クロサンテル
概要
説明
クロサンテルは、サリチルアニリド系に属する合成抗寄生虫剤です。 主に獣医学において、回虫や肝吸虫などの内部寄生虫、および羊の鼻虫や牛のウジ虫などの外部寄生虫の駆除に使用されます . クロサンテルは、農業や家庭用害虫には使用されず、ヒトへの使用は意図されていません .
製造方法
クロサンテルは、さまざまな方法で合成することができます。 一方法は、クロサンテルナトリウム中間体を触媒的水素化によって製造する方法です . 別の方法には、クロサンテルナトリウム注射液の製造が含まれ、エタノールとプロピレングリコールを混合し、混合物を加熱し、クロサンテルナトリウムを加え、水酸化ナトリウム溶液でpHを調整します . これらの方法は効率的で、工業生産に適しています。
科学的研究の応用
Antiparasitic Applications
Closantel is widely recognized for its effectiveness against various parasitic infections in ruminants, particularly against blood-feeding helminths such as Fasciola hepatica and Haemonchus contortus. It operates by inhibiting the metabolism of these parasites, leading to their death.
Efficacy Against Specific Parasites
- Fasciola spp. : Closantel has shown a 100% efficacy rate against Fasciola spp. in clinical settings, significantly reducing fecal egg counts within a week post-treatment .
- Haemonchus spp. : In studies comparing various anthelmintics, closantel demonstrated superior effectiveness against Haemonchus spp., outperforming other treatments like levamisole and fenbendazole .
Pharmacokinetics and Bioavailability
The pharmacokinetic profile of closantel has been extensively studied to optimize its use in livestock. Key findings include:
- High Plasma Protein Binding : Closantel exhibits a high degree of plasma protein binding (approximately 99%), contributing to its prolonged action in the body .
- Bioequivalence Studies : Research has confirmed that different formulations of closantel show similar pharmacokinetic parameters, ensuring consistent therapeutic outcomes across formulations .
Table 1: Pharmacokinetic Parameters of Closantel
| Parameter | Value |
|---|---|
| Cmax | Varies by formulation |
| Tmax | 24-48 hours |
| Half-life | 5-7 days |
| Plasma Protein Binding | ~99% |
Clinical Studies and Milk Production
A randomized controlled trial evaluated the impact of closantel on milk production in dairy cattle. The study found that administering closantel improved milk yield and reduced antibody levels against Fasciola hepatica in milk samples .
Study Design Overview
- Population : First-calf heifers.
- Dosage : 0.2 ml/kg body weight.
- Duration : Administered at dry-off, between 80 and 42 days before calving.
Novel Applications in Oncology
Recent research indicates potential applications of closantel beyond veterinary medicine. It has been identified as a BRAFV600E enzyme inhibitor, suggesting its potential use in preparing drugs for treating certain tumors, including melanoma and colorectal cancer .
Conclusion and Future Directions
Closantel remains a vital compound in veterinary medicine with proven efficacy against various parasitic infections in livestock. Its pharmacokinetic properties support its long-term use, while emerging research suggests novel applications in oncology. Future studies should focus on expanding its therapeutic uses and understanding its mechanisms further.
作用機序
クロサンテルは、寄生虫のミトコンドリアにおける酸化的リン酸化を解離させることで抗寄生虫作用を発揮し、細胞の「燃料」であるアデノシン三リン酸（ATP）の産生を阻害します . この機構により、フマル酸が蓄積され、最終的に寄生虫の死に至ります . クロサンテルは、フマル酸合成に関与する重要な酵素であるフマル酸レダクターゼも阻害します .
類似の化合物との比較
クロサンテルは、その特異的な作用機序とさまざまな寄生虫に対する幅広いスペクトル活性により、抗寄生虫剤の中でも独特です。 類似の化合物には、オキシクロザニドやラフォキサニドなどの他のサリチルアニリド誘導体があります . これらの化合物は、類似の化学構造と作用機序を共有していますが、特定の寄生虫に対する活性スペクトルと有効性に違いがある可能性があります .
生化学分析
Biochemical Properties
Closantel acts mainly via the energy metabolism pathway by uncoupling oxidative phosphorylation in liver flukes . This interaction disrupts the energy balance within the parasite, leading to its death .
Cellular Effects
Closantel has been found to reverse antibiotic resistance in gram-negative bacteria . It increases the activity of antibiotics against these bacteria, both in vitro and in vivo . In humans, accidental ingestion of Closantel can lead to severe visual loss due to the destruction of neurosensory retina and visual pathways .
Molecular Mechanism
Closantel’s mechanism of action involves the disruption of energy metabolism within parasites . It uncouples oxidative phosphorylation, a process crucial for the production of ATP, the energy currency of the cell . This disruption leads to energy depletion within the parasite, ultimately causing its death .
Temporal Effects in Laboratory Settings
It is known that Closantel has a long half-life in plasma, around 15 days , indicating its stability and potential for long-term effects on cellular function.
Dosage Effects in Animal Models
In animals, the usual dose of Closantel is 7.5-10 mg/kg . Overdosing can lead to hypersensitivity reactions, including skin rash, fever, facial swelling, or difficulty breathing . Severe side effects have been reported in humans following accidental ingestion of Closantel .
Metabolic Pathways
Closantel is involved in the energy metabolism pathway within parasites, specifically in the process of oxidative phosphorylation . It acts as an uncoupler, disrupting the flow of protons across the mitochondrial membrane, which is essential for ATP production .
Transport and Distribution
Information on the transport and distribution of Closantel within cells and tissues is limited. It is known that Closantel reaches maximum plasma levels 8 to 24 hours after dosing, and up to 60% of an intramuscular dose is present in the plasma up to about 4 days after injection .
Subcellular Localization
Given its mechanism of action, it is likely that Closantel localizes to the mitochondria, where oxidative phosphorylation occurs .
準備方法
Closantel can be synthesized through various methods. One method involves the preparation of closantel sodium intermediate by catalytic hydrogenation . Another method includes the preparation of closantel sodium injection, which involves mixing ethanol and propylene glycol, heating the mixture, adding sodium closantel, and adjusting the pH with sodium hydroxide solution . These methods are efficient and suitable for industrial production.
化学反応の分析
クロサンテルは、酸化、還元、置換など、いくつかのタイプの化学反応を起こします。 例えば、クロサンテルのエナンチオマー分離は、異なるキラル固定相と移動相組成を用いた高速液体クロマトグラフィー（HPLC）によって達成することができます . これらの反応から生成される主な生成物はクロサンテルのエナンチオマーであり、分離して分析することでさらなる研究を行うことができます .
科学研究アプリケーション
クロサンテルは、幅広い科学研究アプリケーションを持っています。 獣医学では、特に羊や牛などの家畜の寄生虫感染症の駆除に使用されています . 分析化学では、クロサンテルは、HPLCを用いたエナンチオマーのエナンチオ分離に使用されています . さらに、牛乳や動物組織中のクロサンテル残留物は、蛍光検出を用いた液体クロマトグラフィーで測定できます . これらのアプリケーションは、この化合物がさまざまな研究分野で汎用性があることを示しています。
類似化合物との比較
Closantel is unique among antiparasitic agents due to its specific mechanism of action and broad-spectrum activity against various parasites. Similar compounds include other salicylanilide derivatives such as oxyclozanide and rafoxanide . These compounds share similar chemical structures and mechanisms of action but may differ in their spectrum of activity and efficacy against specific parasites .
生物活性
Closantel is an anthelmintic compound primarily used in veterinary medicine for the treatment of parasitic infections, particularly those caused by trematodes and nematodes. Recent studies have expanded its application to include antibacterial properties, showcasing its potential in combating multidrug-resistant bacterial infections. This article explores the biological activity of closantel, focusing on its antimicrobial effects, toxicity, and pharmacokinetics.
Antimicrobial Activity
Closantel has demonstrated significant antibacterial activity, particularly against gram-negative bacteria. A study highlighted the synergistic effects of closantel when combined with polymyxin B against Acinetobacter baumannii, a notorious multidrug-resistant pathogen. The combination therapy was effective in inhibiting the development of resistance to polymyxin B, suggesting that closantel can serve as a valuable adjuvant in treating severe bacterial infections.
Key Findings:
- Minimum Inhibitory Concentration (MIC) : Closantel alone showed MIC values greater than 128 mg/L against most A. baumannii isolates but achieved lower MICs (0.5 mg/L) against certain polymyxin-resistant strains when used in combination with polymyxin B .
- Synergistic Effects : The combination of polymyxin B (2 mg/L) with closantel (4-16 mg/L) effectively inhibited bacterial growth and prevented the emergence of resistance .
Case Studies on Toxicity
Despite its therapeutic benefits, closantel has been associated with adverse effects, particularly ocular toxicity. A notable case involved a 20-year-old female patient who experienced reversible blindness after receiving an incorrect prescription of closantel instead of triclabendazole for Fasciola hepatica infection. The patient's vision impairment was linked to retinal damage caused by the drug.
Case Highlights:
- Symptoms : The patient reported bilateral blurred vision and color blindness after taking closantel for three days.
- Treatment : Plasma exchange and high-dose corticosteroids were administered, resulting in partial recovery of vision over a follow-up period .
Pharmacokinetics
Closantel exhibits a long half-life and high plasma protein binding capacity, which influences its distribution and elimination from the body. Studies indicate that after oral administration, closantel's half-life ranges from 22.7 to 26.7 days, with approximately 80% of the administered dose excreted in feces within eight weeks .
Pharmacokinetic Data:
| Administration Route | Half-Life (Days) | Excretion (Feces) | Excretion (Urine) |
|---|---|---|---|
| Oral | 26.7 | ~80% | ~0.5% |
| Intramuscular | 22.7 | ~80% | ~0.5% |
特性
IUPAC Name |
N-[5-chloro-4-[(4-chlorophenyl)-cyanomethyl]-2-methylphenyl]-2-hydroxy-3,5-diiodobenzamide |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C22H14Cl2I2N2O2/c1-11-6-15(17(10-27)12-2-4-13(23)5-3-12)18(24)9-20(11)28-22(30)16-7-14(25)8-19(26)21(16)29/h2-9,17,29H,1H3,(H,28,30) |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
JMPFSEBWVLAJKM-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CC1=CC(=C(C=C1NC(=O)C2=C(C(=CC(=C2)I)I)O)Cl)C(C#N)C3=CC=C(C=C3)Cl |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C22H14Cl2I2N2O2 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID6040662 |
Source
|
| Record name | Closantel | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID6040662 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
663.1 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
CAS No. |
57808-65-8 |
Source
|
| Record name | Closantel | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=57808-65-8 | |
| Description | CAS Common Chemistry is an open community resource for accessing chemical information. Nearly 500,000 chemical substances from CAS REGISTRY cover areas of community interest, including common and frequently regulated chemicals, and those relevant to high school and undergraduate chemistry classes. This chemical information, curated by our expert scientists, is provided in alignment with our mission as a division of the American Chemical Society. | |
| Explanation | The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated. | |
| Record name | Closantel [USAN:INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0057808658 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
| Record name | Closantel | |
| Source | DTP/NCI | |
| URL | https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=759819 | |
| Description | The NCI Development Therapeutics Program (DTP) provides services and resources to the academic and private-sector research communities worldwide to facilitate the discovery and development of new cancer therapeutic agents. | |
| Explanation | Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source. | |
| Record name | Closantel | |
| Source | DTP/NCI | |
| URL | https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=335306 | |
| Description | The NCI Development Therapeutics Program (DTP) provides services and resources to the academic and private-sector research communities worldwide to facilitate the discovery and development of new cancer therapeutic agents. | |
| Explanation | Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source. | |
| Record name | Closantel | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID6040662 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | Closantel | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.055.407 | |
| Description | The European Chemicals Agency (ECHA) is an agency of the European Union which is the driving force among regulatory authorities in implementing the EU's groundbreaking chemicals legislation for the benefit of human health and the environment as well as for innovation and competitiveness. | |
| Explanation | Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page. | |
| Record name | CLOSANTEL | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/EUL532EI54 | |
| Description | The FDA Global Substance Registration System (GSRS) enables the efficient and accurate exchange of information on what substances are in regulated products. Instead of relying on names, which vary across regulatory domains, countries, and regions, the GSRS knowledge base makes it possible for substances to be defined by standardized, scientific descriptions. | |
| Explanation | Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required. | |
Retrosynthesis Analysis
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