Nomifensine, formerly sold under the brand names Merital and Alival, is a
norepinephrine–dopamine reuptake inhibitor
A norepinephrine–dopamine reuptake inhibitor (NDRI) is a type of drug that inhibits the reuptake of the monoamine neurotransmitters norepinephrine and dopamine and thereby increases extracellular levels of these neurotransmitters and nor ...
(NDRI) drug that was developed in the 1960s by
Hoechst AG
Hoechst AG () was a German chemicals, later life sciences, company that became Aventis Deutschland after its merger with France's Rhône-Poulenc S.A. in 1999. With the new company's 2004 merger with Sanofi-Synthélabo, it became a subsidiar ...
(now
Sanofi-Aventis
Sanofi S.A. is a French multinational pharmaceutical and healthcare company headquartered in Paris, France. The corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 2004, Sanofi-Synthélabo merg ...
), who then
test market
A test market, in the field of business and marketing, is a geographic region or demographic group used to gauge the viability of a product or service in the mass market prior to a wide scale rollout. The criteria used to judge the acceptability ...
ed it in the United States.
Nomifensine was considered an effective
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 ...
that lacked sedative effects. It did not interact significantly with
alcohol
Alcohol may refer to:
Common uses
* Alcohol (chemistry), a class of compounds
* Ethanol, one of several alcohols, commonly known as alcohol in everyday life
** Alcohol (drug), intoxicant found in alcoholic beverages
** Alcoholic beverage, an alco ...
and lacked
anticholinergic
Anticholinergics (anticholinergic agents) are substances that block the action of the acetylcholine (ACh) neurotransmitter at synapses in the central nervous system, central and peripheral nervous system.
These agents inhibit the parasympatheti ...
effects. No
withdrawal symptoms were seen after 6 months treatment. The drug was, however, considered not suitable for agitated patients as it presumably made agitation worse. In January 1986 the drug was withdrawn by its manufacturers for safety reasons.
Some case reports in the 1980s suggested that there was potential for psychological dependence on nomifensine, typically in patients with a history of stimulant addiction, or when the drug was used in very high doses (400–600 mg per day).
In a 1989 study it was investigated for use in treating
attention deficit hyperactivity disorder
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple con ...
(ADHD) in adults and was proven to be effective. In a 1977 study it was not proven of benefit in advanced
parkinsonism
Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), Rigidity (neurology), rigidity, and balance disorder, postural instability.
Both hypokinetic features (bradykinesia and akinesia) and hyperkinetic f ...
, except for depression associated with the parkinsonism.
Medical uses
Nomifensine was investigated for use as an antidepressant in the 1970s, and was found to be a useful antidepressant at doses of 50–225 mg per day, both motivating and anxiolytic.
Adverse effects
During treatment with nomifensine there were relatively few adverse effects, mainly
renal failure
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 ...
, paranoid symptoms,
drowsiness
Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...
or
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 ...
,
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 ...
, and
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 ...
. Side effects affecting the cardiovascular system included
tachycardia
Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ...
and
palpitations
Palpitations occur when a person becomes aware of their heartbeat. The heartbeat may feel hard, fast, or uneven in their chest.
Symptoms include a very fast or irregular heartbeat. Palpitations are a sensory symptom. They are often described as ...
, but nomifensine was significantly less cardiotoxic than the standard tricyclic antidepressants.
Withdrawal from market
Due to a risk of
haemolytic anaemia
Hemolytic anemia or haemolytic anaemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular). This most commonl ...
, the U.S.
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) withdrew approval for nomifensine on March 20, 1992. Nomifensine was subsequently withdrawn from the Canadian and UK markets as well. Some deaths were linked to immunohaemolytic anemia caused by this compound, although the mechanism remained unclear.
Synthesis
Nomifensine was a progenitor to Gastrophenzine.
[ See also: ]Isatin
Isatin, also known as tribulin, is an organic compound derived from indole with formula C8H5NO2. The compound was first obtained by Otto Linné Erdman and Auguste Laurent in 1840 as a product from the oxidation of indigo dye by nitric acid and ...
derivatives.
The alkylation between N-methyl-2-nitrobenzylamine 6222-08-3
6 (six) is the natural number following 5 and preceding 7. It is a composite number and the smallest perfect number.
In mathematics
A six-sided polygon is a hexagon, one of the three regular polygons capable of tiling the plane. A hexagon al ...
(1) and phenacyl bromide
Phenacyl bromide is the organic compound with the formula C6H5C(O)CH2Br. This colourless solid is a powerful lachrymator as well as a useful precursor to other organic compounds.
It is prepared by bromination of acetophenone
Acetophenone is th ...
(2) give
CID:15326127
(3). Catalytic hydrogenation
Hydrogenation is a chemical reaction between molecular hydrogen (H2) and another compound or element, usually in the presence of a catalyst such as nickel, palladium or platinum. The process is commonly employed to reduce or saturate organic ...
over Raney Nickel reduces the nitro group to giv
CID:15113381
(4). The reduction of the ketone group with sodium borohydride
Sodium borohydride, also known as sodium tetrahydridoborate and sodium tetrahydroborate, is an inorganic compound with the formula (sometimes written as ). It is a white crystalline solid, usually encountered as an aqueous basic solution. Sodi ...
to alcohol gives 5514-97-8(5). Acid catalysed ring closure completes the formation of nomifensine (6).
Research
Motivational disorders
Nomifensine has been found to reverse tetrabenazine
Tetrabenazine is a drug for the symptomatic treatment of hyperkinetic movement disorders. It is sold under the brand names Nitoman and Xenazine among others. On August 15, 2008, the US Food and Drug Administration (FDA) approved the use of tet ...
-induced motivational deficits in animals. It shares these pro-motivational effects with other NDRIs like bupropion
Bupropion, formerly called amfebutamone, and sold under the brand name Wellbutrin among others, is an atypical antidepressant that is indicated in the treatment of major depressive disorder, seasonal affective disorder, and to support smo ...
and methylphenidate
Methylphenidate, sold under the brand names Ritalin ( ) and Concerta ( ) among others, is a central nervous system (CNS) stimulant used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It may be taken Oral adm ...
and with selective dopamine reuptake inhibitor
A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dop ...
s like modafinil
Modafinil, sold under the brand name Provigil among others, is a central nervous system (CNS) stimulant and wakefulness-promoting agent, eugeroic (wakefulness promoter) medication used primarily to treat narcolepsy, a sleep disorder characteri ...
and its analogues. Conversely, selective norepinephrine reuptake inhibitor
A norepinephrine reuptake inhibitor (NRI, NERI) or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epinep ...
s like desipramine
Desipramine, sold under the brand name Norpramin among others, is a tricyclic antidepressant (TCA) used in the treatment of depression. It acts as a relatively selective norepinephrine reuptake inhibitor, though it does also have other activiti ...
and atomoxetine
Atomoxetine, formerly sold under the brand name Strattera, is a selective norepinephrine reuptake inhibitor (sNRI) medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, cognitive disengagement syndr ...
and 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 like fluoxetine
Fluoxetine, sold under the brand name Prozac, among others, is an Antidepressant, antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used for the treatment of major depressive disorder, Anxiety disorder, anx ...
and citalopram
Citalopram, sold under the brand name Celexa among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used to treat major depressive disorder, obsessive compulsive disorder, panic disorder, and soci ...
have not shown pro-motivational effects in animals.
Wakefulness
Nomifensine shows wakefulness-promoting
A wakefulness-promoting agent (WPA), or wake-promoting agent, is a drug that increases wakefulness and arousal. They are similar to but distinct from psychostimulants, which not only promote wakefulness but also produce other more overt central n ...
effects in animals and might be useful in the treatment of narcolepsy
Narcolepsy is a chronic neurological disorder that impairs the ability to regulate sleep–wake cycles, and specifically impacts REM (rapid eye movement) sleep. The symptoms of narcolepsy include excessive daytime sleepiness (EDS), sleep-r ...
.
See also
* Amineptine
Amineptine, formerly sold under the brand name Survector among others, is an atypical antidepressant of the tricyclic antidepressant (TCA) family. It acts as a selective and mixed dopamine reuptake inhibitor and releasing agent, and to a le ...
* Diclofensine
* Perafensine
* Tesofensine
Tesofensine (NS2330) is a serotonin-noradrenaline-dopamine reuptake inhibitor, serotonin–noradrenaline–dopamine reuptake inhibitor from the phenyltropane family of drugs, which is being developed for the treatment of obesity. Tesofensine was ...
* The combination of Clobazam
Clobazam, sold under the brand names Frisium, Onfi and others, is a benzodiazepine class medication that was patented in 1968. Clobazam was first synthesized in 1966 and first published in 1969. Clobazam was originally marketed as an anxiosele ...
/ nomifensine is called Psyton 5963-47-2[Jellinger K, Koeppen D, Rössner M. Langzeitbehandlung depressiver Syndrome mit Psyton ong-term treatment of depressive syndromes with Psyton (author's transl) Wien Med Wochenschr. 1982 Apr 30;132(8):183-8. German. PMID 6125057.]
References
{{Monoamine reuptake inhibitors
Anilines
Antidepressants
Hepatotoxins
Norepinephrine–dopamine reuptake inhibitors
Pro-motivational agents
Stimulants
Tetrahydroisoquinolines
Wakefulness-promoting agents
Withdrawn drugs