N-Acetylcysteine for Mitochondrial Disease
Recruiting in Palo Alto (17 mi)
Overseen ByDarryl DeVivo, MD
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Michio Hirano, MD
No Placebo Group
Approved in 4 jurisdictions
Trial Summary
What is the purpose of this trial?N-Acetylcysteine (NAC), an anti-oxidant, will be studied to investigate the effects on brain glutathione levels, cognitive skills, motor skills, and quality of life.
A group of 18 participants will take either 1800, 3600 or 5400 mg per day of N-acetylcysteine (NAC) for 3 months in this dose escalation study. The investigators want to determine first if the 3600 mg dose per day is safe and might provide some efficacy. If the 3600 mg dose is safe, then additional participants will be treated with 5400 mg per day of NAC, for up to a total of 18 participants. If the 3600 mg per day dose is unsafe, then participants will be treated with the 1800 mg per day dose. Data from this pilot study will be used to determine the most safe and effective dose of NAC for a future clinical trial.
What safety data exists for N-Acetylcysteine (NAC)?N-Acetylcysteine (NAC) has been used since the 1960s and is generally well-tolerated. It is used as a prescription and over-the-counter product for various conditions. The PANTHEON study, one of the largest on NAC, found it to be well-tolerated in COPD patients. However, NAC can cause adverse reactions that limit its use, as noted in studies on its use as an ergogenic aid. Its safety in specific populations, like those undergoing haemodialysis, has also been investigated, indicating a need for further research on its pharmacokinetics and safety in rare diseases.247811
Do I have to stop taking my current medications for this trial?The trial protocol does not specify if you need to stop taking your current medications. Please consult with the trial coordinators for more information.
Is the drug N-Acetylcysteine a promising treatment for mitochondrial disease?N-Acetylcysteine (NAC) is a promising treatment for mitochondrial disease because it acts as a powerful antioxidant, which can help protect cells from damage. It has been used successfully in various conditions, showing potential benefits in treating diseases related to mitochondrial dysfunction.1451011
What data supports the idea that N-Acetylcysteine for Mitochondrial Disease is an effective treatment?The available research does not provide specific data supporting the effectiveness of N-Acetylcysteine (NAC) for Mitochondrial Disease. While NAC is known for its antioxidant properties and has been used in various conditions, the research mainly discusses its use in other diseases like multiple sclerosis and cancer, with mixed results. For mitochondrial diseases, there is no comprehensive review or specific evidence presented in the available research to confirm its effectiveness.3691011
Eligibility Criteria
This trial is for adults aged 18-80 with low brain glutathione levels and the m.3243A>G mitochondrial mutation. Participants must be able to follow the study protocol and not be pregnant, lactating, allergic to NAC or sulfur drugs, or medically unstable.Inclusion Criteria
I am between 18 and 80 years old.
I carry or might carry the m.3243A>G mitochondrial mutation.
Exclusion Criteria
I am allergic to NAC or sulfur drugs.
Participant Groups
The study tests different doses of N-Acetylcysteine (NAC) on brain health and quality of life in people with a specific mitochondrial disease. It starts at 3600 mg/day to check safety and effectiveness before possibly increasing to 5400 mg/day or decreasing to 1800 mg/day based on results.
1Treatment groups
Experimental Treatment
Group I: Active drug (NAC)Experimental Treatment1 Intervention
Participants will receive NAC for 3 months.
N-Acetylcysteine is already approved in United States, European Union, Canada, Australia for the following indications:
🇺🇸 Approved in United States as Mucomyst for:
- Mucolytic agent
- Acetaminophen overdose
🇪🇺 Approved in European Union as Fluimucil for:
- Mucolytic agent
- Respiratory tract disorders
🇨🇦 Approved in Canada as N-Acetylcysteine for:
- Mucolytic agent
- Acetaminophen overdose
🇦🇺 Approved in Australia as N-Acetylcysteine for:
- Mucolytic agent
- Respiratory tract disorders
- Paracetamol overdose
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Columbia University Irving Medical CenterNew York, NY
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Who is running the clinical trial?
Michio Hirano, MDLead Sponsor
Darryl C. De Vivo, MDLead Sponsor
United States Department of DefenseCollaborator
References
N-acetylcysteine. [2013]N-acetylcysteine (NAC) is the acetylated precursor of both the amino acid L-cysteine and reduced glutathione (GSH). Historically it has been used as a mucolytic agent in chronic respiratory illnesses as well as an antidote for hepatotoxicity due to acetaminophen overdose. More recently, animal and human studies of NAC have shown it to be a powerful antioxidant and a potential therapeutic agent in the treatment of cancer, heart disease, HIV infection, heavy metal toxicity, and other diseases characterized by free radical oxidant damage. NAC has also been shown to be of some value in treating Sjogren's syndrome, smoking cessation, influenza, hepatitis C, and myoclonus epilepsy.
Pharmacokinetics of N-acetylcysteine following repeated intravenous infusion in haemodialysed patients. [2018]N-acetylcysteine (NAC) is a mucolytic agent with anti-oxidant properties. It might have potential positive effects in renal patients and, therefore, its pharmacokinetics and safety in haemodialysis was investigated.
N-acetylcysteine -- passe-partout or much ado about nothing? [2018]In experimental studies, the old mucolytic agent N-acetylcysteine (NAC) has had beneficial effects in disorders supposedly linked to oxidative stress. Numerous, mainly small clinical trials with variable doses have yielded inconsistent results in a wide variety of diseases. NAC added to the conventional therapy of human immunodeficiency virus infection might be of benefit; in respect of chronic obstructive pulmonary disease, systematic reviews and meta-analyses suggested that prolonged treatment with NAC is efficacious, but a recent multicentre study has questioned this. In a large intervention trial on cancer recurrence, NAC was ineffective. NAC infusions have been widely used in acute hepatic failure but convincing evidence of its benefits is lacking. A preliminary study reported that NAC is effective in preventing radiocontrast-induced nephropathy but thereafter highly mixed results have been published, and even meta-analyses disagree on its efficacy. In intensive care NAC has mostly been a disappointment but recently it has 'given promises' in surgery with cardiopulmonary bypass. NAC therapy is routine only in paracetamol intoxication.
N-acetylcysteine in handgrip exercise: plasma thiols and adverse reactions. [2021]N-acetylcysteine (NAC) is a thiol donor with antioxidant properties that has potential use as an ergogenic aid. However, NAC is associated with adverse reactions that limit its use in humans.
The chemistry and biological activities of N-acetylcysteine. [2022]N-acetylcysteine (NAC) has been in clinical practice for several decades. It has been used as a mucolytic agent and for the treatment of numerous disorders including paracetamol intoxication, doxorubicin cardiotoxicity, ischemia-reperfusion cardiac injury, acute respiratory distress syndrome, bronchitis, chemotherapy-induced toxicity, HIV/AIDS, heavy metal toxicity and psychiatric disorders.
Tolerability and Safety of Combined Glatiramer Acetate and N-Acetylcysteine in Relapsing-Remitting Multiple Sclerosis. [2019]Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system where inflammation and neurodegeneration play key roles. Mounting evidence implicates oxidative stress in the development of irreversible neuronal and glial injury in this condition. N-acetylcysteine (NAC) is a sulfhydryl amino acid derivative with antioxidant and antiapoptotic properties. Administration of NAC to mice attenuated the induction of or improved experimental autoimmune encephalomyelitis (an MS model).
Impact of smoking status and concomitant medications on the effect of high-dose N-acetylcysteine on chronic obstructive pulmonary disease exacerbations: A post-hoc analysis of the PANTHEON study. [2020]N-acetylcysteine (NAC) 600 mg twice daily is a well-tolerated oral antioxidant mucolytic that reduces the risk of moderate to severe chronic obstructive pulmonary disease (COPD) exacerbations. PANTHEON was one of the largest studies to evaluate NAC in COPD. It recruited current, ex- and never-smokers, concomitantly treated with other medications, and used a symptom-based definition of COPD exacerbations rather than the conventional healthcare resource utilisation (HCU) criteria.
Randomized controlled trial of N-acetylcysteine therapy for RYR1-related myopathies. [2020]Label="OBJECTIVE">To investigate the efficacy of N-acetylcysteine (NAC) for decreasing elevated oxidative stress and increasing physical endurance in individuals with ryanodine receptor 1-related myopathies (RYR1-RM).
A master protocol to investigate a novel therapy acetyl-L-leucine for three ultra-rare neurodegenerative diseases: Niemann-Pick type C, the GM2 gangliosidoses, and ataxia telangiectasia. [2021]The lack of approved treatments for the majority of rare diseases is reflective of the unique challenges of orphan drug development. Novel methodologies, including new functionally relevant endpoints, are needed to render the development process more feasible and appropriate for these rare populations and thereby expedite the approval of promising treatments to address patients' high unmet medical need. Here, we describe the development of an innovative master protocol and primary outcome assessment to investigate the modified amino acid N-acetyl-L-leucine (Sponsor Code: IB1001) in three separate, multinational, phase II trials for three ultra-rare, autosomal-recessive, neurodegenerative disorders: Niemann-Pick disease type C (NPC), GM2 gangliosidoses (Tay-Sachs and Sandhoff disease; "GM2"), and ataxia telangiectasia (A-T).
Antiproliferative effects of mitochondria-targeted N-acetylcysteine and analogs in cancer cells. [2023]N-acetylcysteine (NAC) has been used as an antioxidant drug in tumor cells and preclinical mice tumor xenografts, and it improves adaptive immunotherapy in melanoma. NAC is not readily bioavailable and is used in high concentrations. The effects of NAC have been attributed to its antioxidant and redox signaling role in mitochondria. New thiol-containing molecules targeted to mitochondria are needed. Here, mitochondria-targeted NAC with a 10-carbon alkyl side chain attached to a triphenylphosphonium group (Mito10-NAC) that is functionally similar to NAC was synthesized and studied. Mito10-NAC has a free sulfhydryl group and is more hydrophobic than NAC. Mito10-NAC is nearly 2000-fold more effective than NAC in inhibiting several cancer cells, including pancreatic cancer cells. Methylation of NAC and Mito10-NAC also inhibited cancer cell proliferation. Mito10-NAC inhibits mitochondrial complex I-induced respiration and, in combination with monocarboxylate transporter 1 inhibitor, synergistically decreased pancreatic cancer cell proliferation. Results suggest that the antiproliferative effects of NAC and Mito10-NAC are unlikely to be related to their antioxidant mechanism (i.e., scavenging of reactive oxygen species) or to the sulfhydryl group-dependent redox modulatory effects.
N-acetylcysteine Pharmacology and Applications in Rare Diseases-Repurposing an Old Antioxidant. [2023]N-acetylcysteine (NAC), a precursor of cysteine and, thereby, glutathione (GSH), acts as an antioxidant through a variety of mechanisms, including oxidant scavenging, GSH replenishment, antioxidant signaling, etc. Owing to the variety of proposed targets, NAC has a long history of use as a prescription product and in wide-ranging applications that are off-label as an over-the-counter (OTC) product. Despite its discovery in the early 1960s and its development for various indications, systematic clinical pharmacology explorations of NAC pharmacokinetics (PK), pharmacodynamic targets, drug interactions, and dose-ranging are sorely limited. Although there are anecdotal instances of NAC benefits in a variety of diseases, a comprehensive review of the use of NAC in rare diseases does not exist. In this review, we attempt to summarize the existing literature focused on NAC explorations in rare diseases targeting mitochondrial dysfunction along with the history of NAC usage, approved indications, mechanisms of action, safety, and PK characterization. Further, we introduce the research currently underway on other structural derivatives of NAC and acknowledge the continuum of efforts through pre-clinical and clinical research to facilitate further therapeutic development of NAC or its derivatives for rare diseases.