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Butylphthalide (3-n-Butylphthalide / NBP)

1. Identity: Chemical Names, Natural Sources, and Common Forms

Chemical and Botanical Identity

Butylphthalide (3-n-butylphthalide, abbreviated NBP) is one of the chemical constituents in celery oil, along with sedanolide, and is primarily responsible for the aroma and taste of celery. The compound's systematic IUPAC name is 3-butyl-1(3H)-isobenzofuranone. It belongs to the phthalide class of compounds — a family of γ-lactones (cyclic esters) based on the isobenzofuranone ring system. As a light-yellow viscous compound, butylphthalide comprises a family of optical isomers that includes l-3-N-butylphthalide (L-NBP), d-3-N-butylphthalide (D-NBP), and dl-3-N-butylphthalide (DL-NBP).

Phthalides are a class of unique compounds such as ligustilide, butylphthalide, and butylidenephthalide, which have shown multiple bioactivities in new drug research and development. Phthalides are naturally distributed in different plants that have been utilized as herbal treatments for various ailments with a long history in Asia, Europe, and North America.

Natural Botanical Sources

Butylphthalide is extracted from the seed of Apium graveolens, a natural edible plant — commonly known as celery — a member of the Apiaceae (Umbelliferae) family. The species Apium graveolens was described by Carl Linnaeus in Volume One of his Species Plantarum in 1753. Beyond celery, butylphthalide is also found in related Apiaceae plants. It is sourced from the traditional botanical remedy Ligusticum chuanxiong, the rhizome of which is a well-known ingredient in Traditional Chinese Medicine. Examination of the distribution of butylphthalide across various tissues of L. chuanxiong has found significant accumulation in the rhizome. Additional Apiaceae species that contain phthalides, including butylphthalide or its close structural relatives, include lovage (Levisticum officinale), Cnidium officinale, and Angelica species.

The chemical constituents extracted from the roots of A. graveolens var. dulce include the phthalides butylphthalide, neocnidilide, cnidilide, z-ligustilide, and senkyonolide; A. graveolens var. rapaceum contained butylphthalide and z-butylidenephthalide, cnidilide, E- and Z-ligustilide, neocnidilide, and senkyonolide. Butylphthalide (NBP) is a colorless or light yellow viscous oily component isolated from celery seeds.

Common Forms and Preparations

3-N-butylphthalide is a green botanical medicine with a simple and stable chemical structure that has been successfully synthesized for the treatment of ischemic stroke with independent intellectual property rights in China; three different stereo-isomers have been identified: l-, dl-, and d-3-n-butylphthalide. While chemical synthesis offers a viable route, limitations in the production of isomeric variants with compromised bioactivity necessitate alternative strategies.

As a pharmaceutical product, butylphthalide is available in the following documented dosage forms:

• Soft gelatin capsules (oral): Butylphthalide is an oily liquid with a strong flavour of celery; the soft capsule, as a relatively novel dosage form, is particularly advantageous in the preparation of oily active ingredients into oral formulations, in which the active pharmaceutical ingredient is uniformly distributed in the diluent and fractional dosing is accurate.
• Intravenous (IV) injection solution: Used in acute hospital settings for ischemic stroke. In clinical study protocols, patients are given intravenous butylphthalide sodium chloride injection 25 mg twice a day for 7–14 days, followed by oral butylphthalide soft capsule 0.2 g three times a day for the remainder of the treatment period.
• Oral tablets: A tablet form of L-NBP has been developed and studied in pharmacokinetic trials in healthy volunteers.

As a dietary supplement ingredient, modern research has uncovered that much of celery seed's bioactivity is due to the presence of phytonutrients called phthalides, of which 3-n-butylphthalide (3nB) is one of the most well researched.

2. Traditional and Historical Use

dl-3-n-Butylphthalide is derived from a Chinese celery extract traditionally used in Chinese medicine since the Han Dynasty (206 BCE to 220 CE) for various ailments. It has been traditionally used in China to enhance well-being, elevate mood, and reduce hypertension.

Throughout history, phthalide-containing plants have been treasured in traditional medicine, particularly in Chinese, Ayurvedic, and European herbal systems. In traditional Chinese medicine, phthalide-containing herbs like Ligusticum chuanxiong (Sichuan lovage root) have been used for centuries to support healthy blood circulation and alleviate headaches, menstrual discomfort, and muscle tension.

Apium graveolens has been known traditionally to relieve joint pain, gout, and urinary infections. It has also been used traditionally to increase urine excretion, promote menstrual discharge, and treat dengue fever and inflammation or pain in muscles or joints.

Phthalides are a group of naturally occurring organic compounds predominantly found in certain vegetables and herbs, such as celery (Apium graveolens) and lovage. Historically, phthalide-rich plants have been utilized in traditional medicine, particularly in East Asian and Mediterranean cultures, for their purported benefits in promoting cardiovascular health and supporting healthy blood pressure levels.

The use of celery (Apium graveolens, Apiaceae family) as a vegetable dates back to sixteenth-century Italy when the first cultivated varieties appeared. Ancient Greek and Roman records reference celery-like plants (selinon) in both culinary and medicinal contexts; the modern English word "celery" derives from the French céleri, in turn from Italian seleri, ultimately from Ancient Greek selinon, and the earliest-attested form of the word is the Mycenaean Greek se-ri-no, written in Linear B syllabic script.

It is important to distinguish traditional use from scientific validation: the historical uses described above reflect ethnobotanical practice and do not constitute evidence of efficacy as understood in modern clinical research.

3. Key Constituents and Phytochemistry

Butylphthalide is one of multiple bioactive phthalide compounds found in Apiaceae plants. Celery contains many active compounds, including polysaccharides (apiuman), flavonoids (luteolin, apigenin), phthalides (sedanolide, 3-n-butyl phthalide), furanocoumarins (bergapten, xanthotoxin), terpenes (d-limonene), amino acids (L-tryptophan), polyacetylenes (falcarinol, falcarindiol), and vitamins (alpha-tocopherol). Among these, the phthalides — including butylphthalide, ligustilide, senkyunolide, neocnidilide, and cnidilide — are considered the primary pharmacologically relevant fraction.

The pharmacokinetic research of plant-derived phthalides has concentrated on ligustilide, senkyunolide I, and butylphthalide, which represent critical markers in the quality control of botanical drugs.

Pharmacokinetics

NBP undergoes extensive metabolism in humans. The major metabolites in human plasma are 3-OH-NBP, 10-OH-NBP, 10-CO-NBP, and 11-COOH-NBP. The area under the curve (AUC) of metabolites is much larger than that of NBP itself.

In a pharmacokinetic study of L-NBP tablet in healthy Chinese volunteers: in the single-dose study, Cmax was reached at approximately 1 hour, and the mean half-life was approximately 13.76 hours; AUC and Cmax increased with dose escalation, but dose proportionality was not observed over the range of 160 to 480 mg. In the multiple-dose study, steady-state was reached within 3 days with slight accumulation.

Butylphthalide has the characteristics of high lipid solubility, easy passage through the blood-brain barrier, direct action at the infarct site, rapid onset, and significant effects.

A 2024 PLOS ONE study found that antibiotic treatment could affect the intestinal microbiota, decrease CYP3A1 mRNA and protein expressions, and increase NBP exposure in vivo by inhibiting pathways related to NBP metabolism. This suggests that gut microbiota composition influences butylphthalide bioavailability and that antibiotics may alter its pharmacokinetics.

4. Mechanisms of Action

Butylphthalide is described as a multi-target agent. In recent years, NBP has demonstrated potential as a treatment for several neurodegenerative diseases, which has increased interest in its mechanisms of protection and action. Clinical studies and studies using cell or animal models have directly demonstrated neuroprotective effects of NBP via the following mechanisms: (i) inhibiting the inflammatory reaction; (ii) reducing mitochondrial oxidative stress; (iii) regulating apoptosis and autophagy; (iv) inducing resistance to endoplasmic reticulum stress; and (v) decreasing abnormal protein deposition.

Antioxidant and Nrf2/HO-1 Pathway Activation

NBP inhibited oxidative stress in K141N-induced SH-SY5Y cells and in LPS-induced rats through activation of the Kelch-like ECH-associating protein 1 Nrf2-related factor 2–antioxidant response element (Keap1/Nrf2/ARE) signaling pathway. NBP prevented oxidative damage by increasing the activity of superoxide dismutase and lowering levels of malondialdehyde (MDA) and reactive oxygen species (ROS), while simultaneously increasing expression of Nrf2, HO-1, and AMPK.

Mitochondrial Protection

Mitochondrial dysfunction is an initial event of the cascade reactions triggered by ischemic stroke, contributing to the pathogenesis of ischemic brain injury. DL-3-n-butylphthalide exerts neuroprotective effects by improving mitochondrial function in ischemic brain tissues. Accumulating evidence suggests that NBP's neuroprotective function involves multiple mechanisms, including promoting cerebral blood flow, improving mitochondrial function, reducing oxidative stress damage, inhibiting inflammatory responses, and suppressing neuronal apoptosis. Studies also found that NBP may act directly on mitochondrial complex IV to increase its activity.

Anti-Inflammatory Effects

NBP plays a role in different pathophysiological processes in the treatment of ischemic stroke, including antioxidant, anti-inflammatory, anti-apoptotic, anti-thrombotic, and mitochondrial protection actions. In combination studies with ginkgolide meglumine injection, butylphthalide was associated with significant decreases in CRP and TNF-α levels in patients with acute ischemic stroke.

Antiplatelet and Antithrombotic Activity

Butylphthalide likely produces pharmacological effects through mechanisms such as reducing arachidonic acid content, increasing levels of nitric oxide (NO) and prostacyclin I2 (PGI2) in cerebrovascular endothelium, and inhibiting glutamic acid release. Levo-butylphthalide has been shown to regulate the function of the NOS-NO-cGMP system and the metabolism of arachidonic acid in neural cells after cerebral ischemia.

Anti-Apoptotic Effects

Multiple studies have shown that butylphthalide inhibits neuronal apoptosis by blocking the cascade reaction of caspase. NBP can promote the ubiquitination and degradation of hypoxia-inducible factor 1α (HIF-1α), the key transcription factor that regulates the Bax gene, thereby inhibiting cell apoptosis and facilitating neurological function recovery following cerebral ischemia.

Cerebral Microcirculation Enhancement

Butylphthalide, derived from celery seeds, has been shown to provide cerebroprotection in animal models of ischemic stroke. It can ameliorate various pathological processes of ischemic stroke-induced brain injury and significantly improve local microcirculation blood flow in the ischemic area.

5. Scientific Evidence by Area of Use

5.1 Acute Ischemic Stroke

Regulatory status: Since 3-n-butylphthalide (NBP) was approved by the China Food and Drug Administration for the treatment of acute ischemic stroke in 2002, a number of studies have investigated NBP worldwide. A Phase II clinical trial of NBP soft capsules for patients with ischemic stroke began in the United States in 2017 (NCT02905565).

Key clinical trial (JAMA Neurology, 2023): A total of 607 patients were randomly assigned to the butylphthalide group and 609 to the placebo group. A favorable functional outcome at 90 days occurred in 344 patients (56.7%) in the butylphthalide group and 268 patients (44.0%) in the placebo group (odds ratio, 1.70; 95% CI, 1.35–2.14; P < .001). The rate of serious adverse events was similar between the two groups. In this trial, NBP was associated with a higher proportion of patients achieving a favorable functional outcome at 90 days compared with placebo among patients with acute ischemic stroke receiving intravenous thrombolysis and/or endovascular treatment.

Systematic review and meta-analysis (Frontiers in Pharmacology, 2022): The results of this study suggest that DL-3-n-butylphthalide reduces the rate of short-term death and improves the degree of neurological deficit in patients with acute ischemic stroke. However, the review noted important methodological concerns: the methodological quality of the eligible studies was generally low; most studies did not report key information about randomization or blinding, or complete outcomes data, which, to a certain extent, affects the reliability of the results. Although no geographic constraints were imposed during the literature search, all included studies were conducted in China, raising the question of generalizability to other populations.

Chinese national guidelines: The "Guidelines for the Diagnosis and Treatment of Acute Ischemic Stroke in China 2018" recommend butylphthalide for improving neurological deficits in individualized treatment of mild to moderate AIS patients (Class II recommendation, Level B evidence).

Cerebral autoregulation (EBCAS study): The EBCAS study was a multicenter, randomized, controlled, blinded Phase 4 clinical trial registered at ClinicalTrials.gov (NCT03413202), conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the First Hospital of Jilin University. This study investigated whether butylphthalide improves dynamic cerebral autoregulation in patients with acute ischemic stroke.

Evidence strength: For acute ischemic stroke, butylphthalide has the strongest evidence base, including a well-designed 1,216-patient RCT published in JAMA Neurology (2023). However, most earlier supporting evidence comes exclusively from China, and the broader international evidence base remains limited.

5.2 Vascular Cognitive Impairment and Vascular Dementia

Key multicenter RCT (Jia et al., Alzheimer's & Dementia, 2016): Preclinical trials showed that dl-3-n-butylphthalide (NBP) is effective for cognitive impairment of vascular origin. In this randomized, double-blind, placebo-controlled trial, patients aged 50–70 years who had a diagnosis of subcortical vascular cognitive impairment without dementia were enrolled at 15 academic medical centers in China. Patients were randomly assigned to NBP 200 mg three times daily or matched placebo (1:1) for 24 weeks according to a computer-generated randomization protocol. In this Phase 2, randomised, double-blind, placebo-controlled clinical trial enrolling 281 patients, DL-3-n-butylphthalide was shown to be safe and effective at improving cognitive and global functioning (measured with the 12-item Alzheimer's disease assessment scale-cognitive subscale).

Combination with donepezil for vascular dementia: A meta-analysis concluded that butylphthalide combined with donepezil may be a better treatment strategy than donepezil alone for the treatment of vascular dementia in clinical practice. This evidence base, however, is largely drawn from Chinese single-center studies and its quality is variable.

Nutraceuticals, such as Ginkgo biloba and butylphthalide, have some supportive data and may be similarly helpful in vascular cognitive impairment and dementia.

Evidence strength: Moderate. The Jia et al. 2016 trial provides the most rigorous evidence from a multicenter RCT at 15 Chinese academic sites. Data from outside China and from larger, independently replicated trials are lacking.

5.3 Mild Cognitive Impairment Due to Alzheimer's Disease

Ongoing/recent RCT (EBMCI study): The efficacy of multitarget neuroprotective drug DL-3-n-butylphthalide (NBP) in improving cognitive function has been confirmed in patients with vascular cognitive impairment without dementia. However, its efficacy in patients with the symptomatic predementia phase of Alzheimer's disease remains uncertain. This 12-month, randomized, double-blind, placebo-controlled, multicentric trial included patients aged 50 to 85 years with MCI due to AD, with a CDR score of 0.5 and an MMSE score of 20–26. Subjects were randomly assigned to receive either NBP soft capsule (200 mg, three times a day) or an equivalent dose of placebo for up to 12 months. The primary endpoint was the change in the 12-item ADAS-cog after 12 months.

Animal studies have shown that NBP soft capsules can effectively improve cholinesterase activity, activate mitochondrial enzyme, and enhance mitochondrial function in rats with hypoperfusion dementia, thus improving the memory of AD animal models.

Evidence strength: Preliminary; animal and in vitro data are suggestive, but rigorous human RCT data in Alzheimer's disease specifically are still emerging.

5.4 Parkinson's Disease

Evidence for butylphthalide in Parkinson's disease (PD) is currently limited to preclinical studies. Dl-3-n-butylphthalide (NBP), an established natural antioxidant for clinical stroke treatment in China, can reportedly reduce beta-amyloid-induced neuronal toxicity in cultured neuronal cells and attenuate neurodegenerative changes in aged rats. In a rotenone-model study, pretreatment with NBP enhanced cell viability by decreasing nuclear fragmentation, retaining mitochondrial membrane potential, and preventing reactive oxygen species (ROS) generation. In a rodent model, 2-week treatment with NBP was able to ameliorate apomorphine-evoked rotations by 48% and rescue dopaminergic neurons by 30% and striatal dopamine terminal by 49%.

A network pharmacology and molecular docking study found that 36 NBP target genes were predicted to be associated with IS-related CNS diseases, including Alzheimer's disease, epilepsy, major depressive disorder, amyotrophic lateral sclerosis, and dementia. Six target genes (GRIN1, PTGIS, PTGES, ADRA1A, CDK5, and SULT1E1) showing a disease specificity index >0.5 showed good binding affinity with NBP, ranging from −9.2 to −6.7 kcal/mol. NBP may be promising and showed potential to be repurposed for treatments for AD, epilepsy, ALS, and depression, and further investigations are warranted. These are computational predictions only; no clinical trials in PD, ALS, or depression have yet been reported.

Evidence strength: Preclinical and computational only. No controlled human trials in Parkinson's disease have been published to date.

5.5 Post-Stroke Cognitive Impairment

Several studies and meta-analyses have examined NBP's effect on cognitive impairment following stroke. A systematic review and meta-analysis on the efficacy and safety of DL-3-n-butylphthalide in the treatment of post-stroke cognitive impairment has been published (Fan et al., 2022, Frontiers in Pharmacology). The butylphthalide (NBP), isolated from celery seeds, has the effects of anti-inflammation, anti-oxidative stress, protecting the blood-brain barrier, improving cerebral microcirculation, and promoting angiogenesis. It can protect the neurological function of patients with ischemic stroke through a variety of mechanisms, improve the symptoms of patients, and contribute to their long-term recovery.

Evidence strength: Moderate, with multiple Chinese RCTs and meta-analyses, but subject to the same methodological limitations as the broader stroke literature for this compound.

5.6 Blood Pressure / Hypertension

Studies in animal models suggest that butylphthalide may be useful for the treatment of hypertension and may have neuroprotective effects. This effect has not been demonstrated in controlled human clinical trials specific to hypertension, and the blood-pressure evidence remains at the preclinical stage.

Evidence strength: Animal/preclinical only for hypertension as a primary endpoint.

6. Body Systems and Health Areas

Based on the current published research, butylphthalide has been studied in relation to the following body systems and health areas:

• Central nervous system / cerebrovascular system: The primary and best-documented area. Neuroprotective mechanisms include inhibiting the inflammatory reaction, reducing mitochondrial oxidative stress, regulating apoptosis and autophagy, inducing resistance to endoplasmic reticulum stress, and decreasing abnormal protein deposition.
• Cognitive function: Vascular cognitive impairment, post-stroke dementia, and early-phase Alzheimer's disease investigation.
• Cardiovascular / hemostatic system: Antithrombotic and antiplatelet activity documented in preclinical studies. The pharmacological effects of 3-butylphthalide in treating cerebrovascular diseases primarily focus on antiplatelet aggregation, antithrombotic effects, inhibition of neuronal apoptosis, antioxidant activity, protection of mitochondrial function, anti-inflammatory effects, anti-cerebral ischemia, reduction of brain damage, and anti-vascular dementia.
• Musculoskeletal system: Preliminary preclinical data suggest NBP directly protects muscle mitochondria and muscle cells from oxidative damage; notably, NBP reduced muscle cell apoptosis, suggesting that as an antioxidant treatment, NBP may benefit individuals with myopathy.
• Metabolic: 3-N-butylphthalide (NBP) is a component isolated from seeds of Chinese celery, and it was first approved for the treatment of ischemic stroke; with a gradual in-depth understanding of its pharmacological action, it was found that it may have potential effects on treating diabetes and its complications. This remains at the preclinical stage.

7. Dosage Forms and Reported Dosages

The following dosages are reported in published clinical studies and trial protocols, and are presented descriptively only.

• Oral soft capsule (NBP 200 mg, three times daily): This dose (600 mg/day total) was used in the landmark Jia et al. (2016) vascular cognitive impairment RCT where patients were randomly assigned to NBP 200 mg three times daily or matched placebo (1:1) for 24 weeks. The same dose was used in the EBMCI mild cognitive impairment RCT: subjects were randomly assigned to receive either NBP soft capsule (200 mg, three times a day) or equivalent dose of placebo for up to 12 months.
• Intravenous injection followed by oral capsule: In one real-world clinical trial, patients were given intravenous butylphthalide sodium chloride injection 25 mg twice a day for 7–14 days, then oral butylphthalide soft capsule 0.2 g three times a day for 76–83 days.
• L-NBP tablet pharmacokinetic study (healthy volunteers): Subjects were assigned to receive a single dose of L-NBP tablet at either 80, 160, 320, or 480 mg (n=40), or multiple doses of 160 mg twice daily for 7 days (n=12).
• Preclinical (animal) dosing: Four animal studies conducted between 2010 and 2016 focused on Alzheimer's disease using L-3-n-butylphthalide (L-NBP), with an oral dosage of 15 mg/kg for a treatment duration of three months or more.

8. Safety Considerations and Drug Interactions

General Tolerability

Minor side effects were observed in preclinical and clinical studies. The L-NBP tablet was well tolerated in healthy Chinese subjects; slight accumulation appeared after repeated doses. All adverse events in the single- and multiple-dose pharmacokinetic study were mild and of limited duration; no serious adverse event, death, or withdrawal from the study was observed.

Hepatotoxicity (Liver Enzyme Elevation)

The main adverse effect of butylphthalide reported in clinical use is the increase in transaminase levels. The main ones include mild elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, with severe elevations being rare; these can return to normal after discontinuation of the drug. During clinical use, it can cause adverse reactions such as abnormal liver function and gastrointestinal reactions.

Contraindications and Special Populations

Safety during pregnancy and the suckling period has not been established; therefore, it is contraindicated in pregnant and breastfeeding women. Use with caution is indicated in patients with impaired liver or kidney function and in those with psychiatric symptoms. Since no clinical studies have been conducted on butylphthalide for hemorrhagic stroke, it is not recommended for patients with this condition.

Drug–Drug Interactions

A 2024 PLOS ONE animal study demonstrated a pharmacokinetic interaction between butylphthalide and antibiotics via the gut microbiome: antibiotic treatment could affect the intestinal microbiota, decrease CYP3A1 mRNA and protein expression, and increase NBP exposure in vivo by inhibiting pathways related to NBP metabolism. This has been documented in animal models; the clinical significance in humans requires further investigation. KEGG analysis showed that multiple metabolic pathways were significantly downregulated in the antibiotic-treated group, among them pathways of drug metabolism, bile acid biosynthesis and decomposition, and fatty acid synthesis and decomposition relevant to NBP biological metabolism.

In clinical practice, butylphthalide is often used in combination with drugs such as edaravone, alteplase, fasudil, Xingnaojing Injection, and Compound Danshen Injection for treating cerebrovascular diseases, demonstrating good synergistic effects, which provides support for the rational clinical use of NBP. These combination uses have been studied largely in Chinese clinical settings.

Serious Adverse Events in Large Trials

In the large 1,216-patient JAMA Neurology RCT (Wang et al., 2023), the rate of serious adverse events was similar between the butylphthalide and placebo groups. The safety profile reported across meta-analyses of acute ischemic stroke trials is consistent: butylphthalide significantly improves neuronal cell function by protecting mitochondria, alleviating inflammatory response, and enhancing microcirculation, with no serious adverse reactions reported.

Limitations of Safety Data

Population pharmacokinetic modeling in elderly ischemic stroke patients using a 2-compartment model with first-order elimination has been applied to better understand individual variability; studies have examined basic patient information, laboratory test results, concomitant drugs, and comorbidities as covariates. Comprehensive safety data specifically in populations outside East Asia are not yet available in the peer-reviewed literature.

References

• Chen X et al. (2023). LcSAO1, an Unconventional DOXB Clade 2OGD Enzyme from Ligusticum chuanxiong Catalyzes the Biosynthesis of Plant-Derived Natural Medicine Butylphthalide. International Journal of Molecular Sciences, 24(24):17417. PMC.
• Liu J et al. (2014). L-3-n-butylphthalide protects against vascular dementia via activation of the Akt kinase pathway. PMC.
• Javed H et al. (2023). Neurological Applications of Celery (Apium graveolens): A Scoping Review. PMC.
• Luo R, Wangqin R, Zhu L, Bi W. (2019). Neuroprotective mechanisms of 3-n-butylphthalide in neurodegenerative diseases. Biomedical Reports, 11(6):235–240. PubMed.
• Wang S et al. (2019). 3-n-butylphthalide exerts neuroprotective effects by enhancing anti-oxidation and attenuating mitochondrial dysfunction in an in vitro model of ischemic stroke. PubMed.
• Zhao F et al. (2011). Dl-3-n-butylphthalide, a natural antioxidant, protects dopamine neurons in rotenone models for Parkinson's disease. PubMed.
• Wang A et al. (2023). Efficacy and Safety of Butylphthalide in Patients With Acute Ischemic Stroke: A Randomized Clinical Trial. JAMA Neurology, 80(8):851–859. PMC.
• Wang H et al. (2022). DL-3-n-butylphthalide for acute ischemic stroke: An updated systematic review and meta-analysis of randomized controlled trials. Frontiers in Pharmacology, 13:963118. PMC.
• Lv J et al. (2022). Efficacy and safety of butylphthalide in secondary prevention of stroke: study protocol for a multicenter, real world trial based on Internet. BMC Neurology, 22(1):305. PMC.
• Jia J et al. (2016). The effects of DL-3-n-butylphthalide in patients with vascular cognitive impairment without dementia caused by subcortical ischemic small vessel disease: A multicentre, randomized, double-blind, placebo-controlled trial. Alzheimer's & Dementia, 12(2):89–99.
• Efficacy and safety of DL-3-n-butylphthalide in patients with mild cognitive impairment: a multicentre, randomized, double-blind, placebo-controlled trial (EBMCI). PMC.
• Butylphthalide combined with donepezil for the treatment of vascular dementia: a meta-analysis. PubMed.
• Zhao R et al. (2020). Efficacy and safety of butylphthalide as adjunctive therapy for vascular dementia: A protocol for systematic review and meta-analysis. PMC.
• Zhang Y et al. (2021). A Study to Decipher the Potential Effects of Butylphthalide against Central Nervous System Diseases Based on Network Pharmacology and Molecular Docking Integration Strategy. PMC.
• Cerebroprotective action of butylphthalide in acute ischemic stroke: Potential role of Nrf2/HO-1 signaling pathway. PMC.
• DL-3-n-Butylphthalide Protects Mitochondria Against Ischemia/Hypoxia Damage via Suppressing GCN5L1-Mediated Drp1 Acetylation in Neurons and Mouse Brains. CNS Neuroscience & Therapeutics. PMC.
• Meta-analysis of the efficacy and safety of Ginkgolide Meglumine Injection combined with Butylphthalide in the treatment of Acute Ischemic Stroke. PMC.
• Pharmacokinetics, safety and tolerability of L-3-n-butylphthalide tablet after single and multiple oral administrations in healthy Chinese volunteers. Brazilian Journal of Pharmaceutical Sciences.
• Li X et al. (2024). Antibiotics affect the pharmacokinetics of n-butylphthalide in vivo by altering the intestinal microbiota. PLOS ONE.
• Advances in the phytochemistry and pharmacology of plant-derived phthalides. Heliyon. 2023.
• Butylphthalide — an overview. ScienceDirect Topics (Pharmacology).
• Butylphthalide. Wikipedia.
• Research progress on pharmacology of butylphthalide and its derivatives. PubMed.
• Vascular cognitive impairment and dementia: Prevention, treatments, mechanisms and management options for the future. Neuropsychopharmacology. 2026.