Riluzole is a

medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...

used to treat

amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or—in the United States—Lou Gehrig's disease (LGD), is a rare, Terminal illness, terminal neurodegenerative disease, neurodegenerative disorder that results i ...

(ALS) and other motor neuron diseases. Riluzole delays the onset of

ventilator A ventilator is a type of breathing apparatus, a class of medical technology that provides mechanical ventilation by moving breathable air into and out of the lungs, to deliver breaths to a patient who is physically unable to breathe, or breathi ...

-dependence or

tracheostomy Tracheotomy (, ), or tracheostomy, is a surgical airway management procedure which consists of making an incision on the front of the neck to open a direct airway to the trachea. The resulting stoma (hole) can serve independently as an airway ...

in some people and may increase survival by two to three months. Riluzole is available in tablet and liquid form.

Medical uses

Amyotrophic lateral sclerosis

Riluzole was approved in the United States for the treatment of ALS by the US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) in 1995. A

Cochrane Library The Cochrane Library (named after Archie Cochrane) is a collection of databases in medicine and other healthcare specialties provided by Cochrane and other organizations. At its core is the collection of Cochrane Reviews, a database of systema ...

review states a 9% gain in the probability of surviving one year.

Contraindications

Contraindications for riluzole include: known prior hypersensitivity to riluzole or any of the excipients inside the preparations, liver disease, pregnancy or lactation.

Adverse effects

* Very common (>10% frequency):

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

;

weakness Weakness is a symptom of many different medical conditions. The causes are many and can be divided into conditions that have true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, ...

; decreased lung function * Common (1–10% frequency): headache; dizziness; drowsiness; vomiting; abdominal pain; increased

aminotransferase Transaminases or aminotransferases are enzymes that catalyze a transamination reaction between an amino acid and an α- keto acid. They are important in the synthesis of amino acids, which form proteins. Function and mechanism An amino acid c ...

s * Uncommon (0.1–1% frequency):

pancreatitis Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormone A hormone (from the Ancient Greek, Greek participle , "se ...

;

interstitial lung disease Interstitial lung disease (ILD), or diffuse parenchymal lung disease (DPLD), is a group of respiratory diseases affecting the interstitium (the tissue) and space around the alveoli (air sacs) of the lungs. It concerns alveolar epithelium, pulm ...

* Rare (<0.1% frequency):

neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...

; allergic reaction (including angiooedema, anaphylactoid reaction)

Overdose

Symptoms of overdose include: neurological and psychiatric symptoms, acute toxic encephalopathy with stupor, coma and

methemoglobinemia Methemoglobinemia, or methaemoglobinaemia, is a condition of elevated methemoglobin in the blood. Symptoms may include headache, dizziness, shortness of breath, nausea, poor muscle coordination, and blue-colored skin (cyanosis). Complications ma ...

. Severe methemoglobinemia may be rapidly reversible after treatment with methylene blue.

Interactions

CYP1A2 Cytochrome P450 1A2 (abbreviated CYP1A2), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the ''CYP1A2'' gene. Function ...

substrates, inhibitors and inducers would probably interact with riluzole, due its dependency on this cytochrome for metabolism.

Mechanism of action

Riluzole preferentially blocks TTX-sensitive

sodium channel Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell (biology), cell's cell membrane, membrane. They belong to the Cation channel superfamily, superfamily of cation channels. Classific ...

s, which are associated with damaged

neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

s. Riluzole has also been reported to directly inhibit the kainate and

NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other ...

s. The drug has also been shown to postsynaptically potentiate GABA_A receptors via an allosteric binding site. However, the action of riluzole on

glutamate receptor Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate (the conjugate base of glutamic acid) is abundant in the human body, but particularly in the nervous system ...

s 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. 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 Potassium thiocyanate is the chemical compound with the molecular formula KSCN. It is an important salt of the thiocyanate anion, one of the pseudohalides. The compound has a low melting point relative to most other inorganic salts. Uses Ch ...

followed by reaction with bromine, forming the thiazole ring. : Riluzole synthesis

Society and culture

Legal status

Riluzole was approved for medical use in the European Union in October 1996.

Research

A number of

case studies A case study is an in-depth, detailed examination of a particular case (or cases) within a real-world context. For example, case studies in medicine may focus on an individual patient or ailment; case studies in business might cover a particular fi ...

and

randomized controlled trial A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical ...

s have indicated that riluzole, which is neuroprotective and a

glutamate Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...

modulator, may have use in mood and

anxiety disorder Anxiety disorders are a group of mental disorders characterized by significant and uncontrollable feelings of anxiety and fear such that a person's social, occupational, and personal functions are significantly impaired. Anxiety may cause phys ...

s. However, it failed in trials of

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is an incurable neurodegenerative disease that is mostly Genetic disorder#Autosomal dominant, inherited. It typically presents as a triad of progressive psychiatric, cognitive, and ...

and

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

. Riluzole has been investigated in rodent models for its potential ability to protect against

noise-induced hearing loss Noise-induced hearing loss (NIHL) is a Hearing loss, hearing impairment resulting from exposure to loud sound. People may have a loss of perception of a narrow range of Frequency, frequencies or impaired perception of sound including hyperacusi ...

(NIHL) and

cisplatin Cisplatin is a chemical compound with chemical formula, formula ''cis''-. It is a coordination complex of platinum that is used as a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, c ...

-induced ototoxicity. These protective effects are believed to be caused by riluzole's

antioxidant Antioxidants are Chemical compound, compounds that inhibit Redox, oxidation, a chemical reaction that can produce Radical (chemistry), free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Antioxidants ...

and anti- apoptotic properties, but other mechanisms, including modulation of glutamate signaling, are also being investigated. 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 Sublingual (List of abbreviations used in medical prescriptions, abbreviated SL), from the Latin for "under the tongue", refers to the pharmacological route of administration by which substances diffuse into the blood through Tissue (biology), t ...

reformulation of riluzole that originated at

Yale University Yale University is a Private university, private Ivy League research university in New Haven, Connecticut, United States. Founded in 1701, Yale is the List of Colonial Colleges, third-oldest institution of higher education in the United Stat ...

and is known by the code name BHV-0223 is under development for the treatment of

generalized anxiety disorder Generalized anxiety disorder (GAD) is an anxiety disorder characterized by excessive, uncontrollable and often irrational worry about events or activities. Worry often interferes with daily functioning. Individuals with GAD are often overly con ...

and

mood disorder A mood disorder, also known as an affective disorder, is any of a group of conditions of mental and behavioral disorder where the main underlying characteristic is a disturbance in the person's mood. The classification is in the ''Diagnostic ...

s by Biohaven Pharmaceuticals. A

prodrug A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...

formulation of riluzole, troriluzole, has been researched as a potential treatment for several different conditions.

References

{{Authority control Benzothiazoles Drugs with unknown mechanisms of action Experimental anxiolytics GABA reuptake inhibitors Glycine receptor antagonists Trifluoromethyl ethers