Rasagiline, sold under the brand name Azilect among others, 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 ...

which is used in the treatment of

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 ...

. It is used as a monotherapy to treat symptoms in early Parkinson's disease or as an

adjunct therapy Adjuvant therapy, also known as adjunct therapy, adjuvant care, or augmentation therapy, is a therapy that is given in addition to the primary or initial therapy to maximize its effectiveness. The surgeries and complex treatment regimens used in ...

in more advanced cases. The drug is taken

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

Side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s of rasagiline include

insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...

and

orthostatic hypotension Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when they are standing up ( orthostasis) or sitting down. Primary orthostatic hypotension is also often referred to as ne ...

, among others. Rasagiline acts as an

inhibitor Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransmi ...

of the

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

monoamine oxidase Monoamine oxidases (MAO) () are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The fi ...

(MAO) and hence is a

monoamine oxidase inhibitor Monoamine oxidase inhibitors (MAOIs) are a drug class, class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressa ...

(MAOI). More specifically, it is a selective inhibitor of

monoamine oxidase B Monoamine oxidase B (MAO-B) is an enzyme that in humans is encoded by the ''MAOB'' gene. The protein encoded by this gene belongs to the flavin monoamine oxidase family. It is an enzyme located in the outer mitochondrial membrane. It catalyzes ...

(MAO-B). The drug is thought to work by increasing levels of the

monoamine neurotransmitter Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin. All monoamines ...

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

in the

brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

. Rasagiline shows

pharmacological Pharmacology is the science of drugs and medications, including a substance's origin, composition, pharmacokinetics, pharmacodynamics, therapeutic use, and toxicology. More specifically, it is the study of the interactions that occur between ...

differences from the related drug

selegiline Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl, Zelapar, and Emsam among others, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It has also been studied and us ...

, including having no

amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...

-like

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

s, monoamine-releasing activity, or monoaminergic activity enhancer actions, which may result in clinical differences between the medications. Rasagiline was approved for medical use in the

European Union The European Union (EU) is a supranational union, supranational political union, political and economic union of Member state of the European Union, member states that are Geography of the European Union, located primarily in Europe. The u ...

in 2005 and in the

United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...

in 2006. Generic versions of rasagiline are available.

Medical uses

Parkinson's disease

Rasagiline is used to treat symptoms of

both alone and in combination with other drugs. It has shown efficacy in both early and advanced Parkinson's, and appears to be especially useful in dealing with non-motor symptoms like

fatigue Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself. Fatigue (in the medical sense) is sometimes associated wit ...

. Teva conducted clinical trials attempting to prove that rasagiline did not just treat symptoms, but was a disease-modifying drug—that it actually prevented the death of the dopaminergic neurons that characterize Parkinson's disease and slowed disease progression. They conducted two clinical trials, called TEMPO and ADAGIO, to try to prove this. The United States

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) advisory committee rejected their claim in 2011, saying that the clinical trial results did not prove that rasagiline was neuroprotective. The main reason was that in one of the trials, the lower dose (1 mg) was effective at slowing progression, but the higher dose (2 mg) was not, contradicting standard dose-response pharmacology. MAO-B inhibitors like rasagiline may improve certain non-motor symptoms in Parkinson's disease. These may include depression,

sleep disturbance A sleep disorder, or somnipathy, is a medical disorder affecting an individual's sleep patterns, sometimes impacting physical, mental, social, and emotional functioning. Polysomnography and actigraphy are tests commonly ordered for diagnosing s ...

s, and

pain Pain is a distressing feeling often caused by intense or damaging Stimulus (physiology), stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sense, sensory and emotional experience associated with, or res ...

(particularly related to motor fluctuations), but are unlikely to include

cognitive Cognition is the "mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...

olfactory The sense of smell, or olfaction, is the special sense through which smells (or odors) are perceived. The sense of smell has many functions, including detecting desirable foods, hazards, and pheromones, and plays a role in taste. In humans, it ...

dysfunctions. The effects of MAO-B inhibitors like rasagiline on

autonomic dysfunction Dysautonomia, autonomic failure, or autonomic dysfunction is a condition in which the autonomic nervous system (ANS) does not work properly. This condition may affect the functioning of the heart, bladder, intestines, sweat glands, pupils, and b ...

apathy Apathy, also referred to as indifference, is a lack of feeling, emotion, interest, or concern about something. It is a state of indifference, or the suppression of emotions such as concern, excitement, motivation, or passion. An apathetic i ...

, and

impulse control disorder Impulse-control disorder (ICD) is a class of mental disorder, psychiatric disorders characterized by impulsivity – failure to resist a temptation, an urge, or an impulse; or having the inability to not speak on a thought. The fifth edition of ...

s in people with Parkinson's disease remain unknown. Rasagiline has been reported to significantly improve

quality of life Quality of life (QOL) is defined by the World Health Organization as "an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards ...

in people with Parkinson's disease, but the

effect size In statistics, an effect size is a value measuring the strength of the relationship between two variables in a population, or a sample-based estimate of that quantity. It can refer to the value of a statistic calculated from a sample of data, the ...

s were trivial to small and may not be clinically meaningful. It showed a large effect size relative to

placebo A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. Placebos are used in randomized clinical trials ...

for depression in people with Parkinson's disease. In other studies, rasagiline appeared to reduce

in people with Parkinson's disease. However, its effect sizes for this effect in a large trial were described as trivial.

Available forms

Rasagiline is available in the form of 0.5 and 1mg

oral The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or ora ...

tablets.

Contraindications

Rasagiline has not been tested in

pregnant Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

women.

Side effects

The FDA label contains warnings that rasagiline may cause severe

hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...

hypotension Hypotension, also known as low blood pressure, is a cardiovascular condition characterized by abnormally reduced blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood and is ...

, may make people sleepy, may make motor control worse in some people, may cause

hallucination A hallucination is a perception in the absence of an external stimulus that has the compelling sense of reality. They are distinguishable from several related phenomena, such as dreaming ( REM sleep), which does not involve wakefulness; pse ...

s and psychotic-like behavior, may cause

s, may increase the risk of

melanoma Melanoma is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye (uveal melanoma). In very rare case ...

, and upon withdrawal, may cause high

fever Fever or pyrexia in humans is a symptom of an anti-infection defense mechanism that appears with Human body temperature, body temperature exceeding the normal range caused by an increase in the body's temperature Human body temperature#Fever, s ...

confusion In psychology, confusion is the quality or emotional state of being bewildered or unclear. The term "acute mental confusion"

. Side effects when the drug is taken alone include

flu-like symptoms Influenza-like illness (ILI), also known as flu-like syndrome or flu-like symptoms, is a medical diagnosis of possible influenza or other illness causing a set of common symptoms. These include fever, shivering, chills, malaise, dry cough, loss ...

joint pain Arthralgia () literally means 'joint pain'. Specifically, arthralgia is a symptom of injury, infection, illness (in particular arthritis), or an allergic reaction to medication Medication (also called medicament, medicine, pharmaceutic ...

, depression, stomach upset,

headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...

, and

. When taken with

levodopa Levodopa, also known as L-DOPA and sold under many brand names, is a dopaminergic medication which is used in the treatment of Parkinson's disease (PD) and certain other conditions like dopamine-responsive dystonia and restless legs syndrome. ...

, side effects include increased movement problems, accidental injury, sudden drops in blood pressure,

and swelling,

dry mouth Xerostomia, also known as dry mouth, is a subjective complaint of dryness in the mouth, which may be associated with a change in the composition of saliva, reduced salivary flow, or have no identifiable cause. This symptom is very common and is o ...

rash A rash is a change of the skin that affects its color, appearance, or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracke ...

, abnormal dreams and digestive problems including

vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...

loss of appetite Anorexia is a medical term for a loss of appetite. While the term outside of the scientific literature is often used interchangeably with anorexia nervosa, many possible causes exist for a loss of appetite, some of which may be harmless, while o ...

weight loss Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat (adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other conn ...

abdominal pain Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Since the abdomen contains most of the body's vital organs, it can be an indicator of a wide variety of diseases. Given th ...

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 ...

, and

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The Human feces, stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the ...

. When taken with Parkinson's drugs other than levodopa, side effects include peripheral edema, fall, joint pain, cough, and insomnia. In a 2013

meta-analysis Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...

, none of the most frequently reported side effects of rasagiline occurred significantly more often than with

. It was concluded that rasagiline is well-tolerated. Rasagiline has been found to produce

as a side effect. Rates of orthostatic hypotension in a selection of different

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s have been 1.2- to 5-fold higher than those of placebo, ranging from 3.1 to 44% with rasagiline and 0.6 to 33% with placebo. Orthostatic hypotension tends to be worst in the first 2months of treatment and then tends to decrease with time. Rasagiline can also cause

while

supine In grammar, a supine is a form of verbal noun used in some languages. The term is most often used for Latin, where it is one of the four principal parts of a verb. The word refers to a position of lying on one's back (as opposed to ' prone', l ...

and unrelated to standing. In a clinical trial, the rate of hypotension was 3.2% with rasagiline versus 1.3% with placebo. Rarely, rasagiline has been reported to induce

s,Galvez-Jimenez, N. (2008, July). Rasagiline-and selegiline-induced hypersexuality and other impulse control disorders (ICB) in Parkinson's disease (PD): Report of 3 cases. In MOVEMENT DISORDERS (Vol. 23, No. 9, pp. 1347-1347). COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA: WILEY-BLACKWELL.Senol, M., & Kendirli, M. (2018, October). Rasagiline as Adjunctive Therapy Induced Impulse Control Disorders in Parkinson's Disease. In MOVEMENT DISORDERS (Vol. 33, pp. S832-S832). 111 RIVER ST, HOBOKEN 07030-5774, NJ USA: WILEY. obsessive–compulsive symptoms,

hypersexuality Hypersexuality is a proposed medical condition said to cause unwanted or excessive sexual arousal, causing people to engage in or think about sexual activity to a point of distress or impairment., according to the website of ''Psychology Toda ...

, and spontaneous orgasm or

ejaculation Ejaculation is the discharge of semen (the ''ejaculate''; normally containing sperm) from the penis through the urethra. It is the final stage and natural objective of male sexual stimulation, and an essential component of natural conception. ...

. Other rare adverse effects associated with rasagiline include pleurothotonus (Pisa syndrome),

livedo reticularis Livedo reticularis is a common skin finding consisting of a mottled reticulated vascular pattern that appears as a lace-like purplish discoloration of the skin. The discoloration is caused by reduction in blood flow (ischemia) through the arter ...

tendon rupture Tendon rupture is a condition in which a tendon separates in whole or in part from tissue to which it is attached, or is itself torn or otherwise divided in whole or in part. Examples include: * Achilles tendon rupture * Biceps tendon rupture * A ...

, and

hypoglycemia Hypoglycemia (American English), also spelled hypoglycaemia or hypoglycæmia (British English), sometimes called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's tria ...

Serotonin syndrome Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain Serotonin, serotonergic medications or Recreational drug use, drugs. The symptoms can range from mild to severe, and are potentially fatal. Symptoms in mild c ...

has been reported rarely with rasagiline both alone and in combination with

selective serotonin reuptake inhibitor Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs primarily work by blo ...

s (SSRIs) like

escitalopram Escitalopram ( ), sold under the brand names Lexapro and Cipralex, among others, is an antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class. It is mainly used to treat major depressive disorder, generalized ...

paroxetine Paroxetine ( ), sold under the brand name Paxil among others, is an Antidepressant, antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used to treat major depressive disorder, obsessive-compulsive disorder, o ...

, and

sertraline Sertraline, sold under the brand name Zoloft among others, is an Antidepressant, antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used to treat major depressive disorder, generalized anxiety disorder, socia ...

and other MAOIs like

linezolid Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics. Linezolid is active against most Gram-positive bacteria that cause disease, including streptococci, va ...

. A

withdrawal syndrome Withdrawal means "an act of taking out" and may refer to: * Anchoresis (withdrawal from the world for religious or ethical reasons) * '' Coitus interruptus'' (the withdrawal method) * Drug withdrawal A drug is any chemical substance other th ...

associated with rasagiline has been reported.

Overdose

Rasagiline has been studied at single doses of up to 20mg and at repeated doses of up to 10mg/day and was well-tolerated at these doses. However, in a dose-escalation study with concomitant

therapy, a dosage of 10mg/day rasagiline was associated with

cardiovascular In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart a ...

side effects including

and

in some people. The symptoms of rasagiline

overdose A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended. Retrieved on September 20, 2014.

may be similar to the case of non-selective MAOIs. Onset of symptoms may be delayed by 12hours and may not peak for 24hours. A variety of different symptoms may occur and the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

and

cardiovascular system In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart a ...

are prominently involved. Death may result and immediate hospitalization is warranted.

has occurred with rasagiline overdose and

body temperature Thermoregulation is the ability of an organism to keep its body temperature within certain boundaries, even when the surrounding temperature is very different. A thermoconforming organism, by contrast, simply adopts the surrounding temperature ...

should be monitored closely. There is no specific

antidote An antidote is a substance that can counteract a form of poisoning. The term ultimately derives from the Greek term φάρμακον ἀντίδοτον ''(pharmakon antidoton)'', "(medicine) given as a remedy". An older term in English which is ...

for overdose and treatment is supportive and based on symptoms.

Interactions

Rasagiline is

contraindicated In medicine, a contraindication is a condition (a situation or factor) that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a rea ...

with known serotonergic agents like

s (SSRIs),

serotonin–norepinephrine reuptake inhibitor Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant medications used to treat major depressive disorder (MDD), anxiety disorders, social phobia, chronic neuropathic pain, fibromyalgia syndrome (FMS), and menopaus ...

s (SNRIs),

tricyclic antidepressant Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants. TCAs were discovered in the early 1950s and were marketed later in the decade. They are named after their chemical structure, which contains ...

s (TCAs),

tetracyclic antidepressant Tetracyclic antidepressants (TeCAs) are a class of antidepressants that were first introduced in the 1970s. They are named after their tetracyclic chemical structure, containing four cyclic compound, rings of atoms, and are closely related to th ...

s (TeCAs), triazolopyridines or serotonin antagonists and reuptake inhibitors (SARIs) like

trazodone Trazodone is an antidepressant medication used to treat major depressive disorder, anxiety disorders, and insomnia. It is a phenylpiperazine compound of the serotonin antagonist and reuptake inhibitor (SARI) class. The medication is taken or ...

, and other

s (MAOIs), as well as

meperidine Pethidine, also known as meperidine and sold under the brand name Demerol among others, is a fully synthetic opioid pain medication of the phenylpiperidine class. Synthesized in 1938 as a potential anticholinergic agent by the German chemist Ot ...

(pethidine),

tramadol Tramadol, sold under the brand name Tramal among others, is an opioid analgesic, pain medication and a serotonin–norepinephrine reuptake inhibitor (SNRI) used to treat moderately severe pain. When taken by mouth in an immediate-release form ...

methadone Methadone, sold under the brand names Dolophine and Methadose among others, is a synthetic opioid used medically to treat chronic pain and opioid use disorder. Prescribed for daily use, the medicine relieves cravings and opioid withdrawal sym ...

, propoxyphene,

dextromethorphan Dextromethorphan, sold under the brand name Robitussin among others, is a cough suppressant used in many cough and Common cold, cold medicines. In 2022, the US Food and Drug Administration (FDA) approved the combination dextromethorphan/bupropi ...

St. John's wort ''Hypericum perforatum'', commonly known as St. John's wort (sometimes perforate St. John's wort or common St. John's wort), is a flowering plant in the family Hypericaceae. It is a hairless, Perennial, perennial herb with woody Root, roots, y ...

, and

cyclobenzaprine Cyclobenzaprine, sold under several brand names including, historically, Flexeril, is a muscle relaxer used for muscle spasms from musculoskeletal conditions of sudden onset. It is not useful in cerebral palsy. It is taken by mouth. Common ...

, due to potential risk of

serotonin syndrome Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain Serotonin, serotonergic medications or Recreational drug use, drugs. The symptoms can range from mild to severe, and are potentially fatal. Symptoms in mild c ...

. However, the risk appears to be low, based on a large study of 1,504people which looked for serotonin syndrome in people with Parkinson's disease who were treated with rasagiline plus antidepressants, rasagiline without antidepressants, or antidepressants plus Parkinson's drugs other than either rasagiline or selegiline, and in which no cases were identified. There is a risk of

psychosis In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or inco ...

or bizarre behavior if rasagiline is used with dextromethorphan. There is a risk of non-selective MAO inhibition and hypertensive crisis if rasagiline is used with other MAOIs. Rasagiline may have a risk of

hypertensive crisis Severely elevated blood pressure (equal to or greater than 180 mmHg systolic or 120 mmHg diastolic) is referred to as a hypertensive crisis (sometimes termed malignant or accelerated hypertension), due to the high risk of complications. People ...

in combination with sympathomimetic agents such as

ephedrine Ephedrine is a central nervous system (CNS) stimulant and sympathomimetic agent that is often used to prevent hypotension, low blood pressure during anesthesia. It has also been used for asthma, narcolepsy, and obesity but is not the preferred ...

epinephrine Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands a ...

, isometheptene, and

pseudoephedrine Pseudoephedrine, sold under the brand name Sudafed among others, is a sympathomimetic medication which is used as a decongestant to treat nasal congestion. It has also been used off-label for certain other indications, like treatment of lo ...

. However, based on widespread clinical experience with the related selective MAO-B inhibitor

, occasional use of

over-the-counter Over-the-counter (OTC) drugs are medicines sold directly to a consumer without a requirement for a prescription from a healthcare professional, as opposed to prescription drugs, which may be supplied only to consumers possessing a valid pres ...

sympathomimetics like pseudoephedrine appears to pose minimal risk of hypertensive crisis. In any case, the combination of sympathomimetics with MAO-B inhibitors like rasagiline and selegiline should be undertaken with caution.

Pharmacology

Pharmacodynamics

Monoamine oxidase inhibitor

is characterized by the death of cells that produce

, a

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

. An enzyme called

(MAO) breaks down neurotransmitters. MAO has two forms,

MAO-A Monoamine oxidase A, also known as MAO-A, is an enzyme ( E.C. 1.4.3.4) that in humans is encoded by the ''MAOA'' gene. This gene is one of two neighboring gene family members that encode mitochondrial enzymes which catalyze the oxidative deamin ...

and

MAO-B Monoamine oxidase B (MAO-B) is an enzyme that in humans is encoded by the ''MAOB'' gene. The protein encoded by this gene belongs to the flavin monoamine oxidase family. It is an enzyme located in the outer mitochondrial membrane. It catalyze ...

. MAO-B is involved in the metabolism of

. Rasagiline prevents the breakdown of dopamine by irreversibly binding to MAO-B. Dopamine is therefore more available, somewhat compensating for the diminished quantities made in the brains of people with Parkinson's disease. Rasagiline acts as a selective and potent irreversible inhibitor of the

s (MAO)

(MAO-B) and

monoamine oxidase A Monoamine oxidase A, also known as MAO-A, is an enzyme ( E.C. 1.4.3.4) that in humans is encoded by the ''MAOA'' gene. This gene is one of two neighboring gene family members that encode mitochondrial enzymes which catalyze the oxidative dea ...

(MAO-A). It is selective for inhibition of MAO-B over MAO-A, but can also inhibit MAO-A at high doses or concentrations. MAO-B is involved in the

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

of the

in the body and brain. By inhibiting MAO-B, rasagiline is thought to increase dopamine levels. In the case of

, increased dopamine levels in the

striatum The striatum (: striata) or corpus striatum is a cluster of interconnected nuclei that make up the largest structure of the subcortical basal ganglia. The striatum is a critical component of the motor and reward systems; receives glutamat ...

are thought to be responsible for rasagiline's therapeutic effectiveness in treating the condition. Rasagiline inhibits platelet MAO-B activity with single doses by 35% one-hour after 1mg, 55% after 2mg, 79% after 5mg, and 99% after 10mg in healthy young people. With all dose levels, maximum inhibition is maintained for at least 48hours after the dose. With repeated doses, rasagiline reaches greater than 99% platelet MAO-B inhibition after 6days of 2mg/day, 3days of 5mg/day, and 2 days of 10mg/day. Similarly, repeated administration of 0.5, 1, and 2mg/day rasagiline resulted in complete MAO-B inhibition. Clinically relevant inhibition of MAO-B is thought to require 80% inhibition and above. Following the last dose, platelet MAO-B levels remain significantly inhibited for 7days and return to baseline after 2weeks. In people with Parkinson's disease, rasagiline at a dose of 1mg/day achieved near-complete inhibition of platelet MAO-B after 3days of dosing. The recommended dosing schedule of rasagiline in Parkinson's disease (1mg/day) has been described as somewhat questionable and potentially excessive from a pharmacological standpoint. The half-time for recovery of brain MAO-B following discontinuation of an MAO-B inhibitor (specifically selegiline) has been found to be approximately 40days. Similarly, recovery of brain MAO-B following rasagiline discontinuation was gradual and occurred over 6weeks. The clinical effectiveness of rasagiline in Parkinson's disease has been found to persist during a 6-week washout phase with discontinuation of the medication. Rasagiline is about 30 to 100times more potent in inhibiting MAO-B than MAO-A ''

in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

'' and is about 17 to 65times more potent in inhibiting MAO-B over MAO-A ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...

'' in rodents. Rasagiline does not importantly potentiate the pressor effects of

tyramine Tyramine ( ) (also spelled tyramin), also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the bl ...

challenge in humans, indicating that it is selective for MAO-B inhibition and does not meaningfully inhibit MAO-A. It is expected that at sufficiently high doses rasagiline would eventually become non-selective and additionally inhibit MAO-A in humans. However, it is unknown what dose threshold would be required for this to occur. Rasagiline is the ''R''(+)-enantiomer of AGN-1135, a

racemic mixture In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...

of rasagiline (TVP-1012) and the ''S''(–)-enantiomer (TVP-1022). Virtually all of the MAO-inhibiting activity of AGN-1135 lies in the ''R''(+)-enantiomer rasagiline, with this enantiomer having 1,000-fold greater inhibitory potency of MAO-B than the ''S''(–)-enantiomer. In addition, the ''S''(–)-enantiomer is poorly selective for MAO-B over MAO-A. As a result, the purified ''R''(+)-enantiomer rasagiline was the form of the compound advanced for clinical development.

Selegiline Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl, Zelapar, and Emsam among others, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It has also been studied and us ...

was the first selective MAO-B inhibitor. Selegiline and rasagiline have similar

selectivity Selectivity may refer to: Psychology and behaviour * Choice, making a selection among options * Discrimination, the ability to recognize differences * Socioemotional selectivity theory, in social psychology Engineering * Selectivity (radio), a ...

for inhibition of MAO-B over MAO-A. However, rasagiline is 5- to 10-fold more potent than selegiline at inhibiting MAO-B, which results in the former being used at lower doses clinically than the latter (1mg/day versus 5–10mg/day, respectively). In addition, selegiline is

metabolized Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

into

levomethamphetamine Levomethamphetamine (International Nonproprietary Name, INN: levmetamfetamine) is an optical isomer of methamphetamine primarily used as a Topical decongestant, topical nasal decongestant. Levomethamphetamine is used to treat nasal congestion f ...

and

levoamphetamine Levoamphetamine is a stimulant medication which is used in the treatment of certain medical conditions. It was previously marketed by itself under the brand name Cydril, but is now available only in combination drug, combination with dextroam ...

. These metabolites induce the release of norepinephrine and dopamine, have sympathomimetic and

psychostimulant Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition ...

effects, and may contribute to the effects and

side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s of selegiline. In contrast to selegiline, rasagiline does not convert into

s with amphetamine-like effects. The amphetamine metabolites of selegiline may contribute to significant clinical differences between selegiline and rasagiline. Rasagiline metabolizes into (''R'')-1-aminoindan which has no amphetamine-like effects and shows neuroprotective properties in cells and in animal models. Selective MAO-B inhibitors including rasagiline and selegiline have been found to increase dopamine levels in the striatum in rats ''

''. It has been theorized that this might be due to strong inhibition of the metabolism of

β-phenylethylamine Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amine ...

, which is an

endogenous Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell. For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...

MAO-B substrate that has monoaminergic activity enhancer and

norepinephrine–dopamine releasing agent A norepinephrine–dopamine releasing agent (NDRA) is a type of drug which induces the synapse, release of norepinephrine (and epinephrine) and dopamine in the body and/or brain. Many of these are amphetamine type stimulants. Examples Examples ...

actions. β-Phenylethylamine has been described as "endogenous amphetamine" and its brain levels are dramatically increased (10- to 30-fold) by MAO-B inhibitors like selegiline. Elevation of β-phenylethylamine may be involved in the effects of MAO-B inhibitors in the treatment of Parkinson's disease. In 2021, it was discovered that MAO-A is solely or almost entirely responsible for striatal dopamine

catabolism Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, lipid ...

in the rodent brain and that MAO-B is not importantly involved. In contrast, MAO-B appears to mediate tonic

γ-aminobutyric acid GABA (gamma-aminobutyric acid, γ-aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. GA ...

(GABA) synthesis from

putrescine Putrescine is an organic compound with the formula (CH2)4(NH2)2. It is a colorless solid that melts near room temperature. It is classified as a diamine. Together with cadaverine, it is largely responsible for the foul odor of Putrefaction, putref ...

in the striatum, a minor and alternative

metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell (biology), cell. The reactants, products, and Metabolic intermediate, intermediates of an enzymatic reaction are known as metabolites, which are ...

of GABA synthesis, and this synthesized GABA in turn inhibits dopaminergic neurons in this brain area. MAO-B specifically mediates the

transformation Transformation may refer to: Science and mathematics In biology and medicine * Metamorphosis, the biological process of changing physical form after birth or hatching * Malignant transformation, the process of cells becoming cancerous * Trans ...

s of putrescine into γ-aminobutyraldehyde (GABAL or GABA aldehyde) and ''N''-acetylputrescine into ''N''-acetyl-γ-aminobutyraldehyde (''N''-acetyl-GABAL or ''N''-acetyl-GABA aldehyde),

metabolic product In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

s that can then be converted into GABA via

aldehyde dehydrogenase Aldehyde dehydrogenases () are a group of enzymes that catalyse the oxidation of aldehydes. They convert aldehydes (R–C(=O)) to carboxylic acids (R–C(=O)). The oxygen comes from a water molecule. To date, nineteen ALDH genes have ...

(ALDH) (and an unknown deacetylase

in the case of ''N''-acetyl-GABAL). These findings may warrant a rethinking of the pharmacological actions of MAO-B inhibitors like selegiline and rasagiline in the treatment of Parkinson's disease.

Other actions

Rasagiline is selective for inhibition of MAOs over interactions with other

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

s, including α-adrenergic receptors,

β-adrenergic receptor The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like bet ...

muscarinic acetylcholine receptor Muscarinic acetylcholine receptors (mAChRs) are acetylcholine receptors that form G protein-coupled receptor, G protein-coupled receptor complexes in the cell membranes of certain neurons and other Cell (biology), cells. They play several role ...

s, and other

target Target may refer to: Warfare and shooting * Shooting target, used in marksmanship training and various shooting sports ** Bullseye (target), the goal one for which one aims in many of these sports ** Aiming point, in field artille ...

s. The major metabolite of rasagiline, (''R'')-1-aminoindan, is either devoid of MAO inhibition or shows only weak inhibition of MAO-B. It also has no

-like activity. However, 1-aminoindan is not lacking in pharmacological activity. Like rasagiline, 1-aminoindan shows neuroprotective activity in some experimental models. In addition, 1-aminoindan has been found to enhance striatal

dopaminergic Dopaminergic means "related to dopamine" (literally, "working on dopamine"), a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic pathways, Dopaminergic brain pathways facil ...

neurotransmission Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron ...

and improve

motor An engine or motor is a machine designed to convert one or more forms of energy into mechanical energy. Available energy sources include potential energy (e.g. energy of the Earth's gravitational field as exploited in hydroelectric power gene ...

function independent of MAO inhibition in

animal model An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...

s of Parkinson's disease. 2-Aminoindan, a closely related

positional isomer In chemistry, a structural isomer (or constitutional isomer in the IUPAC nomenclature) of a compound is a compound that contains the same number and type of atoms, but with a different connectivity (i.e. arrangement of bonds) between them. The ...

of 1-aminoindan, is known to inhibit the reuptake and induce the release of dopamine and norepinephrine and to produce

-like effects in rodents, albeit with lower

potency Potency may refer to: * Potency (pharmacology), a measure of the activity of a drug in a biological system * Virility * Cell potency, a measure of the differentiation potential of stem cells * In homeopathic dilutions, potency is a measure of ho ...

than

, but rasagiline does not metabolize into this compound. 1-Aminoindan has been found to inhibit the reuptake of norepinephrine 28-fold less potently than 2-aminoindan and to inhibit the reuptake of dopamine 300-fold less potently than 2-aminoindan, with values for dopamine reuptake inhibition in one study of 0.4μM for

, 3.3μM for 2-aminoindan, and 1mM for 1-aminoindan. In contrast to 2-aminoindan, which increased locomotor activity in rodents (+49%), 1-aminoindan suppressed locomotor activity (–69%). On the other hand, 1-aminoindan has been found to enhance the psychostimulant-like effects of amphetamine in rodents. Whereas selegiline is a catecholaminergic activity enhancer, which may be mediated by

agonism Agonism (from Greek 'struggle') is a political and social theory that emphasizes the potentially positive aspects of certain forms of conflict. It accepts a permanent place for such conflict in the political sphere, but seeks to show how indivi ...

of the

TAAR1 Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the ''TAAR1'' gene. TAAR1 is a primarily intracellular amine-activated and G protein-coupled receptor (GPCR) that is p ...

, rasagiline does not possess this action. Instead, rasagiline actually antagonizes selegiline's effects as a catecholaminergic activity enhancer, which may be mediated by TAAR1 antagonism. Rasagiline has been reported to directly bind to and inhibit glyceraldehyde-3-phosphate dehydrogenase (GAPDH). This might play a modulating role in its clinical effectiveness for Parkinson's disease. Selegiline also binds to and inhibits GAPDH. Rasagiline has been found to bind reversibly to α-synuclein, a major

involved in the

pathophysiology Pathophysiology (or physiopathology) is a branch of study, at the intersection of pathology and physiology, concerning disordered physiological processes that cause, result from, or are otherwise associated with a disease or injury. Pathology is ...

of Parkinson's disease, and this action might be neuroprotective.

Pharmacokinetics

Absorption

Rasagiline is rapidly absorbed from the

gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the Digestion, digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascula ...

with

oral administration Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

and has approximately 36%

absolute bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

. The

peak Peak or The Peak may refer to: Basic meanings Geology * Mountain peak ** Pyramidal peak, a mountaintop that has been sculpted by erosion to form a point Mathematics * Peak hour or rush hour, in traffic congestion * Peak (geometry), an (''n''-3)-d ...

and area-under-the-curve levels of rasagiline are linear and dose-proportional over a dose range of 0.5 to 10mg. The time to peak levels of rasagiline is 0.5 to 0.7hours and

steady-state In systems theory, a system or a process is in a steady state if the variables (called state variables) which define the behavior of the system or the process are unchanging in time. In continuous time, this means that for those properties ''p'' ...

peak levels are on average 8.5ng/mL. At steady-state, the time to peak levels of rasagiline's major metabolite (''R'')-1-aminoindan is 2.1hours, its peak levels are 2.6ng/mL, and its area-under-the-curve levels are 10.1ng/h/mL. Taking rasagiline with

food Food is any substance consumed by an organism for Nutrient, nutritional support. Food is usually of plant, animal, or Fungus, fungal origin and contains essential nutrients such as carbohydrates, fats, protein (nutrient), proteins, vitamins, ...

(as a high-fat meal) increases peak levels by approximately 60% and area-under-the-curve levels by approximately 20%, whereas time to peak levels is unchanged. Because exposure to rasagiline is not substantially modified, rasagiline can be taken with or without food.

Distribution

The mean

volume of distribution In pharmacology, the volume of distribution (VD, also known as apparent volume of distribution, literally, ''volume of dilution'') is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same c ...

of rasagiline is 87L or 182 to 243L depending on the source. It readily crosses the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

and enters the

. The

plasma protein binding Plasma protein binding refers to the degree to which medications attach to blood proteins within the blood plasma. A drug's efficacy may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse o ...

of rasagiline is 60 to 70% or 88 to 94% depending on the source. In the case of the latter range, 61 to 63% of binding was to

albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All of the proteins of the albumin family are water- soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Alb ...

Metabolism

Rasagiline is extensively

in the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

. It is metabolized primarily by hepatic ''N''-dealkylation via the

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

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 ...

which forms the major

(''R'')-1-aminoindan. It is also metabolized by

hydroxylation In chemistry, hydroxylation refers to the installation of a hydroxyl group () into an organic compound. Hydroxylations generate alcohols and phenols, which are very common functional groups. Hydroxylation confers some degree of water-solubility ...

via cytochrome P450 enzymes to form 3-hydroxy-''N''-propargyl-1-aminoindan (3-OH-PAI) and 3-hydroxy-1-aminoindan (3-OH-AI). Rasagiline and its metabolites also undergo

conjugation Conjugation or conjugate may refer to: Linguistics *Grammatical conjugation, the modification of a verb from its basic form *Emotive conjugation or Russell's conjugation, the use of loaded language Mathematics *Complex conjugation, the change o ...

via

glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gly ...

. Use of rasagiline should be monitored carefully in people taking other drugs that inhibit or

induce Induce may refer to: * Induced consumption * Induced innovation * Induced character * Induced coma * Induced menopause * Induced metric * Induced path * Induced topology * Induce (musician), American musician * Labor induction Labor indu ...

CYP1A2. Variants in CYP1A2 have been found to modify exposure to rasagiline in some studies but not others.

Tobacco smoking Tobacco smoking is the practice of burning tobacco and ingesting the resulting smoke. The smoke may be inhaled, as is done with cigarettes, or released from the mouth, as is generally done with pipes and cigars. The practice is believed to hav ...

, a known inhibitor of CYP1A2, did not modify rasagiline exposure. Drug transporters may be more important in influencing the pharmacokinetics of rasagiline than metabolizing enzymes. Exposure to rasagiline is increased in people with hepatic impairment. In those with mild hepatic impairment, peak levels of rasagiline are increased by 38% and area-under-the-curve levels by 80%, whereas in people with moderate hepatic impairment, peak levels are increased by 83% and area-under-the-curve levels by 568%. As a result, the dosage of rasagiline should be halved to 0.5mg/day in people with mild hepatic impairment and rasagiline is considered to be

in people with moderate to severe hepatic impairment.

Elimination

Rasagiline is eliminated primarily in

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

(62%) and to a much lesser extent in

feces Feces (also known as faeces American and British English spelling differences#ae and oe, or fæces; : faex) are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the ...

(7%). Rasagiline is excreted unchanged in urine at an amount of less than 1%. Hence, it is almost completely metabolized prior to excretion. The

elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

of rasagiline is 1.34hours. At

, its half-life is 3hours. As rasagiline acts as an irreversible inhibitor of MAO-B, its actions and duration of effect are not dependent on its half-life or sustained concentrations in the body. The oral clearance of rasagiline is 94.3L/h and is similar to normal liver blood flow (90L/h). This indicates that non-hepatic mechanisms are not significantly involved in the elimination of rasagiline. Moderate

renal impairment Kidney failure, also known as renal failure or end-stage renal disease (ESRD), is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney fa ...

did not modify exposure to rasagiline, whereas that of (''R'')-1-aminoindan was increased by 1.5-fold. Since (''R'')-1-aminoindan is not an MAO inhibitor, mild to moderate renal impairment does not require dosage adjustment of rasagiline. No data are available in the case of severe or end-stage renal impairment.

Chemistry

Rasagiline, also known as (''R'')-''N''-propargyl-1-aminoindan and by its former developmental code name TVP-1012, is a secondary cyclic

benzylamine Benzylamine, also known as phenylmethylamine, is an Organic chemistry, organic chemical compound with the Structural formula#Condensed formulas, condensed structural formula C6H5CH2NH2 (sometimes abbreviated as Phenyl group#Nomenclature, PhCH2NH2 ...

propargylamine. It is the ''R''(+)-

enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...

of the

chiral Chirality () is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek language, Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is dist ...

racemic In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...

compound AGN-1135 (''N''-propargyl-1-aminoindan), whereas the ''S''(–)-enantiomer is TVP-1022 ((''S'')-''N''-propargyl-1-aminoindan). Rasagiline is a potent and selective

, whereas TVP-1022 is a very weak and poorly selective MAO inhibitor. Both the

hydrochloride In chemistry, a hydrochloride is an acid salt resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base (e.g. an amine). An alternative name is chlorhydrate, which comes from French. An archaic alternati ...

and

mesylate In organosulfur chemistry, a mesylate is any salt or ester of methanesulfonic acid (). In salts, the mesylate is present as the anion. When modifying the international nonproprietary name of a pharmaceutical substance containing the gr ...

salt In common usage, salt is a mineral composed primarily of sodium chloride (NaCl). When used in food, especially in granulated form, it is more formally called table salt. In the form of a natural crystalline mineral, salt is also known as r ...

s of rasagiline were studied and were found to have similar

pharmacokinetic Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to describing how the body affects a specific subs ...

, and

toxicological Toxicology is a scientific discipline (academia), discipline, overlapping with biology, chemistry, pharmacology, and medicine, that involves the study of the adverse effects of chemical substances on living organisms and the practice of diagnos ...

profiles. However, the mesylate salt of rasagiline was ultimately selected for its use as a

pharmaceutical drug Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the ...

due to favorable

chemical stability In chemistry, chemical stability is the thermodynamic stability of a chemical system, in particular a chemical compound or a polymer. Colloquially, it may instead refer to kinetic persistence, the shelf-life of a metastable substance or system; t ...

. The propargyl moiety is essential in the

pharmacodynamics Pharmacodynamics (PD) is the study of the biochemistry, biochemical and physiology, physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or comb ...

of rasagiline. It binds

covalently A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atoms ...

and irreversibly with the

flavin adenine dinucleotide In biochemistry, flavin adenine dinucleotide (FAD) is a redox-active coenzyme associated with various proteins, which is involved with several enzymatic reactions in metabolism. A flavoprotein is a protein that contains a flavin group, which ma ...

(FAD) moiety of the MAO

. The

of rasagiline for

over

depends on the maintenance of a distance of no more than two carbon atoms between the

aromatic ring In organic chemistry, aromaticity is a chemical property describing the way in which a conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibits a stabilization stronger than would be expected from conjugation alone. The e ...

and the ''N''-propargyl group. The propargyl group of rasagiline is also essential for its neuroprotective and antiapoptopic actions, which are independent of its MAO inhibition. Rasagiline is closely structurally related to

(''R''(–)-''N''-propargylmethamphetamine). However, in contrast to selegiline, rasagiline is not a

substituted amphetamine Substituted amphetamines, or simply amphetamines, are a chemical class, class of compounds based upon the amphetamine structure; it includes all derivative (chemistry), derivative compounds which are formed by replacing, or substitution reacti ...

and is instead an 1-aminoindan

derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...

. The

chemical structure A chemical structure of a molecule is a spatial arrangement of its atoms and their chemical bonds. Its determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target m ...

s of the amphetamines and aminoindans are very similar. However, whereas selegiline metabolizes into

and

and can produce

-like effects, rasagiline does not do so. Instead, it metabolizes into (''R'')-1-aminoindan (TVP-136) and has no such actions. SU-11739 (AGN-1133; ''N''-methyl-''N''-propargyl-1-aminoindan), the ''N''-

methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula (whereas normal methane has the formula ). In formulas, the group is often abbreviated as ...

ated analogue of rasagiline, is also an MAO-B-preferring MAOI. However, it is less selective for inhibition of MAO-B over MAO-A than rasagiline. Another structurally related selective MAO-B inhibitor, ladostigil (''N''-propargyl-(3''R'')-aminoindan-5-yl-''N''-propylcarbamate; TV-3326), was developed from structural modification of rasagiline and additionally acts as an

acetylcholinesterase inhibitor Acetylcholinesterase inhibitors (AChEIs) also often called cholinesterase inhibitors, inhibit the enzyme acetylcholinesterase from breaking down the neurotransmitter acetylcholine into choline and acetate, thereby increasing both the level an ...

due to its

carbamate In organic chemistry, a carbamate is a category of organic compounds with the general Chemical formula, formula and Chemical structure, structure , which are formally Derivative (chemistry), derived from carbamic acid (). The term includes orga ...

moiety. Rasagiline and its metabolite (''R'')-1-aminoindan are structurally related to 2-aminoindan and

s like 5,6-methylenedioxy-2-aminoindane (MDAI), 5,6-methylenedioxy-''N''-methyl-2-aminoindane (MDMAI), and 5-iodo-2-aminoindane (5-IAI).

History

AGN-1135, the racemic form of the drug, was invented by Aspro Nicholas in the early 1970s. Moussa B. H. Youdim identified it as a potential drug for Parkinson's disease, and working with collaborators at Technion – Israel Institute of Technology in Israel and the drug company,

Teva Pharmaceuticals Teva Pharmaceutical Industries Ltd. (also known as Teva Pharmaceuticals) is an Israeli multinational Pharmaceutical industry, pharmaceutical company. Teva specializes primarily in generic drugs, but other business interests include branded-drug ...

, identified the R-isomer as the active form of the drug. Teva brought it to market in partnership with

Lundbeck H. Lundbeck A/S, commonly referred to as Lundbeck, is a Denmark, Danish international pharmaceutical company engaged in the research, development, manufacturing, marketing and sale of pharmaceuticals across the world. The company’s products ar ...

in the European Union and Eisai in the United States and elsewhere. Prior to the discovery of rasagiline, a closely related analogue called SU-11739 (AGN-1133; J-508; ''N''-methyl-''N''-propargyl-1-aminoindan) was

patent A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an sufficiency of disclosure, enabling discl ...

ed in 1965. At first, the ''N''-methyl was necessary for the agent to be considered a ring cyclized analogue of pargyline with about 20times the potency. However, the ''N''-methyl compound was a non-selective MAOI. In addition, SU-11739 has been reported to have strong catecholamine-releasing actions.

Racemic In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...

rasagiline was discovered and patented by Aspro Nicholas in the 1970s as a drug candidate for treatment of

. 5453446 was the patent at issue in Moussa B. H. Youdim was involved in developing

as a drug for Parkinson's, in collaboration with Peter Reiderer. He called the compound AGN 1135. In 1996 Youdim, in collaboration with scientists from Technion and the US

National Institutes of Health The National Institutes of Health (NIH) is the primary agency of the United States government responsible for biomedical and public health research. It was founded in 1887 and is part of the United States Department of Health and Human Service ...

, and using compounds developed with

, published a paper in which the authors wrote that they were inspired by the racemic nature of deprenyl and the greater activity of one of its stereoisomers, L-deprenyl, which became

, to explore the qualities of the isomers of the Aspro compound, and they found that the R-isomer had almost all the activity; this is the compound that became rasagiline. They called the mesylate salt of the R-isomer TVP-1012 and the hydrochloride salt, TVP-101. Teva and Technion filed patent applications for this racemically pure compound, methods to make it, and methods to use it to treat Parkinson's disease and other disorders, and Technion eventually assigned its rights to Teva. Teva began

development Development or developing may refer to: Arts *Development (music), the process by which thematic material is reshaped * Photographic development *Filmmaking, development phase, including finance and budgeting * Development hell, when a proje ...

of rasagiline, and by 1999 was in Phase III trials, and entered into a partnership with

in which Lundbeck agreed to share the costs and obtained the joint right to market the drug in the European Union. In 2003, Teva partnered with Eisai, giving Eisai the right to jointly market the drug for Parkinson's in the US, and to co-develop and co-market the drug for

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

and other neurological diseases. It was approved by the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...

for Parkinson's in 2005 and in the United States in 2006. Following its approval, rasagiline was described by some authors as a " me-too drug" that offered nothing new in terms of effectiveness and tolerability compared to selegiline. However, others have contended that rasagiline shows significant differences from and improvements over selegiline, like its lack of

s and associated

monoamine releasing agent A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of one or more monoamine neurotransmitters from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrati ...

effects, which may improve tolerability and

safety Safety is the state of being protected from harm or other danger. Safety can also refer to the control of recognized hazards in order to achieve an acceptable level of risk. Meanings The word 'safety' entered the English language in the 1 ...

. Conversely, others have maintained that rasagiline may be less efficacious than selegiline due to its lack of catecholaminergic activity enhancer actions.

Society and culture

Names

''Rasagiline'' is the generic name of the drug and its and . It is also known by its former developmental code name ''TVP-1012''. Rasagiline is marketed under the brand name Azilect, among others.

Generic forms

Lower-cost generic versions of rasagiline are available.

Research

Neurodegenerative diseases

Rasagiline was under development for the treatment of

. However, development was discontinued. Rasagiline was tested for efficacy in people with

multiple system atrophy Multiple system atrophy (MSA) is a rare neurodegenerative disorder characterized by tremors, slow movement, muscle rigidity, postural instability (collectively known as parkinsonism), autonomic dysfunction and ataxia. This is caused by progr ...

in a large randomized, placebo-controlled, double-blind disease-modification trial; the drug failed. Rasagiline has been reported to improve symptoms in people with freezing gait. Rasagiline has been studied in the treatment of

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; Lou Gehrig's disease).

Psychiatric disorders

Rasagiline has been described as an emerging potential

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

. MAO-B inhibitors have been found to reduce depressive symptoms in people with Parkinson's disease with a small

. However, rasagiline does not appear to have been studied in the treatment of depression in people without Parkinson's disease and it has not been developed nor approved for the treatment depression. In an

animal study Animal testing, also known as animal experimentation, animal research, and ''in vivo'' testing, is the use of animals, as model organisms, in experiments that seek answers to scientific and medical questions. This approach can be contrasted ...

was effective in

model A model is an informative representation of an object, person, or system. The term originally denoted the plans of a building in late 16th-century English, and derived via French and Italian ultimately from Latin , . Models can be divided in ...

s of

-like activity, whereas rasagiline was ineffective. The antidepressant effects of selegiline in animals appear to be independent of monoamine oxidase inhibition and may be related to its catecholaminergic activity enhancer (CAE) activity, which rasagiline lacks. Rasagiline has not been studied in the treatment of psychostimulant addiction as of 2015.

Other conditions

Rasagiline has been reported to improve

restless legs syndrome Restless legs syndrome (RLS), also known as Willis–Ekbom disease (WED), is a neurological disorder, usually chronic, that causes an overwhelming urge to move one's legs. There is often an unpleasant feeling in the legs that improves temporaril ...

(RLS).

Notes

References

{{Authority control 1-Aminoindanes Antidepressants Antiparkinsonian agents Drugs with unknown mechanisms of action Enantiopure drugs Monoamine oxidase inhibitors Monoaminergic activity enhancer antagonists Neuroprotective agents Propargyl compounds