N-acetil leucina

Otros Nombres

(2R)-2-(acetylamino)-4-methylpentanoic acid(2R)-2-acetamido-4-methyl-pentanoic acid(2R)-2-acetamido-4-methylpentanoic acid(2S)-2-(acetylamino)-4-methylpentanoic acid(2S)-2-acetamido-4-methyl-pentanoic acid(2S)-2-acetamido-4-methyl-valeric acid(2S)-2-acetamido-4-methylpentanoic acid(E)-N-(1-Hydroxyethylidene)-L-leucine(R)-N-acetyl-leucine(S)-N-acetyl-leucine(S)-N-Acetylleucine2-(acetylamino)-4-methylpentanoic acid2-acetamido-4-methylpentanoic acid2-Acetylamino-4-methyl-pentanoic acidAc-D-Leu-OHAc-DL-Leu-OHAc-L-Leu-OHAc-Leu-OHAC-LEUCINEAcetileucinaAcetyl-D-leucineAcetyl-DL-leucineAcetyl-L-leucineAcetylleucineAcetylleucinumD-Leucine, N-acetyl-DL-Leucine, N-acetyl-L-Leucine, N-(1-hydroxyethylidene)-, (E)-L-Leucine, N-acetyl-Leucine, N-acetyl-Leucine, N-acetyl-, L-LevacetylleucineN-Ac-L-Leu-OHN-Acetyl-D-leucinN-Acétyl-D-leucineN-Acetyl-D-leucineN-Acetyl-DL-leucineN-Acetyl-L-leucinN-Acetyl-L-leucineN-Acétyl-L-leucineN-acetyl-LeuN-AcetylleucinN-AcétylleucineN-AcetylleucineN-Alpha-acetyl-DL-leucineN-Alpha-acetyl-L-leucineNALL

Sinopsis

N-Acetyl Leucine (Levacetylleucine)

1. Identity: Chemical Name, Structure, and Common Forms

N-acetyl leucine exists in several chemically distinct forms that are important to distinguish from one another. Acetyl-L-leucine (N-acetyl-L-leucine) is an N-acylated derivative of the branched-chain amino acid L-leucine, with the formal IUPAC name (2S)-2-acetamido-4-methylpentanoic acid and molecular formula C₈H₁₅NO₃. Its molecular weight is 173.21 g/mol. The molecule features an acetamide moiety on the α-amino group, a terminal carboxylic acid, and a hydrophobic isobutyl side chain, preserving the chiral (S) configuration at the α-carbon. This combination of a polar amide and carboxylate functionality with a nonpolar side chain affords a balanced amphipathic profile and moderate polarity, reflected in its topological polar surface area (TPSA) of 66.4.

The compound is also known by the synonyms levacetylleucine, NALL, IB1001, and NSC 206316. Its CAS registry number is 1188-21-2. A racemic mixture of the N-acetyl derivatives of L-leucine and D-leucine, known as N-acetyl-DL-leucine, also exists, with the same molecular formula C₈H₁₅NO₃ and a molecular weight of 173.21 g/mol. A study of N-acetyl-L-leucine and N-acetyl-D-leucine in a rat model of unilateral labyrinthectomy revealed that N-acetyl-L-leucine, but not N-acetyl-D-leucine, is the pharmacologically active substance that improves central vestibular compensation.

This compound is a white to off-white crystalline powder, soluble in water and organic solvents, which makes it versatile for various applications. Common pharmaceutical preparations include oral tablets (500 mg per tablet, used in the Tanganil formulation), and oral granules for suspension in a sachet. The FDA-approved Aqneursa formulation is an oral suspension containing 1 gram of levacetylleucine per unit-dose packet.

2. Traditional and Historical Use

N-acetyl leucine in its racemic form (N-acetyl-DL-leucine) has a history of medical use in France that predates most modern clinical evidence. The racemic mixture, N-acetyl-DL-leucine (DL-NAL), has been used as a medication for the treatment of acute vertigo and vertiginous symptoms in France since 1957. First introduced as an over-the-counter treatment in 1957 under the brand name Tanganil by Laboratoires Pierre Fabre, it has been widely used for acute vertigo episodes.

As N-acetyl-leucine was developed before realization of the importance of drug chirality, it was and continues to be marketed as a racemate (Tanganil®, Laboratoires Pierre Fabre). Acetyl-leucine in racemate form (acetyl-DL-leucine) and salts of the same are effective in the treatment of vertigo of various origins, notably Ménière's vertigo and vertigo of inflammatory (vestibular neuritis) or toxic origin. Acetyl-leucine is marketed by Pierre Fabre Médicament in racemate form as an anti-vertigo medicament under the name Tanganil®.

N-acetyl-DL-leucine has been used in France for over 50 years for the treatment of acute vertigo and has been demonstrated to improve postural compensation in patients after vestibular neurotomy and labyrinthectomy. Acetyl-DL-leucine has been used in France to treat acute vertigo since 1957 and has an excellent safety profile, but its long-term safety in chronic use has not been determined.

This use arose empirically and through clinical observation rather than from a deep understanding of biochemical mechanisms, which — as discussed below — remained poorly characterized for decades. The preparation used historically was an oral tablet formulation of the racemic mixture. There is no documented pre-modern traditional use of this compound in herbal or indigenous medicine traditions, as it is a synthetic derivative rather than a naturally occurring plant constituent.

3. Key Constituents, Structural Features, and Mechanisms of Action

3.1 Prodrug Behavior and Blood-Brain Barrier Penetration

This acetylated derivative of L-leucine functions as a prodrug, with the acetyl group rendering it a substrate for the monocarboxylate transporter (MCT) family of transporters to allow appreciable penetration of the blood-brain barrier and its efficient uptake into cells. The parent molecule, L-leucine, is a zwitterion at physiological pH, and is transported into cells by the easily saturable transporter L-type amino-acid transporter (LAT1). Addition of the acetyl moiety to L-leucine confers a net negative charge to the molecule at physiological pH, allowing levacetylleucine to be taken up into cells by high-capacity monocarboxylate transporters (MCTs), which are ubiquitously expressed, thereby delivering the drug to all tissues, including the central nervous system, by readily crossing the blood-brain barrier.

3.2 Intracellular Metabolism and L-Leucine Liberation

Inside cells, levacetylleucine undergoes metabolism catalysed by acylases, and the resultant high quantities of L-leucine enter metabolic pathways which enhance mitochondrial bioenergetics and, as previously demonstrated, indirectly ameliorate lysosomal function. Inside cells, levacetylleucine enters enzyme-controlled pathways that correct metabolic dysfunction and enhance energy (ATP) production, which also leads to an improvement in lysosomal function. This has multiple consequential effects: mitochondrial and lysosomal function are intrinsically linked and interact at membrane contact sites, and the normalization of energy metabolism improves lysosomal function, leading to a reduction in the storage of unesterified cholesterol and sphingolipids.

3.3 TFEB Modulation and Lysosomal Biogenesis

A novel aspect of levacetylleucine's mechanism of action involves a direct effect on lysosomal function through its rapid modulation of the translocation of the transcription factor TFEB, a master regulator of lysosomal biogenic and autophagic genes, from cytoplasm to nucleus. In wild-type cells, NALL stimulates TFEB translocation to the nucleus, which would serve to enhance lysosomal biogenesis, function, and autophagic flux, and may therefore be potentially beneficial in neurodegenerative diseases. This TFEB-activating effect appears to be stereospecific: levacetylleucine (the L-enantiomer) both activates TFEB in healthy cells and, importantly, normalizes TFEB activity that is already aberrantly elevated in NPC disease cells.

3.4 Membrane Contact Sites and Organelle Communication

Levacetylleucine corrects aberrant membrane contact sites in NPC patient cells where there is a deficit of endoplasmic reticulum (ER)-lysosomal contacts for efficient lipid transfer and a concomitant inappropriate gain of mitochondrial-ER contacts with resultant mitochondrial lipid accumulation.

3.5 Vestibular and Neuronal Membrane Stabilization

Electrophysiological studies in a guinea pig model of acute unilateral vestibulopathy demonstrated that DL-NAL can restore the membrane potential of abnormally polarized neurons of the medial vestibular nucleus. Despite numerous hypotheses, including stabilisation of membrane potential, its pharmacological and electrophysiological modes of action remain unclear. Research using PET imaging of regional cerebral glucose metabolism in a rat model of unilateral labyrinthectomy demonstrated that the N-acetyl-L-leucine group showed on day 3 a significant decrease of rCGM in the ipsilesional, on day 7 in the ipsilesional greater than contralesional posterolateral thalamus and subthalamic region. On day 15 an increase of rCGM was found in the centromedian thalamus and subthalamic region. On day 3, rCGM was significantly increased in the ipsilesional, on day 7 in the bilateral paraflocculus/flocculus (vestibulocerebellum) in the N-acetyl-L-leucine group.

3.6 Neuroprotection and Neuroinflammation

In various animal models, levacetylleucine treatment shows a slowing of neurodegeneration and also leads to a dampening of neuroinflammation, consistent with the drug's neuroprotective effects; the latter was also shown in patients with NPC. Due to its multi-modal mechanism of action, levacetylleucine has potential and is being developed for a range of rare and common neurodegenerative and neurodevelopmental disorders.

3.7 Chirality and the D-Enantiomer

Subsequent studies in models of vertigo on the individual enantiomers have revealed that the therapeutic effects of N-acetyl-DL-leucine are due to the L-enantiomer. Investigation of the pharmacokinetics of the enantiomers of N-acetyl-leucine after administration of the racemate (N-acetyl-DL-leucine) or purified, pharmacologically active L-enantiomer (N-acetyl-L-leucine) suggested that during chronic administration of the racemate, the D-enantiomer would accumulate, which could have negative effects. When administered as the racemate, both the maximum plasma concentration (C_max) and the area under the plasma drug concentration over time curve (AUC) were much greater for the D-enantiomer relative to the L-enantiomer. These pharmacokinetic findings motivated the development of the pure L-enantiomer as a pharmaceutical agent distinct from the historical racemic product.

4. Areas of Scientific Investigation and Evidence by Use

4.1 Vestibular Disorders and Acute Vertigo

Traditional/historical use: For 40 years, the amino acid acetyl-DL-leucine (Tanganil) has been used in clinical practice to reduce imbalance and autonomic manifestations associated with acute vertigo crises. Clinical results of Tanganil® reported by various authors demonstrate an improvement in vertigo symptomology in more than 95% of cases, including the disappearance of vertigo attacks.

Animal evidence: In animal models, acetyl-DL-leucine accelerates vestibular compensation following unilateral labyrinthectomy, and has only minor effects on normal vestibular function. In rat models, levacetylleucine (60 mg/kg, i.v., administered on days 1, 2, and 3 for 15 days) decreases the postural imbalance scores and accelerates the course of postural compensation induced by unilateral labyrinthectomy.

Human/clinical evidence: A 2019 systematic review of randomised controlled trials (Eur J Clin Pharmacol, PMID 30613860) assessed the efficacy of acetylleucine in vertigo and dizziness. Acetyl-DL-leucine improves cerebellar ataxia (three observational studies); it also accelerates central compensation in an animal model of acute unilateral lesion, but RCTs were negative. The exact role of N-acetyl-L-leucine in vertigo is unknown.

Evidence strength for vertigo: Long-standing empirical use exists, supported by animal mechanistic data, but formal randomised controlled trials for acute vertigo have been negative. The historical clinical use data predates modern RCT standards. The evidence base for vestibular indications is therefore characterized as historically established but formally unconfirmed by high-quality RCTs.

4.2 Niemann-Pick Disease Type C (NPC)

NPC is a rare, fatal autosomal recessive lysosomal storage disorder. Niemann-Pick disease type C (NPC) is a rare (1:120,000 live births), prematurely fatal, autosomal recessive, neurovisceral lysosomal disease that predominantly affects children. NPC results from mutations in the NPC1 or NPC2 genes that impair intracellular cholesterol trafficking, leading to debilitating neurological and systemic symptoms.

Phase IIb Evidence: The modified amino acid N-acetyl-leucine has been associated with positive symptomatic and neuroprotective, disease-modifying effects in various studies, including animal models of NPC, observational clinical case studies, and a multinational, rater-blinded phase IIb clinical trial. In a case series, short-term treatment with N-acetyl-DL-leucine was found to improve ataxia, cognition, and quality of life in 12 patients with NPC.

Phase III Pivotal Trial (IB1001-301): The FDA approval was based on data from the phase 3 double-blind, placebo-controlled, crossover trial IB1001-301 (NCT05163288), which investigated levacetylleucine among 60 patients aged between 5 years and 67 years of age with NPC over 12 weeks. In the trial, levacetylleucine met its primary efficacy endpoint, measured by the functional version of the Scale for the Assessment and Rating of Ataxia (fSARA), and all secondary endpoints. The safety profile of levacetylleucine was favorable, with no serious adverse events reported during the clinical trial. The pivotal trial result was published in the New England Journal of Medicine (2024;390:421–431).

Regulatory status: Aqneursa was approved by the U.S. Food and Drug Administration (FDA) on 24 September 2024 for the treatment of neurological manifestations of Niemann-Pick disease type C (NPC) in adults and pediatric patients weighing ≥15 kg. The European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) subsequently issued a positive opinion recommending approval of Aqneursa® (levacetylleucine) for the treatment of Niemann-Pick disease type C (NPC).

Evidence strength for NPC: Strong — supported by a phase 3 double-blind, placebo-controlled, crossover RCT meeting primary and all secondary endpoints, with FDA and pending EMA approval. This represents the highest level of regulatory-grade evidence for any indication involving this compound.

4.3 GM2 Gangliosidoses (Tay-Sachs and Sandhoff Diseases)

GM2 gangliosidoses are rare autosomal recessive neurodegenerative lysosomal storage diseases with no previously available symptomatic or disease-modifying treatments. A clinical trial investigated N-acetyl-L-leucine (NALL), an orally administered modified amino acid, in pediatric (≥6 years) and adult patients with GM2 gangliosidoses.

Phase IIb Evidence (IB1001-202): In this phase IIb, multinational, open-label, rater-blinded study, male and female patients aged ≥6 years with a genetically confirmed diagnosis of GM2 gangliosidoses received orally administered NALL for a 6-week treatment period (4 g/d in patients ≥13 years, weight-tiered doses for patients 6–12 years), followed by a 6-week posttreatment washout period. Thirty patients between the age of 6 and 55 years were enrolled. Twenty-nine had an on-treatment assessment and were included in the primary modified intention-to-treat analysis. The study met its Clinical Impression of Change in Severity (CI-CS) primary endpoint (mean difference 0.71, SD = 2.09, 90% CI 0.00, 1.50, p = 0.039), as well as secondary measures of ataxia and global impression. NALL was safe and well tolerated, with no serious adverse reactions. This study provides Class IV evidence that NALL improves outcomes for patients with GM2 gangliosidoses.

Evidence strength for GM2 gangliosidoses: Moderate — a phase IIb open-label study meeting its primary endpoint. Class IV evidence (single open-label study with blinded outcome assessment); a pivotal phase III trial would be needed for regulatory approval.

4.4 Cerebellar Ataxia (Hereditary and Non-Hereditary)

Prior to the pivotal NPC trial, the largest human investigation of N-acetyl leucine was conducted in the heterogeneous population of cerebellar ataxia.

Observational studies: A case series applying acetyl-DL-leucine (500 mg, 4-3-3 tablets per day) in different types of cerebellar ataxia showed improved walking stability in 14 out of 18 patients measured on a GAITRite system. Two additional case series also demonstrated improvements in ataxia scores, as noted in the ALCAT trial protocol literature.

ALCAT Randomised Controlled Trial: The Acetyl-DL-leucine on Cerebellar Ataxia (ALCAT) trial was an investigator-initiated, multicenter, double-blind, randomized, placebo-controlled, clinical crossover trial conducted at 7 university hospitals in Germany and Austria between January 25, 2016, and February 17, 2017. Patients were aged at least 18 years and diagnosed with cerebellar ataxia of hereditary (suspected or genetically confirmed) or nonhereditary or unknown type, presenting with a total SARA score of at least 3 points. Patients were randomly assigned (1:1) to receive acetyl-DL-leucine orally (5 g per day after 2 weeks up-titration) followed by matched placebo, each for 6 weeks, separated by a 4-week washout, or vice versa.

Among 108 patients who were randomly assigned to sequence groups, 55 (50.9%) were female; the mean (SD) age was 54.8 (14.4) years; and the mean (SD) SARA total score was 13.33 (5.57) points. The full analysis set included 105 patients (80 patients with hereditary, 25 with nonhereditary or unknown cerebellar ataxia). There was no evidence of a difference in the mean absolute change from baseline to week 6 in SARA total scores between both treatments (mean treatment difference: 0.23 points [95% CI, −0.40 to 0.85 points]). In this large multicenter, double-blind, randomized, placebo-controlled clinical crossover trial, acetyl-DL-leucine in the investigated dosage and treatment duration was not superior to placebo for the symptomatic treatment of certain types of ataxia. The drug was well tolerated.

ALCAT failed to demonstrate effectiveness of acetyl-DL-leucine in a range of ataxias. This trial raises several issues: pre-specified subgroup analyses were acknowledged to be under-powered, and the range of ataxias may have masked any effect.

Evidence strength for general cerebellar ataxia: A well-conducted RCT (ALCAT) failed to demonstrate superiority over placebo on its primary endpoint. Earlier promising signals from observational case series were not confirmed. However, important caveats exist: the trial tested the racemic mixture (not the pure L-enantiomer), and pooling of heterogeneous ataxia subtypes may have obscured disease-specific effects. Ongoing investigation with the pure L-enantiomer in specific genetic subtypes (such as ataxia telangiectasia) is underway.

4.5 Ataxia Telangiectasia (A-T)

Ataxia telangiectasia is a rare genetic disorder of DNA repair that includes prominent symptoms of progressive ataxia. In January 2020, IntraBio began a Phase 2 trial for the symptomatic treatment of ataxia telangiectasia. This rare genetic disorder of DNA repair includes prominent symptoms of ataxia. The trial assessed six weeks of up to 4 grams daily NALL in 39 children and adults, with a primary endpoint of clinician impression of change in severity.

A subsequent pivotal Phase III trial (IB1001-303, NCT06673056) was registered in late 2024 and began enrolling in March 2025, with an estimated primary completion date of December 2027. IntraBio's Phase III pivotal trial investigating N-Acetyl-L-Leucine (levacetylleucine) for ataxia telangiectasia completed recruitment in under two months, ultimately over-enrolling the trial by over 167%.

Evidence strength for A-T: Currently preliminary; Phase III trial active but not yet reporting results.

4.6 Parkinson's Disease (Preclinical)

Research into N-acetyl-L-leucine's potential in Parkinson's disease has so far been conducted in animal models. N-acetyl-L-leucine (100 mg/kg per day) increases the latency to fall from the rotarod, increases substantia nigra levels of tyrosine hydroxylase, and decreases serum levels of IL-6 in a mouse model of MPTP-induced Parkinson's disease. A 2026 publication in the Journal of Clinical Investigation reported that NALL lowers α-synuclein levels and improves synaptic function in Parkinson's disease models. Clinical and preclinical studies have suggested that acetyl-leucine derivatives may provide symptomatic or functional benefits in another lysosomal storage disorder, GM2 gangliosidoses, as well as in some cases of cerebellar ataxia. Limited exploratory evidence also suggests possible effects in conditions such as restless legs syndrome, and more recently REM sleep behavior disorder that is considered a prodrome of PD, though these findings require cautious interpretation and further validation.

Evidence strength for Parkinson's disease: Preclinical only (animal models). No human clinical evidence has been reported as of the time of writing.

4.7 Traumatic Brain Injury (Preclinical)

N-acetyl-L-leucine decreases lesion size and improves sensorimotor deficits in the beam walk test in a mouse model of controlled cortical impact-induced traumatic brain injury (TBI) when administered at a dose of 100 mg/kg per day. Levacetylleucine (100 mg/kg, oral gavage, administered daily for 28 days) attenuates cortical cell death after traumatic brain injury in N-acetyl-L-leucine-treated TBI mouse cortices.

Evidence strength for TBI: Preclinical only. No human trials are currently reported.

5. Body Systems and Health Areas

Based on the published research, N-acetyl leucine and its derivatives are primarily associated with the following body systems:

Central nervous system: The primary focus of all modern research; relevant to vestibular function, cerebellar motor control, lysosomal storage diseases affecting the brain, neurodegeneration, and neuroinflammation.
Lysosomal-mitochondrial axis: Aqneursa (levacetylleucine) regulates energy metabolism, enhances mitochondrial and lysosomal function, and provides neuroprotective effects.
Vestibular system: Long-standing use for modulation of vestibular compensation and management of acute imbalance and vertigo.
Autophagic-lysosomal pathway: Via TFEB modulation, with potential implications for diseases involving impaired autophagy and lysosomal storage.
Inflammatory pathways: Neuroinflammation dampening has been documented in animal models of NPC and TBI.

6. Dosage Forms and Dosages Reported in Studies

The following dosages and dosage forms are drawn directly from published study protocols and prescribing information.

6.1 FDA-Approved Dosing (Aqneursa / Levacetylleucine for NPC)

The recommended dosage of Aqneursa is based on the patient's actual body weight (kg) and is to be administered orally up to three times daily. Patients aged ≥13 years or aged 4–12 years weighing ≥35 kg receive 4 g/day of orally administered NALL (granules in a sachet for suspension) three times per day (2 g in the morning, 1 g in the afternoon, and 1 g in the evening). Patients aged 4–12 years weighing less than 35 kg receive weight-tiered doses two or three times per day based on an approximate total dose of 0.1 g/kg/day. Aqneursa can be taken with or without food.

6.2 Dosing in GM2 Gangliosidosis Trial (IB1001-202)

In the phase IIb study, male and female patients aged ≥6 years with a genetically confirmed diagnosis of GM2 gangliosidoses received orally administered NALL for a 6-week treatment period (4 g/d in patients ≥13 years, weight-tiered doses for patients 6–12 years), followed by a 6-week posttreatment washout period.

6.3 Dosing in the ALCAT Cerebellar Ataxia Trial

Participants received study medication at the beginning of each treatment period and were instructed to apply a 2-week uptitration scheme (initial dosage of 1.5 g acetyl-DL-leucine per day taking 1 tablet of 500 mg each 3 times per day in the first week, 3 g per day taking 2 tablets of 500 mg each 3 times per day in the second week). Full dosage (5 g per day taking 3 tablets in the morning, 3 tablets at noon, and 4 tablets in the evening of 500 mg each) was maintained for 4 weeks.

6.4 Ataxia Telangiectasia Phase 2 Dosing

The A-T phase 2 trial assessed six weeks of up to 4 grams daily NALL in 39 children and adults.

6.5 Tanganil (Racemic, Historical/OTC)

The approved dosage of the historical Tanganil formulation used in France involved the racemic mixture in 500 mg tablets. The dose schedule used in clinical studies and observational records has included 5 g per day in divided doses, consistent with French prescribing practice for the anti-vertigo indication.

7. Safety Considerations and Notable Interactions

7.1 Overall Safety Profile

NALL was observed to be well tolerated in all observational and clinical studies completed to date, with no reports of serious adverse reactions. The racemic mixture has a well-established safety profile after decades of use in France. In the pivotal NPC phase 3 trial, the safety profile of levacetylleucine was favorable, with no serious adverse events reported.

7.2 Common Adverse Reactions (From Aqneursa Prescribing Information)

The most common side effects are abdominal pain, difficulty swallowing (dysphagia), upper respiratory tract infections, and vomiting. The safety of Aqneursa was evaluated in Trial 1, which included a total of 60 patients with NPC in a placebo-controlled, randomized, crossover trial. The mean (SD) treatment duration of Aqneursa was 86.2 (4.7) days.

7.3 Drug Interactions: N-Acetyl-D-Leucine / Racemate

Concomitant use of Aqneursa with N-acetyl-DL-leucine and N-acetyl-D-leucine should be avoided. The D-enantiomer, N-acetyl-D-leucine, competes with levacetylleucine for monocarboxylate transporter uptake, which may reduce levacetylleucine efficacy. This is a clinically significant and mechanistically specific interaction: patients taking Aqneursa (levacetylleucine) should not simultaneously take the racemic Tanganil product, as the D-enantiomer component would competitively reduce cellular uptake of the active L-enantiomer.

7.4 Drug Interactions: P-Glycoprotein Substrates

Levacetylleucine inhibits P-glycoprotein (P-gp). However, the clinical significance of this finding has not been fully characterized. Clinicians should monitor more frequently for P-glycoprotein substrate-related adverse reactions when Aqneursa is used concomitantly. P-glycoprotein (P-gp) is a transporter that mediates the efflux of a large number of commonly used drugs; inhibition of P-gp by levacetylleucine has the theoretical potential to raise plasma concentrations of co-administered P-gp substrates, though the clinical magnitude of this effect remains uncharacterised.

7.5 Pregnancy and Embryo-Fetal Toxicity

Based on findings from animal reproduction studies, Aqneursa may cause embryo-fetal harm when administered during pregnancy. In animal reproduction studies, an increase in embryo-fetal death (post-implantation loss/resorption), decrease in fetal body weight, and increase in external and skeletal malformations were observed in rats and rabbits when levacetylleucine was administered during the period of organogenesis. Females of reproductive potential should use effective contraception during treatment and for 7 days after the last dose if Aqneursa is discontinued.

7.6 D-Enantiomer Accumulation Risk with Chronic Racemic Use

Investigation of the pharmacokinetics of the enantiomers of N-acetyl-leucine revealed that during chronic administration of the racemate, the D-enantiomer would accumulate, which could have negative effects. Pharmacokinetic studies demonstrate that the D-enantiomer is not metabolized and could accumulate relative to the L-enantiomer during chronic administration of the racemate, having the potential for long-term negative effects. This finding was a key factor in the regulatory and scientific decision to develop the pure L-enantiomer as a drug rather than the racemic mixture for chronic disease applications.

7.7 Long-Term Safety

Acetyl-DL-leucine has been used in France to treat acute vertigo since 1957 and has an excellent safety profile, but its long-term safety in chronic use has not been determined. Long-term extension data for levacetylleucine (L-enantiomer) in NPC patients beyond the pivotal 12-week trial period are being accumulated but remain limited at the time of this article's preparation.

References

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Retinopatía DiabéticaCientífico
N-acetyl leucine (N-acetyl-DL-leucine, Tanganil) has been used in clinical practice for over 50 years as a symptomatic treatment for acute vertigo, particularly in France. It accelerates vestibular compensation following unilateral labyrinthine lesions by normalizing abnormal vestibular neuronal membrane potentials and activating the vestibulocerebellum. A clinical study in post-labyrinthectomy patients and multiple animal models confirm its antivertiginous efficacy.

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