these subtypes may improve on the therapeutic index of Sodium Channel modulators. However, few subtype-selective small-molecule Sodium Channel Blockers have been described. This review provides an overview of the NaV1 Channel subtypes that are preferentially expressed in nociceptive neurons, the assay technologies used to develop NaV1 Channel Blockers, and a summary of recent advances in the development of subtype-selective and novel state-dependent NaV1 Channel Blockers.
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Discovery of a novel class of isoxazoline voltage gated Sodium Channel Blockers
Bioorganic & Medicinal Chemistry Letters, 2009Co-Authors: Pengcheng Shao, Ann E. Weber, Kathryn A. Lyons, William H. Parsons, Maria L. Garcia, Birgit T. Priest, Mchardy M. Smith, John P. FelixAbstract:Analogs of the previously reported voltage gated Sodium Channel blocker CDA54 were prepared in which one of the amide functions was replaced with aromatic and non-aromatic heterocycles. Replacement of the amide with an aromatic heterocycle resulted in significant loss of Sodium Channel blocking activity, while non-aromatic heterocycle replacements were well tolerated.
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imidazopyridines a novel class of hnav1 7 Channel Blockers
Bioorganic & Medicinal Chemistry Letters, 2008Co-Authors: Clare London, Brande S. Williams, William H. Parsons, Birgit T. Priest, Mchardy M. Smith, Scott B. Hoyt, Vivien A Warren, Richard Tschirretguth, Erin Mcgowan, William J. MartinAbstract:Abstract—A series of imidazopyridines were evaluated as potential Sodium Channel Blockers for the treatment of neuropathic pain.Several members were identified with good hNa v 1.7 potency and excellent rat pharmacokinetic profiles. Compound 4 had good effi-cacy (52% and 41% reversal of allodynia at 2 and 4 h post-dose, respectively) in the Chung rat spinal nerve ligation (SNL) model ofneuropathic pain when dosed orally at 10 mg/kg. 2008 Elsevier Ltd. All rights reserved. Neuropathic pain is a chronic and debilitating diseasecaused by injury or pathological changes to the periph-eral or central nervous systems. These changes result inthe abnormal processing of external stimuli (e.g., touch,temperature) by the affected pain sensing neurons (noci-ceptors). 1,2 Voltage-gated Sodium Channels (Na v 1AEx) arestrongly expressed in nociceptors and are known to beimportant in nociception. 3 Clinically, it has been shownthat voltage-gated Sodium Channel Blockers such asmexiletine (1) and carbamazepine (2)(Fig. 1) are effica-cious in the treatment of neuropathic pain. These thera-pies, however, are restricted by their dose limiting CNSside effects.
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subtype selective Sodium Channel Blockers promise a new era of pain research
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Birgit T. Priest, Gregory J KaczorowskiAbstract:Chronic pain affects ≈1.5 million patients worldwide. Despite several treatment options, successful pain management is difficult to achieve, and this area of therapy remains a major unmet medical need. Chronic pain is thought to originate from aberrant electrical signaling in the nervous system. Pain-sensing neurons of the peripheral nervous system express several Sodium Channel (Nav1) subtypes. Their relative contribution to pain signaling is the subject of intense research and debate, and they may vary depending on the cause, anatomical location, and sensory qualities of pain. Knockdown of individual Sodium Channel subtypes in rodents, either by genetic ablation or through treatment with antisense oligonucleotides, has provided important information on this subject. However, interpretation of the results may be confounded by compensatory mechanisms, in the case of genetic ablation, or residual protein expression and inflammation associated with the oligonucleotide administration, in the case of the antisense technology. Subtype-selective pharmacological agents are needed to identify unambiguously the roles of individual Nav1 subtypes, but, despite years of efforts, such agents have been difficult to identify. The manuscript by Jarvis et al. (1) in this issue of PNAS reveals the first reputed Nav1.8-selective small-molecule Sodium Channel blocker to be publicly disclosed. By providing a much-sought-after exciting new tool, this work represents a …
Shiro Kamakura - One of the best experts on this subject based on the ideXlab platform.
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effect of Sodium Channel blockade on early repolarization in inferior lateral leads in patients with idiopathic ventricular fibrillation and brugada syndrome
Heart Rhythm, 2012Co-Authors: Hiro Kawata, Takashi Noda, Yuko Yamada, Hideo Okamura, Kazuhiro Satomi, Takeshi Aiba, Hiroshi Takaki, Naohiko Aihara, Mitsuaki Isobe, Shiro KamakuraAbstract:Background A high incidence of early repolarization (ER) pattern in the inferolateral leads has been reported in patients with idiopathic ventricular fibrillation (IVF). Brugada syndrome (BS) is characterized by J-point or ST-segment elevation in the right precordial leads and ventricular fibrillation, and some patients with BS also have ER in the inferolateral leads. Objective To compare the clinical characteristics and effects of Sodium-Channel blockade on ER between IVF patients with ER (early repolarization syndrome [ERS]) and BS patients with or without ER. Methods Fourteen patients with ERS and 21 patients with BS were included in this study. ER was defined as an elevation of at least 0.1 mV from baseline in the QRS–T junction in the inferorolateral leads. Provocative tests with Sodium-Channel Blockers were conducted in all patients with ERS to distinguish ERS from BS. Results In the ERS group, all patients were male and most patients experienced ventricular fibrillation during sleep or low activity (79%). ER was attenuated by Sodium-Channel Blockers in most patients with ERS (13/14, 93%) and BS (5/5, 100%), whereas ST-segment elevation was augmented in the right precordial leads in the BS group. The rates of positive late potentials were significantly higher in the BS group (60%) than in the ERS group (7%) ( P Conclusions Some similarities were observed between ERS and BS, including gender, arrhythmia triggers, and response of ER to Sodium-Channel Blockers. Unlike the ST segment in the right precordial leads in BS, ER was attenuated in patients with both ERS and BS, suggesting a differential mechanism between ER in the inferolateral leads and ST elevation in the right precordial leads.
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abnormal response to Sodium Channel Blockers in patients with brugada syndrome augmented localised wall motion abnormalities in the right ventricular outflow tract region detected by electron beam computed tomography
Heart, 2003Co-Authors: Masahiko Takagi, Shiro Kamakura, N Aihara, S Kuribayashi, Atsushi Taguchi, Takashi Kurita, K Suyama, M TakamiyaAbstract:Objective: To investigate the relation between the wall motion abnormalities and Sodium Channel abnormalities in cases of the Brugada syndrome. Design: Consecutive prospective case‐control study in a single hospital. Setting: Tertiary referral centre. Patients: 13 consecutive patients with Brugada syndrome and 13 age and sex matched control subjects. Interventions: Each subject underwent electron beam computed tomography (EBT) and a 12 lead ECG before and after disopyramide injection. Main outcome measures: QRS width and the magnitude of ST segment elevation in the 12 lead ECG; wall motion by EBT. Results: After disopyramide, EBT revealed deterioration of focal wall motion abnormalities in the right ventricular outflow tract region in eight of the 13 patients (62%). Prolongation of the QRS width after disopyramide injection in lead V2, which usually reflects the electrical activity in right ventricular outflow tract region, was greater in these eight patients (p < 0.01) than in the other five patients, in whom wall motion did not change after disopyramide. The degree of augmentation of ST segment elevation did not differ significantly between the two groups Conclusions: The deterioration of wall motion abnormalities in the right ventricular outflow tract region after disopyramide suggests the presence of functional abnormalities of the Sodium Channel. Some patients with Brugada syndrome may have arrhythmogenic substrates with abnormal responses to Sodium Channel Blockers.
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effect of Sodium Channel Blockers on st segment qrs duration and corrected qt interval in patients with brugada syndrome
Journal of Cardiovascular Electrophysiology, 2000Co-Authors: Wataru Shimizu, Charles Antzelevitch, Kazuhiro Suyama, M Takashi D Kurita, M Atsushi D Taguchi, M Naohiko D Aihara, M Hiroshi D Takaki, Kenji Sunagawa, Shiro KamakuraAbstract:ST Elevation in Brugada Syndrome. Introduction: Brugada syndrome is characterized by an ST segment elevation in leads V1-V3 and a high incidence of ventricular fibrillation (VF). A mutation in a cardiac Na+ Channel gene, SCN5A, has been linked to Brugada syndrome, and Sodium Channel Blockers have been shown to be effective in unmasking the syndrome when concealed. The aim of this study was to examine the effects of Na+ Channel Blockers on ST segment elevation, QRS, corrected QT (QTc) interval, and ventricular arrhythmias in patients with Brugada syndrome. Methods and Results: We examined the effects of three different Na+ Channel Blockers (flecainide, disopyramide, and mexiletine) on the amplitude of the ST segment 20 msec after the end of QRS (ST20), QRS duration, QTc interval measured from 12-lead ECG, and ventricular arrhythmias in 12 Brugada and 10 control patients. Maximum ST20 observed in the V2 or V3 leads under baseline conditions was greater in the Brugada patients than in control patients, whereas QRS duration and maximum QTc interval were no different between the two groups. Flecainide and disopyramide, but not mexiletine, significantly increased maximum ST20 and QRS duration in both groups, although these effects were much more pronounced in the Brugada patients. The increases in ST20 and QRS duration with flecainide were significantly larger than those with disopyramide. An increase of 0.15 mV in ST20 with flecainide separated the two groups without overlap. Ventricular premature complexes developed only with flecainide in Brugada patients (3/12) displaying a marked ST elevation but not widening of QRS. Conclusion: Our findings suggest that Na+ Channel Blockers amplify existing INa and possibly other ion Channel defects, with a potency inversely proportional to the rate of dissociation of the drug from the Na+ Channel, thus causing a prominent elevation of the ST segment and, in some cases, prolongation of QRS duration in patients with Brugada syndrome.
Brande S. Williams - One of the best experts on this subject based on the ideXlab platform.
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substituted biaryl pyrazoles as Sodium Channel Blockers
Bioorganic & Medicinal Chemistry Letters, 2010Co-Authors: Sriram Tyagarajan, Prasun K. Chakravarty, Bishan Zhou, Michael H. Fisher, Mathew J. Wyvratt, Kathy Lyons, Tracy Klatt, Sanjeev Kumar, Brett Taylor, Brande S. WilliamsAbstract:Voltage-gated Sodium Channels have been shown to play a critical role in neuropathic pain. A series of low molecular weight biaryl substituted pyrazole carboxamides were identified with good in-vitro potency and in-vivo efficacy. Compound 26, a Nav1.7 blocker has excellent efficacy in the Chung model of neuropathic pain.
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Substituted biaryl oxazoles, imidazoles, and thiazoles as Sodium Channel Blockers.
Bioorganic & Medicinal Chemistry Letters, 2010Co-Authors: Sriram Tyagarajan, Prasun K. Chakravarty, Bishan Zhou, Michael H. Fisher, Mathew J. Wyvratt, Kathy Lyons, Tracy Klatt, Sanjeev Kumar, Brande S. WilliamsAbstract:Voltage-gated Sodium Channels have been shown to play a critical role in neuropathic pain. With a goal to develop potent peripherally active Sodium Channel Blockers, a series of low molecular weight biaryl substituted imidazoles, oxazoles, and thiazole carboxamides were identified with good in vitro and in vivo potency.
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imidazopyridines a novel class of hnav1 7 Channel Blockers
Bioorganic & Medicinal Chemistry Letters, 2008Co-Authors: Clare London, Brande S. Williams, William H. Parsons, Birgit T. Priest, Mchardy M. Smith, Scott B. Hoyt, Vivien A Warren, Richard Tschirretguth, Erin Mcgowan, William J. MartinAbstract:Abstract—A series of imidazopyridines were evaluated as potential Sodium Channel Blockers for the treatment of neuropathic pain.Several members were identified with good hNa v 1.7 potency and excellent rat pharmacokinetic profiles. Compound 4 had good effi-cacy (52% and 41% reversal of allodynia at 2 and 4 h post-dose, respectively) in the Chung rat spinal nerve ligation (SNL) model ofneuropathic pain when dosed orally at 10 mg/kg. 2008 Elsevier Ltd. All rights reserved. Neuropathic pain is a chronic and debilitating diseasecaused by injury or pathological changes to the periph-eral or central nervous systems. These changes result inthe abnormal processing of external stimuli (e.g., touch,temperature) by the affected pain sensing neurons (noci-ceptors). 1,2 Voltage-gated Sodium Channels (Na v 1AEx) arestrongly expressed in nociceptors and are known to beimportant in nociception. 3 Clinically, it has been shownthat voltage-gated Sodium Channel Blockers such asmexiletine (1) and carbamazepine (2)(Fig. 1) are effica-cious in the treatment of neuropathic pain. These thera-pies, however, are restricted by their dose limiting CNSside effects.
Arthur A M Wilde - One of the best experts on this subject based on the ideXlab platform.
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scn5a mutation type and topology are associated with the risk of ventricular arrhythmia by Sodium Channel Blockers
International Journal of Cardiology, 2018Co-Authors: Ahmad S Amin, Yolan J Reckman, Elena Arbelo, Anne M Spanjaart, Pieter G Postema, Rafik Tadros, Michael W T Tanck, Maarten P Van Den Berg, Arthur A M WildeAbstract:Abstract Background Ventricular fibrillation in patients with Brugada syndrome (BrS) is often initiated by premature ventricular contractions (PVCs). Presence of SCN5A mutation increases the risk of PVCs upon exposure to Sodium Channel Blockers (SCB) in patients with baseline type-1 ECG. In patients without baseline type-1 ECG, however, the effect of SCN5A mutation on the risk of SCB-induced arrhythmia is unknown. We aimed to establish whether presence/absence, type, and topology of SCN5A mutation correlates with PVC occurrence during ajmaline infusion. Methods and results We investigated 416 patients without baseline type-1 ECG who underwent ajmaline testing and SCN5A mutation analysis. A SCN5A mutation was identified in 88 patients (S+). Ajmaline-induced PVCs occurred more often in patients with non-missense mutations (Snon-missense) or missense mutations in transmembrane or pore regions of SCN5A-encoded Channel protein (Smissense-TP) than patients with missense mutations in intra-/extracellular Channel regions (Smissense-IE) and patients without SCN5A mutation (S−) (29%, 24%, 9%, and 3%, respectively; P Conclusions SCN5A mutation is associated with an increased risk of drug-induced ventricular arrhythmia in patients without baseline type-1 ECG. In particular, Snon-missense and Smissense-TP are at high risk.