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Clomethiazole
Clomethiazole
Clomethiazole
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Clomethiazole
Clinical data
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • BR: Class C1 (Other controlled substances)[1]
  • UK: POM (Prescription only)[2]
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Elimination half-life3.6–5 hours
Identifiers
  • 5-(2-Chloroethyl)-4-methyl-1,3-thiazole
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.007.788 Edit this at Wikidata
Chemical and physical data
FormulaC6H8ClNS
Molar mass161.65 g·mol−1
3D model (JSmol)
  • ClCCC1=C(C)N=CS1
  • InChI=1S/C6H8ClNS/c1-5-6(2-3-7)9-4-8-5/h4H,2-3H2,1H3 checkY
  • Key:PCLITLDOTJTVDJ-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Clomethiazole (also called chlormethiazole) is a sedative and hypnotic originally developed by Hoffmann-La Roche in the 1930s.[3] The drug is typically used in treating and preventing symptoms of acute alcohol withdrawal, anxiety and as a sedative-hypnotic.

It is structurally related to thiamine (vitamin B1), but acts like a sedative, hypnotic, anxiolytic, muscle relaxant and anticonvulsant, having the same mechanism of action as traditional barbiturates. It is also used for the management of agitation, restlessness, and Parkinson's disease. In the UK, it is sold under the brand Heminevrin (AstraZeneca Pharmaceuticals). Other brand names include Nevrin in Romania, Distraneurin in Germany and Distraneurine in Spain. The drug is marketed either as a free base in an oily solution containing 192 mg in capsule form, or as clomethiazole edisylate syrup. Due to its high toxicity compared to benzodiazepines it is not recommended as a first-line treatment for any indication and is particularly dangerous to patients with an elevated risk for drug abuse such as those with a personal or familial history of addiction.

Pharmacology

[edit]

Clomethiazole acts as a positive allosteric modulator at the barbiturate/picrotoxin site of the GABAA receptor. It works to enhance the action of the neurotransmitter GABA at this receptor. GABA is the major inhibitory neurotransmitter in the brain and produces anxiolytic, anticonvulsant, sedative, and hypnotic effects. Clomethiazole appears to also have another mechanism of action mediating some of its hypothermic and neuroprotective effects.[4] The oxazole homologue is also known[5] providing a little QSAR information.

As opposed to barbiturates, clomethiazole doesn't affect the electrophysiological responses to excitatory aminoacids, and additionally, it also directly acts on chloride ion channels.[citation needed]

Clomethiazole is a potent CYP2E1 enzyme inhibitor which slows down the metabolism of ethanol, hence its use in alcohol withdrawal. It is also an inhibitor of CYP2B6 and possibly CYP2A6 and thus can affect the plasma clearance of substrates of those enzymes.

When clomethiazole is administered via IV in addition to carbamazepine, its clearance is increased by 30%, which results in a proportional reduction in plasma concentration. Therefore, when co-administered with carbamazepine or other potent CYP3A4 inducers via IV, it is necessary to increase the dose of clomethiazole.[6]

Adverse effects

[edit]

Long term and frequent use of clomethiazole can cause tolerance and physical dependence. Abrupt withdrawal may result in symptoms similar to those of sudden withdrawal of alcohol, short-acting barbiturates or short-acting benzodiazepines.[7]

Overdose

[edit]

Clomethiazole is particularly toxic and dangerous if overdosed and is potentially fatal. Alcohol multiplies the effect. As the drug can be fatal in high doses, prescribing clomethiazole for the management of alcohol dependence outside of a controlled environment, for example a hospital, is not recommended, especially because there are much less toxic alternatives, such as diazepam. Diazepam is one of many drugs belonging to the benzodiazepine class, with a long half-life (50–100 hours) and a very low risk of a fatal overdose, so long as the patient does not also consume alcohol or certain other types of medication.[8]

Due to clomethiazole's unique chemical structure the benzodiazepine antidote flumazenil cannot reverse the effects of overdose; overdose treatment is restricted to the application of a mechanical ventilation apparatus until enough of the drug has been metabolized or excreted for the patient to breathe sufficiently without assistance.

Drummer Keith Moon of the rock band The Who died of a recreational clomethiazole overdose.[9]

See also

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Clomethiazole

View on Grokipedia
from Grokipedia
Clomethiazole, also spelled chlormethiazole, is a sedative-hypnotic and drug belonging to the class, structurally related to (vitamin B1), and primarily indicated for the management of acute alcohol withdrawal symptoms, restlessness, agitation, and short-term severe in elderly patients. It exerts its effects through positive allosteric modulation of the gamma-aminobutyric acid type A (GABA_A) receptor complex in the , enhancing inhibitory neurotransmission by potentiating GABA binding and inhibiting the binding of [35S]t-butylbicyclophosphorothionate (TBPS), a GABA_A . Developed in the 1930s by Hoffmann-La Roche, clomethiazole has a long clinical history as a non-benzodiazepine alternative for sedation and seizure control, particularly in alcohol dependence, though its use is restricted to short-term therapy due to risks of tolerance and dependence. It is available in certain countries, such as the United Kingdom, under the brand name Heminevrin, but is not approved for use in the United States. In clinical practice, it is administered orally in capsule form, with dosing regimens tailored to the indication: for alcohol withdrawal, typically 2–4 capsules initially under hospital supervision, followed by a tapering regimen over up to 9 days, with daily doses adjusted based on symptoms (e.g., up to 12 capsules on day 1 in divided doses, each capsule 192 mg); for restlessness or insomnia in the elderly, 1 capsule three times daily or 1–2 capsules at bedtime. The drug is contraindicated in patients with hypersensitivity to clomethiazole or acute pulmonary insufficiency; it should not be used in patients who continue to consume alcohol, as it can potentiate respiratory depression and lead to coma. Special caution is advised in those with chronic pulmonary, renal, or hepatic impairment, sleep apnea, or a history of substance abuse, and it is not recommended for children. Common adverse effects include nasal congestion, conjunctival irritation, drowsiness, and headache, which are generally mild and transient, while rarer reactions encompass anaphylaxis, paradoxical excitement, and dependence with prolonged use. Overdose can result in severe respiratory depression, hypotension, hypothermia, and coma, necessitating immediate supportive care including mechanical ventilation. Beyond its established roles, clomethiazole has been investigated for neuroprotective properties in ischemic stroke models due to its GABA_A enhancement and potential to reduce excitotoxicity, though large-scale trials like the Clomethiazole Acute Stroke Study (CLASS) did not demonstrate significant clinical benefits, limiting its approval to traditional indications. Pharmacokinetically, it undergoes rapid absorption and metabolism primarily via the liver, with a short half-life supporting its use in acute settings, but interpatient variability requires careful monitoring.

Medical uses

Alcohol withdrawal

Clomethiazole serves as a primary treatment for acute in alcohol-dependent individuals, functioning as a sedative-hypnotic and to alleviate symptoms including tremors, anxiety, seizures, and . It is particularly valued for its rapid onset in preventing complications during , with administration typically under medical supervision in inpatient settings to monitor response and adjust dosing. The standard oral regimen begins with 9 to 12 capsules (each containing 192 mg clomethiazole edisylate) per day, divided into 3 or 4 doses during the first 24 hours, followed by a tapered reduction: 6 to 8 capsules on day 2, 4 to 6 on day 3, and further gradual decreases over days 4 to 6 until discontinuation, with total treatment not exceeding 9 days. This symptom-triggered or fixed-schedule approach allows flexibility based on withdrawal severity, ensuring safe symptom control while minimizing prolonged use. Clinical trials demonstrate clomethiazole's efficacy in reducing withdrawal severity, with a double-blind study of 40 patients showing it comparable to chlordiazepoxide in alleviating symptoms like anxiety and tremors over 7 days. Similarly, a randomized comparison with reported equivalent effectiveness in symptom relief and patient retention during acute withdrawal. Versus , clomethiazole significantly improves quality and overall symptom scores in alcohol-dependent patients undergoing withdrawal. In practice, although benzodiazepines such as chlordiazepoxide are first-line, clomethiazole may be offered as an alternative for mild or moderate acute alcohol withdrawal under hospital supervision.

Insomnia and restlessness

Clomethiazole is indicated for the short-term treatment of severe in elderly patients unresponsive to other therapies, typically administered as 1–2 capsules (192 mg each) at bedtime. This dosing regimen aims to induce without excessive residual effects the following day, leveraging the drug's short . In geriatric and psychiatric contexts, clomethiazole addresses restlessness and agitation, particularly in patients with , where it has demonstrated superiority over in improving clinical parameters. It may also alleviate associated symptoms such as behavioral disturbances in , providing to reduce nocturnal disruptions. Clinical evidence from randomized controlled trials supports its efficacy, with a of eight studies involving 424 elderly participants showing clomethiazole significantly increased duration compared to (standardized mean difference = 0.61, 95% CI 0.11–1.11) and enhanced overall sleep quality. These trials also reported fewer instances of or daytime drowsiness relative to alternative hypnotics. Due to the risk of tolerance and dependence, clomethiazole is recommended for short-term use only, limited to a maximum of 14 days. Its sedative properties arise from positive allosteric modulation of GABA_A receptors, enhancing inhibitory neurotransmission in the central nervous system.

Pharmacology

Pharmacodynamics

Clomethiazole functions primarily as a positive allosteric modulator of the GABA_A receptor, enhancing the binding of γ-aminobutyric acid (GABA) to its site and increasing chloride ion influx through the receptor channel. This action leads to neuronal hyperpolarization, thereby producing sedative, anxiolytic, and anticonvulsant effects central to its therapeutic profile. At the cellular level, clomethiazole shifts the GABA concentration-response curve, potentiating GABA-induced currents by up to 7-fold at therapeutically relevant concentrations (e.g., EC₅₀ shift from 10.4 μM to 1.6 μM in α₁β₂γ₂ receptors with 300 μM clomethiazole), while exhibiting minimal direct activation of the receptor (<5% at 1 mM). Unlike benzodiazepines, which bind to a specific allosteric site between the α and γ subunits of the GABA_A receptor, clomethiazole interacts at a distinct site, likely an anesthetic-like modulatory pocket, without competing for the binding site. This difference is attributed in part to its unique ring structure, which facilitates binding independent of the classical . Electrophysiological studies confirm no displacement of benzodiazepine ligands, supporting this non-overlapping mechanism. Clomethiazole displays subtype selectivity within the GABA_A receptor family, with enhanced potentiation at receptors containing α₄β₂γ₂ (up to 646%) or α₆β₂γ₂ (up to 695%) subunits compared to α₁β₂γ₂ (298%), though it also modulates α₁- and α₂-containing subtypes associated with and actions, respectively. Additionally, clomethiazole potently inhibits , slowing the alternative pathway of ethanol metabolism and reducing associated , which may contribute to its efficacy in managing alcohol withdrawal symptoms and protecting against alcoholic liver injury.

Pharmacokinetics

Clomethiazole is rapidly absorbed from the following , with peak plasma concentrations typically achieved within 30-60 minutes in healthy adults. Its is approximately 25-42%, limited primarily by extensive first-pass metabolism in the liver. The drug exhibits a high , estimated at 3-6 L/kg, reflecting wide tissue distribution including efficient crossing of the blood-brain barrier to exert effects. It is moderately bound to plasma proteins, with binding ranging from 63-65%. Clomethiazole undergoes extensive hepatic metabolism primarily via enzymes and , yielding inactive metabolites such as 5-(1-hydroxyethyl)-4-methylthiazole and 4-methyl-5-thiazoleacetic acid. The elimination is 3.6-5 hours in young healthy adults, but it is prolonged in the elderly due to higher plasma levels and reduced clearance, as well as in patients with liver impairment where clearance can decrease significantly. Excretion occurs mainly via the kidneys, with 70-80% of the dose eliminated as metabolites in and less than 1% as unchanged drug, resulting in minimal accumulation during short-term use.

Adverse effects and contraindications

Adverse effects

Clomethiazole is associated with several common adverse effects during therapeutic use, primarily related to its sedative and depressant properties. The most frequently reported include excessive or drowsiness, which can impair daily activities, and or irritation, often manifesting as a runny or blocked shortly after . These effects are generally mild and transient, with nasal symptoms typically appearing 15 to 20 minutes post-dose and potentially diminishing with continued use. Other common effects encompass , conjunctival irritation (such as sore or watery eyes), and gastrointestinal disturbances like or gastric irritation. In clinical studies, has been a prominent issue, leading to treatment withdrawal in approximately 15.6% of patients receiving clomethiazole compared to 4.2% on . is described as common, though specific incidence rates vary; it affects a notable proportion of users but is not typically dose-limiting in short-term therapy. Gastrointestinal upset occurs less frequently but can include and abdominal discomfort in susceptible individuals. Serious adverse effects are less common but can include respiratory depression and , particularly with higher doses or in vulnerable patients, though these are more pronounced in overdose scenarios. Paradoxical reactions, such as excitation or confusion, have been reported rarely, with increased risk in the elderly due to altered . Prolonged high-dose use may lead to tolerance, , and withdrawal symptoms such as convulsions or tremors. Risk factors for amplified adverse effects include advanced age, which heightens susceptibility to and paradoxical responses; elevated doses beyond recommended levels; and concurrent use of alcohol or other depressants, which potentiate respiratory depression and overall . Monitoring is advised in these scenarios to mitigate potential harm during treatment.

Contraindications

Clomethiazole is contraindicated in patients with to the active substance or any of the excipients. It is also absolutely contraindicated in cases of acute pulmonary insufficiency, as the drug may exacerbate respiratory depression. Additionally, it should not be used in patients with severe respiratory depression or during , particularly in those with ongoing alcohol consumption, due to the risk of fatal cardiorespiratory collapse. Relative contraindications include (COPD) or other forms of chronic pulmonary insufficiency, where the drug's sedative effects could worsen respiratory function. Hepatic impairment, especially gross liver damage, warrants great caution, as it may lead to prolonged drug and mask symptoms of liver coma. In , clomethiazole should be avoided, particularly in the first and third trimesters, due to potential fetal and other risks, unless there are compelling clinical reasons. Concomitant use with central nervous system (CNS) depressants, such as opioids or benzodiazepines, requires caution and substantial dose reduction due to additive effects causing severe respiratory depression and potential fatality. Clomethiazole is not recommended for use in children under 18 years of age, and it should be avoided in those under 12. In elderly patients, caution is advised owing to increased , delayed elimination, and heightened risk of falls from .

Overdose and management

Symptoms

Clomethiazole overdose typically presents with early symptoms resembling acute , including profound , , and slurred speech (), often accompanied by and impaired judgment. As toxicity progresses, severe manifestations emerge, characterized by respiratory depression, , , and , the latter attributed to effects and prolonged unconsciousness. Increased upper airway secretions contribute to a heightened risk of in affected individuals. The severity of symptoms is dose-dependent, with toxic effects observed at blood concentrations exceeding 1.6 mg/L (1600 ng/mL), associated with levels above approximately 10 mg/L, and fatal outcomes reported at concentrations greater than 8 mg/L (8000 ng/mL), up to 170 mg/L in some cases. Ingestion of large quantities of capsules—such as dozens—can lead to these life-threatening effects, particularly when combined with alcohol or other depressants. Compared to , clomethiazole intoxication involves less prominent myorelaxation but features more pronounced and increased salivation or upper airway secretions.

Treatment

The management of clomethiazole overdose focuses on supportive and symptomatic care, as there is no specific available. Initial stabilization follows the ABCs (airway, breathing, circulation), with immediate attention to securing the airway and providing respiratory support if depression is present. If the overdose occurred within 1-2 hours of presentation, administration of activated charcoal (1 g/kg orally or via nasogastric tube) can help reduce drug absorption, though its efficacy diminishes thereafter. Supportive measures are paramount and include for severe , intravenous fluids and vasopressors to address , and continuous monitoring of , oxygenation, and cardiac function in an setting. Enhanced elimination techniques, such as charcoal haemoperfusion, are ineffective for clomethiazole. is not recommended, as clomethiazole acts as a positive at a distinct site on the GABA_A receptor complex, rendering unable to reverse its effects; moreover, its use may precipitate seizures in cases of dependence due to abrupt reversal of activity. With prompt and appropriate supportive intervention, the prognosis for clomethiazole overdose is generally favorable, with most patients recovering fully within 24-48 hours absent complications like or co-ingestants. Patients should receive long-term follow-up for potential dependence, given clomethiazole's role in managing alcohol withdrawal and its abuse potential.

Chemistry

Chemical structure

Clomethiazole has the molecular formula C₆H₈ClNS and a molecular weight of 161.65 g/mol. The compound features a five-membered ring, a heterocycle containing adjacent and atoms, with a methyl at the 4-position and a 2-chloroethyl chain (-CH₂CH₂Cl) attached at the 5-position. Its systematic IUPAC name is 5-(2-chloroethyl)-4-methyl-1,3-. This simple thiazole-based structure distinguishes clomethiazole from barbiturates, which are derived from a six-membered pyrimidine-2,4,6-trione ring, and from benzodiazepines, which contain a seven-membered diazepine ring fused to a moiety. The core is analogous to the heterocyclic component in (vitamin B₁). Clomethiazole is prepared via a variant of the Hantzsch thiazole synthesis, entailing the condensation of a thioamide precursor, such as thioacetamide, with an α-haloketone like 4-chloro-2-butanone, followed by cyclization and substituent modification through chlorination of the corresponding hydroxyethyl analog.

Physical properties

Clomethiazole is a white to off-white crystalline powder. The edisilate salt exhibits good in polar solvents, being freely soluble in and soluble in , while practically insoluble in . The pKa value is reported as 3.18 for the strongest basic site. Clomethiazole is sensitive to oxidation by air and light, necessitating storage in airtight containers under inert atmosphere at 2-8°C to maintain stability. In pharmaceutical formulations, it is commonly available as oral capsules containing 192 mg of clomethiazole base equivalent and as an injectable 0.5% aqueous solution of the edisilate salt.

History and society

Development and approval

Clomethiazole, also known as chlormethiazole, was originally developed in the 1930s by Hoffmann-La Roche as a sedative-hypnotic agent. Early research focused on its potential to mitigate symptoms of alcohol withdrawal by potentiating GABAergic activity, leading to initial controlled clinical trials in the 1960s that demonstrated its efficacy in reducing agitation, tremors, and other withdrawal symptoms compared to placebo. These trials, including a double-blind study published in 1965, established clomethiazole as a viable option for managing acute alcohol withdrawal phases, prompting further investigation into its anticonvulsant properties. In the , clomethiazole received marketing authorization under the brand name Heminevrin on December 15, 1967, for indications including restlessness and agitation in the elderly, severe insomnia, and alcohol withdrawal symptoms. During the , additional studies reinforced its role in treating severe alcohol withdrawal complications, such as ; for instance, a 1972 clinical report highlighted its rapid effects via intravenous administration in eight patients with severe cases, leading to quick resolution of symptoms without significant adverse events. These findings contributed to its widespread adoption in European clinical practice for short-term use in protocols. In the late and early , research explored clomethiazole's neuroprotective potential in acute ischemic , based on preclinical evidence of GABA-mediated against ischemia-induced damage. Astra (now part of ) sponsored the Clomethiazole Acute Study (CLASS), a phase II completed in 1999, suggested possible benefits in patients with larger infarcts, leading to the phase III Clomethiazole Acute Study in Ischemic (CLASS-I) involving over 1,300 patients. However, CLASS-I, reported in 2001, failed to demonstrate significant improvement in functional outcomes, resulting in the discontinuation of further development for this indication. Clomethiazole has never been approved by the U.S. , remaining unavailable in the United States primarily due to concerns over its abuse potential and risk of dependence, as evidenced by reports of tolerance and withdrawal symptoms similar to benzodiazepines. It has also been withdrawn or severely restricted in certain markets, such as parts of , following assessments of its dependency liability in animal and human studies. Clomethiazole is classified as a prescription-only medicine in the , where it requires a valid prescription from a healthcare professional for dispensing and is marketed under the brand name Heminevrin. In many other countries, including those in such as (under the brand Distraneurin), it is similarly restricted to prescription use due to its properties and potential for misuse. The drug is not approved by the (FDA) and is unavailable in the market, primarily due to concerns associated with its pharmacological profile, which resembles that of barbiturates, including risks of dependence and respiratory depression. Although not scheduled as a by the (DEA) in the , clomethiazole faces restrictions in various nations owing to its potential for abuse and overdose. Clomethiazole remains available in parts of Europe, Asia (such as Singapore), and Australia, typically as oral capsules in strengths like 192 mg, though periodic supply shortages have been reported in some regions. Its use has declined in certain markets since the early 2000s, partly due to the availability of safer alternatives like benzodiazepines for managing conditions such as alcohol withdrawal.

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