Remacemide is a

drug A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhal ...

which acts as a low-affinity

NMDA antagonist NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the ''N''-Methyl-D-aspartate receptor ( NMDAR). They are commonly used as anesthetics for animals and humans; the state of anesthesia they induc ...

with

sodium Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable ...

channel blocking properties. It has been studied for the treatment of acute

ischemic stroke Stroke (also known as a cerebrovascular accident (CVA) or brain attack) is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, ...

epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical ...

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an uns ...

, and

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

. Because remacemide has only a modest effect on seizure frequency and causes

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

, it is no longer believed that remacemide will be an effective treatment for epilepsy. Although no such statement has been made about remacemide's potential for treating stroke, Huntington's, or Parkinson's, remacemide is no longer being developed for these conditions. Remacemide is also known as remacemide hydrochloride, (±)-2-amino-''N''-(1-methyl-1,2-diphenylethyl)-acetamide hydrochloride, or FPL 12924AA.

Adverse effects

*dizziness *nausea

Lack of adverse effects

Unlike many other treatments for epilepsy, remacemide does not appear to impair cognitive performance or driving performance in humans, although the evidence for effects on cognitive performance in animals has been mixed. Remacemide is not a sedative.

Toxicity

The median toxic dose of remacemide for neural impairment tests in mice is 5.6 mg/kg. Its estimated

median lethal dose In toxicology, the median lethal dose, LD50 (abbreviation for "lethal dose, 50%"), LC50 (lethal concentration, 50%) or LCt50 is a toxic unit that measures the lethal dose of a toxin, radiation, or pathogen. The value of LD50 for a substance is ...

is about 927.3 mg/kg in mice. It has a favorable therapeutic index of 28.1 in mice.

Drug interactions

Levodopa

Remacemide delays the absorption of

levodopa -DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DOPA ...

(300 mg of remacemide one hour before levodopa treatment delays mean time to peak levodopa plasma concentration by 20%) but not its total absorption (area-under-the-curve for levodopa plasma concentration was unchanged).

Sodium valproate

Remacemide does not interact with sodium valproate, a treatment for epilepsy.

Carbamazepine

Ramacemide does interact with

carbamazepine Carbamazepine (CBZ), sold under the trade name Tegretol among others, is an anticonvulsant medication used primarily in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other medi ...

. Remacemide inhibits the metabolism of carbamazepine, while carbamazepine induces the metabolism of remacemide and FPL 12495.

Alcohol

Remacemide salts

Remacemide is most commonly synthesized as the

salt Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the larger class of salts; salt in the form of a natural crystalline mineral is known as rock salt or halite. Salt is present in vast quanti ...

remacemide hydrochloride. However, there has been some investigation into other remacemide salts and their

crystal A crystal or crystalline solid is a solid material whose constituents (such as atoms, molecules, or ions) are arranged in a highly ordered microscopic structure, forming a crystal lattice that extends in all directions. In addition, macr ...

s, as different remacemide salts might taste more pleasant or have a

solubility In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution. The extent of the solub ...

more suitable for a pediatric suspension formulation.

Mechanism of action

Remacemide binds weakly and noncompetitively to the ionic channel site of the NMDA receptor complex. Remacemide binds both allosterically and in the channel. However, because remacemide binds so weakly to NMDAR, much of remacemide's ''in vivo'' effect against

excitotoxicity In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate ...

is thought to be caused by its metabolic transformation to the more potent desglycine derivative FPL 12495. That is, remacemide may actually act as a prodrug to deliver the active

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, ...

FPL 12495 to the central nervous system.

Epilepsy

In a well validated and described genetic model of absence epilepsy, rats of the WAG/Rij strain, remacemide and its metabolite FPL 12495 were found to have a common for glutamate antagonist usual effect on the number of spike/wave discharges EEG, the drugs decrease spike/wave discharges dose dependently. However, in contrast to most other glutamate antagonists, FPL 12495 increased the duration of the spike-wave discharges.

Pharmacokinetics

Blood–brain barrier

The brain uptake index (BUI), a measure of a drug's ability to pass the blood–brain barrier that involves the injection of radiolabeled test and reference substances into the

common carotid artery In anatomy, the left and right common carotid arteries (carotids) (Entry "carotid"
in
(-)

stereoisomer In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms i ...

of remacemide is of equal potency to the racemic mixture in preventing maximal electroshock seizures when administered orally to rats, while the (+)stereoisomer is less potent.

Metabolites

FPL 12495

Much of remacemide's effect ''in vivo'' is thought to be caused by the desglycine derivative FPL 12495 (±). FPL 12495 (±) binds specifically and non-competitively to NMDAR. Its effect on maximal electroconvulsive shock is more potent than remacemide. The S isomer (FPL 12859) is even more potent than the

racemic mixture In chemistry, a racemic mixture, or racemate (), is one that has equal amounts 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 racemates. ...

, while the R isomer is less potent than the racemate. FPL 12495 is sometimes referred to as ARL 12495AA.

Other metabolites

FPL 15053

FPL 15053 is the ''N''- of remacemide, and exhibits modest binding to NMDAR and modest effects on convulsions and mortality in test mice and rats.

FPL 14331 and FPL 14465

FPL 14331 and FPL 14465 are the ''p''- of remacemide, and they exhibit some efficacy against maximal electroconvulsive shock after i.p. and i.v. dosing.

FPL 15455

FPL 15455 is an oxoacetate metabolite of remacemide, but has no demonstrated biological activity.

FPL 14991 and FPL 14981

FPL 14991 and FPL 14981 are both ''β''- of remacemide, and they display modest efficacy against maximal electroconvulsive shock in mice. However FPL 14981 and not FPL 14991 prevents NMDLA-induced convulsions and mortality in mice.

FPL 13592 and FPL 15112

The hydroxy-methyl derivative of remacemide (FPL 13592) and its (FPL 15112) prevents electric shock-induced convulsions only after i.v. administration; only the desglycine derivative binds to NMDAR.

FPL 14467

FPL 14467 (''p''-) is inactive ''in vivo'' and weak in binding NMDAR.

Pharmacodynamics

The values for 50% displacement of were 68 μM for remacemide and 0.48 μM for FPL 12495AA.

History

Current status

Remacemide is an experimental drug most recently being developed by the British multinational

pharmaceutical company The pharmaceutical industry discovers, develops, produces, and markets drugs or pharmaceutical drugs for use as medications to be administered to patients (or self-administered), with the aim to cure them, vaccinate them, or alleviate sympt ...

AstraZeneca AstraZeneca plc () is a British-Swedish multinational pharmaceutical and biotechnology company with its headquarters at the Cambridge Biomedical Campus in Cambridge, England. It has a portfolio of products for major diseases in areas includ ...

. However, there has been little news of its progress since 2000. A few sources indicate that its development has been discontinued.

Changing hands

Remacemide was one of the last drugs under development by the now-defunct English pharmaceutical company Fisons. In 1995, it was acquired along with most of Fisons'

research and development Research and development (R&D or R+D), known in Europe as research and technological development (RTD), is the set of innovative activities undertaken by corporations or governments in developing new services or products, and improving existi ...

operations by the Swedish pharmaceutical company

Astra Astra may refer to: People * Astra (name) Places * Astra, Chubut, a village in Argentina * Astra (Isauria), a town of ancient Isauria, now in Turkey * Astra, one suggested name for a hypothetical fifth planet that became the asteroid belt Ent ...

, which in 1999 merged with the British company

Zeneca Zeneca (officially Zeneca Group PLC) was a British multinational pharmaceutical company headquartered in London, United Kingdom. It was formed in June 1993 by the demerger of the pharmaceuticals and agrochemicals businesses of Imperial Chemic ...

to form

. In 2000, AstraZeneca considered possibly licensing out remacemide to some other pharmaceutical company, but there has been little news about remacemide since then. Remacemide's development may have been discontinued in July 2001.

Discovery and development under Fisons

In 1990, researchers at Fisons found that remacemide acted as an

anticonvulsant Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of ...

in mice and rats . Because of remacemide's potential as a neuroprotective agent through preventing

glutamate toxicity In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate re ...

, it was soon also under investigation as a treatment for

and

Astra

By 1995, when

acquired remacemide, it was already in Phase IIb clinical development as an anti-epileptic drug and

Phase I Phase 1, Phase I or Phase One may refer to: Media * Marvel Cinematic Universe: Phase One, six American superhero films from 2008–2012 * ''Phase One'' (Art Ensemble of Chicago album), 1971 * ''Phase One'' (Saga album), 1998 * ''Phase One'', r ...

clinical development as a treatment for Huntington's .

AstraZeneca

By 1998, when Astra announced its merger with

, remacemide had progressed to Phase III trials for epilepsy and

Phase II Phase II, Phase 2 or Phase Two may refer to: Media * Marvel Cinematic Universe: Phase Two, six American superhero films from 2013–2015 * ''Star Trek: Phase II'', an unrealized television series based on the characters of Gene Roddenberry's ''S ...

trials for Parkinson's disease, and Astra was also investigating its potential for treating

neuropathic pain Neuropathic pain is pain caused by damage or disease affecting the somatosensory system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli ( allodynia). It may have continuo ...

In 1999, after the merger, AstraZeneca reported that they were investigating remacemide for its neuroprotective effects, and that they planned regulatory submissions for

in 2001 and for

and

in 2003. Remacemide, under the trade name Ecovia, was designated an

orphan drug An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment o ...

for the treatment of

by the FDA in March 2000. Remacemide was last mentioned in

's reports on its R&D pipeline in 2000, when it was in Phase III

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 for remacemide in the treatment of

and

for treatment of

. At that time, the submission of the New Drug Application (NDA) to the FDA and the Marketing Authorization Application to the CHMP was projected for Huntington's in 2001 and for Parkinson's after 2003, but there has been no news of such submission. In this report, it was also noted that remacemide was "under strategic review and a potential candidate for licensing activity" (see thi
external article
about drug

licensing A license (or licence) is an official permission or permit to do, use, or own something (as well as the document of that permission or permit). A license is granted by a party (licensor) to another party (licensee) as an element of an agreeme ...

Current news

There are no clinical trials of remacemide in progress, according to the Huntington Study Group, and the Parkinson Study Group.

Availability

Remacemide is an experimental drug not available to the public and not currently undergoing

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

References

External links

Huntington's Outreach Project for Education, at Stanford
{{Ionotropic glutamate receptor modulators Acetamides Amino acid derivatives Dissociative drugs NMDA receptor antagonists Diarylethylamines Sodium channel blockers