Riluzole

Riluzole is a medication used to treat amyotrophic lateral sclerosis. Riluzole delays the onset of ventilator-dependence or tracheostomy in some people and may increase survival by two to three months. Riluzole is available in tablet and liquid form. Riluzole was approved in the United States for the treatment of ALS by the FDA in 1995. A Cochrane Library review states a 9% gain in the probability of surviving one year. Symptoms of overdose include: neurological and psychiatric symptoms, acute toxic encephalopathy with stupor, coma and methemoglobinemia. Severe methemoglobinemia may be rapidly reversible after treatment with methylene blue. Contraindications for riluzole include: known prior hypersensitivity to riluzole or any of the excipients inside the preparations, liver disease, pregnancy or lactation. CYP1A2 substrates, inhibitors and inducers would probably interact with riluzole, due its dependency on this cytochrome for metabolism. Riluzole preferentially blocks TTX-sensitive sodium channels, which are associated with damaged neurons. Riluzole has also been reported to directly inhibit the kainate and NMDA receptors. The drug has also been shown to postsynaptically potentiate GABAA receptors via an allosteric binding site. 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. 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. In addition to its role in accelerating glutamate clearance from the synapse, riluzole may also prevent glutamate release from presynaptic terminals. These effects combined could significantly reduce glutamate signaling and cause indirect antagonism without acting at glutamate receptors themselves. Furthermore, riluzole ability to inhibit with an ATP-competitive mechanism the protein kinase CK1δ has been recently demonstrated. 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. Riluzole can be prepared beginning with the reaction of 4-(trifluoromethoxy)aniline with potassium thiocyanate followed by reaction with bromine, forming the thiazole ring. A number of recent case studies have indicated that riluzole may have use in mood and anxiety disorders.