Benzonatate
(Synonyms: 苯佐那酯,Benzononatine) 目录号 : GC42919A voltage-gated sodium channel blocker
Cas No.:104-31-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Benzonatate is a reversible voltage-gated sodium channel blocker.[1] It blocks Nav1.7 currents in a concentration- and voltage-dependent manner (IC50s = 5.9 and 1.4 μM at holding potentials of -100 and -70 mV, respectively) and inhibits action potential firing in catecholamine A differentiated (CAD) cells. Benzonatate also blocks 80% of Nav1.3 currents in N1E-115 cells when used at a concentration of 100 μM. In vivo, benzonatate (0.85 mg/min) reduces the frequency, but has no effect on the amplitude, of the cough reflex in anesthetized dogs.[2] Formulations containing benzonatate have been used as antitussive agents for the treatment of coughs.
Reference:
[1]. Evans, M.S., Maglinger, G.B., and Fletcher, A.M. Benzonatate inhibition of voltage-gated sodium currents. Neuropharmacology 101, 179-187 (2016).
[2]. Yanaura, S., Hosokawa, T., Kitagawa, H., et al. Effects of peripheral airway response on the cough reflex (author’s transl). Nihon Yakurigaku Zasshi. 76(8), 709-716 (1980).
| Cas No. | 104-31-4 | SDF | |
| 别名 | 苯佐那酯,Benzononatine | ||
| 化学名 | 4-(butylamino)-benzoic acid, 3,6,9,12,15,18,21,24,27-nonaoxaoctacos-1-yl ester | ||
| Canonical SMILES | O=C(OCCOCCOCCOCCOCCOCCOCCOCCOCCOC)C1=CC=C(NCCCC)C=C1 | ||
| 分子式 | C30H53NO11 | 分子量 | 603.8 |
| 溶解度 | DMF: 50 mg/ml,DMSO: 50 mg/ml,Ethanol: 50 mg/ml,Ethanol:PBS(pH 7.2) (1:1): 0.5 mg/ml | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.6562 mL | 8.2809 mL | 16.5618 mL |
| 5 mM | 0.3312 mL | 1.6562 mL | 3.3124 mL |
| 10 mM | 0.1656 mL | 0.8281 mL | 1.6562 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Benzonatate Exposure Trends and Adverse Events
Pediatrics 2022 Dec 1;150(6):e2022057779.PMID:36377394DOI:10.1542/peds.2022-057779.
Background and objectives: Adverse events (AE), including death, occur in children with Benzonatate use. This study aims to understand recent trends in Benzonatate exposure and clinical consequences in pediatric patients. Methods: This retrospective analysis of data from IQVIA pharmacy drug dispensing, National Poison Data System, National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance Project, FDA Adverse Event Reporting System, and the medical literature evaluated exposure trends and medication-related AEs with Benzonatate. Trends for comparator narcotic and nonnarcotic antitussive medications were analyzed where possible for context. Results: During the study period, pediatric Benzonatate prescription utilization increased but remained low compared with pediatric utilization of dextromethorphan-containing prescription antitussive medications. Among the 4689 pediatric Benzonatate exposure cases reported to US poison control centers from 2010 to 2018, 3727 cases (80%) were for single-substance exposures. Of these, 3590 cases (77%) were unintentional exposures and most involved children 0 to 5 years old (2718 cases, 83%). Cases involving intentional Benzonatate exposure increased among children 10 to 16 years old with a more pronounced increase for multiple-substance exposures. Most Benzonatate cases involving misuse or abuse were for children 10 to 16 years old (59 cases, 61%). The proportion of cases with serious adverse effects was low. There were few cases annually of serious AEs with Benzonatate in children. Conclusions: There were rising patterns of unintentional ingestion of Benzonatate in children 0 to 5 years old and intentional Benzonatate ingestion in children 10 to 16 years old. Rational prescribing and improved provider and caregiver awareness of Benzonatate toxic effects may reduce risks associated with Benzonatate exposure.
Benzonatate as a local anesthetic
PLoS One 2023 Apr 12;18(4):e0284401.PMID:37043508DOI:10.1371/journal.pone.0284401.
Introduction: Benzonatate is an FDA-approved antitussive agent that resembles tetracaine, procaine, and cocaine in its chemical structure. Based on structural similarities to known local anesthetics and recent findings of Benzonatate exerting local anesthetic-like effects on voltage-gated sodium channels in vitro, we hypothesized that Benzonatate will act as a local anesthetic to yield peripheral nerve blockade. Methods: Benzonatate was injected at the sciatic nerve of Sprague-Dawley rats. Sensory and motor blockade were assessed using a modified hot plate test and a weight-bearing test, respectively. Additionally, the effect of co-injection with tetrodotoxin and Tween 80 (a chemical permeation enhancer) was examined. Myotoxicity of Benzonatate was assessed in vivo by histological analysis. Results: Benzonatate produced a concentration-dependent sensory and motor nerve blockade with no appreciable systemic effects. Co-injection with tetrodotoxin or Tween 80 produced prolongation of sensory nerve blockade. Histologic assessment showed significant inflammation and myotoxicity from Benzonatate injection, even at low concentrations. Conclusion: This study demonstrates that Benzonatate does act as a local anesthetic at the peripheral nerve, with sensory and motor nerve blockade. Benzonatate interacts with tetrodotoxin and Tween 80 to prolong nerve blockade. However, Benzonatate causes significant myotoxicity, even at subtherapeutic concentrations.
Benzonatate Safety and Effectiveness: A Systematic Review of the Literature
Ann Pharmacother 2023 Jan 23;10600280221135750.PMID:36688284DOI:10.1177/10600280221135750.
Objective: To review the available literature regarding the treatment effects and efficacy of Benzonatate needed to better inform patients, providers, and regulators evaluating its role in modern medical therapies. Data sources: Comprehensive literature searches were conducted in PubMed, Embase (Elsevier), Cochrane Library, and Scopus for original research articles evaluating the effectiveness, tolerability, and safety profile of Benzonatate from January 1956 through August 2022. Study selection and data extraction: The identified studies were screened for relevance and then assessed for inclusion through a full-text review, data extraction, and quality assessment by multiple reviewers using the online software Covidence. Data synthesis: The selection process resulted in 37 articles consisting of 21 cohort studies, 5 experimental studies, and 11 case studies and series. Initial clinical studies exploring potential therapeutic benefits collected data from very small populations and limited clinical settings. Safety is primarily assessed in terms of toxicity due to overdose or inappropriate use. Quality assessment raised concerns for high degrees of biases primarily related to the limited sample size, data collection, generalizability, and study design. Relevance to patient care and clinical practice: This review reveals substantial limitations within existing evidence pertaining to the safety and clinical effectiveness of Benzonatate and thus, a need for large observational studies or randomized trials to better characterize its role and value in modern medical practice. Conclusions: Rising safety concerns should bring closer scrutiny upon the prescription of Benzonatate whose approval is founded upon evidence that would not stand up to current regulatory review.
Benzonatate inhibition of voltage-gated sodium currents
Neuropharmacology 2016 Feb;101:179-87.PMID:26386152DOI:10.1016/j.neuropharm.2015.09.020.
Benzonatate was FDA-approved in 1958 as an antitussive. Its mechanism of action is thought to be anesthesia of vagal sensory nerve fibers that mediate cough. Vagal sensory neurons highly express the Nav1.7 subtype of voltage-gated sodium channels, and inhibition of this channel inhibits the cough reflex. Local anesthetics inhibit voltage-gated sodium channels, but there are no reports of whether Benzonatate affects these channels. Our hypothesis is that Benzonatate inhibits Nav1.7 voltage-gated sodium channels. We used whole cell voltage clamp recording to test the effects of Benzonatate on voltage-gated sodium (Na(+)) currents in two murine cell lines, catecholamine A differentiated (CAD) cells, which express primarily Nav1.7, and N1E-115, which express primarily Nav1.3. We found that, like local anesthetics, Benzonatate strongly and reversibly inhibits voltage-gated Na(+) channels. Benzonatate causes both tonic and phasic inhibition. It has greater effects on channel inactivation than on activation, and its potency is much greater at depolarized potentials, indicating inactivated-state-specific effects. Na(+) currents in CAD cells and N1E-115 cells are similarly affected, indicating that Benzonatate is not Na(+) channel subtype-specific. Benzonatate is a mixture of polyethoxy esters of 4-(butylamino) benzoic acid having varying degrees of hydrophobicity. We found that Na(+) currents are inhibited most potently by a Benzonatate fraction containing the 9-ethoxy component. Detectable effects of Benzonatate occur at concentrations as low as 0.3 μM, which has been reported in humans. We conclude that Benzonatate has local anesthetic-like effects on voltage-gated sodium channels, including Nav1.7, which is a possible mechanism for cough suppression by the drug.
Benzonatate Overdose Presenting as Cardiac Arrest with Rapidly Narrowing QRS Interval
J Med Toxicol 2022 Oct;18(4):344-349.PMID:PMC9492832DOI:10.1007/s13181-022-00904-4.
Introduction: Benzonatate is a local anesthetic-like sodium channel antagonist that is widely prescribed as an antitussive. While it may be reasonable to assume that patients would present with a prolonged QRS interval following Benzonatate overdose, the published literature does not support this. We report a case of a patient presenting following a Benzonatate overdose with a prolonged QRS on her initial electrocardiograph (ECG) rhythm strip with rapid normalization of QRS duration. Case report: A 14-year-old girl presented in cardiac arrest following a Benzonatate overdose. The patient was found in cardiac arrest within minutes of last being known well. Bystanders immediately provided cardiopulmonary resuscitation (CPR), and she was in asystole on emergency medical services (EMS) arrival. Return of spontaneous circulation (ROSC) was obtained following administration of intraosseous epinephrine and naloxone. EMS obtained an ECG rhythm strip following ROSC demonstrating a sinus rhythm with a QRS duration of 160 ms. Over the ensuing 30 minutes, there was progressive narrowing of the QRS. A 12-lead ECG obtained on arrival in the emergency department (ED) 44 minutes later demonstrated a QRS duration of 94 ms. Initially, EMS ECG rhythm strips were unavailable and an isolated Benzonatate ingestion was considered less likely as ECG intervals were normal. Benzonatate exposure was later confirmed with a urine Benzonatate concentration, which was 8.5 mcg/mL. The patient made a full recovery. Discussion: Cases of pediatric Benzonatate overdose with rapid development of cardiac arrest and full recovery have been previously reported. In this case, evidence of cardiac sodium channel blockade was demonstrated with a prolonged QRS interval on initial ECG rhythm strip analysis. However, unlike previous cases, rapid resolution of QRS prolongation occurred in this case. While transient QRS prolongation may be observed, finding a normal QRS interval should not discount the possibility of Benzonatate overdose.