Riluzole

Riluzole is a medication used to treat amyotrophic lateral sclerosis (ALS) and other motor neuron diseases. Riluzole delays the onset of ventilator-dependence or tracheostomy in some people and may increase survival by two to three months.<ref name="Coch">Template:Cite journal</ref> Riluzole is available in tablet and liquid form. A thin film version of riluzole which dissolves on the tongue (commercially known as Exservan or Emylif) is available in the United States and United Kingdom.<ref name=":0">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Medical uses

Amyotrophic lateral sclerosis

Riluzole was approved in the United States for the treatment of ALS by the US Food and Drug Administration (FDA) in 1995.<ref>Template:Cite book</ref> In 1996, riluzole was approved for use in treating ALS by the European Medicines Agency (EMA).<ref name=":0" /> A Cochrane Library review states a 9% gain in the probability of surviving one year.<ref name = Coch/>

Contraindications

Contraindications for riluzole include: known prior hypersensitivity to riluzole or any of the excipients inside the preparations, liver disease, pregnancy or lactation.<ref name="TGA" />

Adverse effects

• Very common (>10% frequency):<ref name="MSR">{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref> nausea; weakness; decreased lung function

• Common (1–10% frequency):<ref name="AMH">Template:Cite book</ref> headache; dizziness; drowsiness; vomiting; abdominal pain; increased aminotransferases
• Uncommon (0.1–1% frequency):<ref name = AMH/> pancreatitis; interstitial lung disease
• Rare (<0.1% frequency):<ref name = AMH/> neutropenia; allergic reaction (including angiooedema, anaphylactoid reaction)

Overdose

Symptoms of overdose include: neurological and psychiatric symptoms, acute toxic encephalopathy with stupor, coma and methemoglobinemia.<ref name = TGA/> Severe methemoglobinemia may be rapidly reversible after treatment with methylene blue.<ref name = TGA/>

Interactions

CYP1A2 substrates, inhibitors and inducers would probably interact with riluzole, due its dependency on this cytochrome for metabolism.<ref name = TGA/>

Mechanism of action

Riluzole preferentially blocks TTX-sensitive sodium channels, which are associated with damaged neurons.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Riluzole has also been reported to directly inhibit the kainate and NMDA receptors.<ref name="pmid7685290">Template:Cite journal</ref> The drug has also been shown to postsynaptically potentiate GABA_A receptors via an allosteric binding site.<ref>Template:Cite journal</ref> However, the action of riluzole on glutamate receptors has been controversial, as no binding of the drug to any known sites has been shown for them.<ref>Template:Cite journal</ref><ref name="pmid9750003">Template:Cite journal</ref> In addition, as its antiglutamatergic action is still detectable in the presence of sodium channel blockers, it is also uncertain whether or not it acts via this way. Rather, its ability to stimulate glutamate uptake seems to mediate many of its effects.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> In addition to its role in accelerating glutamate clearance from the synapse, riluzole may also prevent glutamate release from presynaptic terminals.<ref>Template:Cite journal</ref> Since CK1δ plays a key role in TDP-43 proteinopathy, a pathological hallmark of ALS, this could help to better decipher drug mechanism of action.

Synthesis

Riluzole can be prepared beginning with the reaction of 4-(trifluoromethoxy)aniline with potassium thiocyanate followed by reaction with bromine, forming the thiazole ring.<ref>Template:Cite journal</ref><ref>Template:Cite patent; Template:Cite patent</ref><ref>Template:US patent</ref>

File:Riluzole synthesis.png

Riluzole synthesis

Template:Clear-left

Society and culture

Legal status

Riluzole was approved for medical use in the European Union in October 1996.<ref name="Rilutek EPAR">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Research

A number of case studies and randomized controlled trials have indicated that riluzole, which is neuroprotective and a glutamate modulator, may have use in mood and anxiety disorders.<ref name="pmid37463744">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="pmid18721116">Template:Cite journal</ref> Riluzole is thought to have "neuroprotective" properties mainly owing to its ability to modulate glutamate release.<ref>Template:Cite journal</ref> However, it failed in trials of Huntington's disease and Parkinson's disease.<ref name="pmid18721116"/> A 2024 study comparing the effects of riluzole in patients with traumatic spinal cord injury to a control group found riluzole treated patients had higher American Spinal Injury Association (ASIA) motor scores and lower mortality rates at 3 months, though the scores were not statistically significant.<ref>Template:Cite journal</ref>

Riluzole has been investigated in rodent models for its potential ability to protect against noise-induced hearing loss (NIHL) and cisplatin-induced ototoxicity. These protective effects are believed to be caused by riluzole's antioxidant and anti-apoptotic properties, but other mechanisms, including modulation of glutamate signaling, are also being investigated.<ref name="pmid31360245">Template:Cite journal</ref><ref name="pmid15973153">Template:Cite journal</ref> However, further research, especially in human trials, is necessary to confirm these findings and establish riluzole's clinical efficacy for treating hearing loss.

A sublingual reformulation of riluzole that originated at Yale University and is known by the code name BHV-0223<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> is under developmentTemplate:When for the treatment of generalized anxiety disorder and mood disorders by Biohaven Pharmaceuticals.<ref name="Harris2015">Template:Cite journal</ref><ref name="Terry 2018">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> A prodrug formulation of riluzole, troriluzole, has been researched as a potential treatment for several different conditions.<ref name="pmid36368186">Template:Cite journal</ref><ref name="pmid35780243">Template:Cite journal</ref>