A Comprehensive Monograph on Butylphthalide (DB12749): From Celery Seed to Neuroprotective Agent

I. Executive Summary

Butylphthalide, also known by the abbreviation NBP, is a small molecule compound with the DrugBank accession number DB12749. Originally identified and isolated from the seeds of celery (Apium graveolens), it has been synthetically developed into a significant therapeutic agent, particularly in the field of neuropharmacology.[1] This report provides an exhaustive analysis of its chemical properties, complex pharmacology, clinical applications, safety profile, and global regulatory status.

The pharmacological profile of Butylphthalide is uniquely characterized by its pleiotropic, multi-target mechanism of action. Unlike many pharmaceuticals that act on a single receptor or enzyme, Butylphthalide exerts its neuroprotective effects by concurrently modulating several key pathophysiological pathways implicated in ischemic and neurodegenerative damage. Its core mechanisms include the reconstruction of cerebral microcirculation, protection of mitochondrial function against ischemic stress, and potent anti-inflammatory, antioxidant, and anti-apoptotic activities.[4] This multifaceted approach is believed to be central to its clinical efficacy in complex neurological disorders.

Clinically, Butylphthalide has an established role in the management of acute ischemic stroke. It was first approved for this indication in 2002 by China's National Medical Products Administration (NMPA) and is now widely used in the country.[1] Its efficacy and safety were robustly demonstrated in the landmark BAST (Butylphthalide for Acute Ischemic Stroke Patients Receiving Intravenous Thrombolysis or Endovascular Treatment) trial (NCT03539445). This pivotal study provided Level 1 evidence that Butylphthalide, when used as an adjunctive therapy to modern reperfusion strategies, significantly improves long-term functional outcomes compared to placebo, filling a critical gap where many previous neuroprotective agents have failed.[10]

Beyond its approved indication, the therapeutic horizon for Butylphthalide is expanding. A growing body of evidence supports its investigational use in other neurological conditions. Clinical trials are actively evaluating its potential in treating vascular dementia and post-stroke cognitive impairment (PSCI), suggesting a shift in its application from acute neurological rescue to long-term cognitive preservation.[5] Furthermore, its fundamental neuroprotective properties have led to its investigation in primary neurodegenerative diseases. Notably, the U.S. Food and Drug Administration (FDA) has granted Butylphthalide an Orphan Drug Designation for the treatment of Amyotrophic Lateral Sclerosis (ALS), facilitating its development for this devastating condition.[15]

The safety profile of Butylphthalide is well-characterized and generally favorable. The most common adverse events are mild to moderate gastrointestinal discomfort and elevations in liver transaminases, which necessitate clinical monitoring.[16] The primary safety concern stems directly from its therapeutic mechanism: its antiplatelet activity creates a heightened risk of bleeding, especially when co-administered with other anticoagulant or antiplatelet medications. This requires careful risk-benefit assessment and patient monitoring but does not preclude its use.[6] Its regulatory status is distinct, being a standard-of-care therapy in China while remaining an investigational drug in the United States and not yet approved in Europe, highlighting the need for further global clinical trials to broaden its accessibility.[8]

In conclusion, Butylphthalide represents a significant advancement in neuroprotective therapy. With a proven role in improving outcomes in acute ischemic stroke and substantial, evidence-backed potential for broader applications in a range of neurovascular and neurodegenerative diseases, it stands as a critical area for ongoing global research, clinical evaluation, and therapeutic development.

II. Compound Identification and Physicochemical Properties

A thorough understanding of Butylphthalide begins with its precise chemical identity and physical characteristics. These fundamental properties dictate its formulation, stability, absorption, distribution, and ultimately, its biological activity. This section provides a comprehensive profile of the compound, consolidating its nomenclature, structural details, and key physicochemical parameters.

Nomenclature and Chemical Identifiers

To ensure unambiguous identification across diverse scientific and regulatory domains, Butylphthalide is catalogued under numerous systematic names and registry numbers. Its generic name is Butylphthalide.[6] The systematic name assigned by the International Union of Pure and Applied Chemistry (IUPAC) is 3-Butyl-2-benzofuran-1(3H)-one, though it is also frequently cited as 3-butyl-3H-2-benzofuran-1-one.[1]

The compound is widely known by several synonyms and abbreviations in scientific literature and clinical practice. The most common are 3-n-Butylphthalide and its abbreviation, NBP. The racemic mixture, which is the form used clinically, is often specified as DL-3-n-butylphthalide.[1] Other chemical names include 3-Butyl-1(3H)-isobenzofuranone and 3-butylphthalide.[20] In China, where the drug is marketed, it is associated with the brand name En Bi Pu.[23]

Its unique identity is codified by a series of registry numbers, the most critical being its Chemical Abstracts Service (CAS) number, 6066-49-5.[24] Its entry in the DrugBank database is DB12749.[6] Other key identifiers are provided in the table below for comprehensive cross-referencing.

Table 1: Comprehensive Chemical Identifiers for Butylphthalide

Identifier Type	Value	Source(s)
CAS Number	6066-49-5	24
DrugBank ID	DB12749	6
PubChem CID	61361	3
UNII (FDA)	822Q956KGM	3
EC Number	228-000-8	19
ChemSpider ID	55293	3
ChEBI ID	CHEBI:177504	19
InChIKey	HJXMNVQARNZTEE-UHFFFAOYSA-N	19

This consolidation of identifiers is essential for researchers and clinicians, as it bridges the nomenclature used in chemical databases, pharmacological resources, and regulatory filings, ensuring precise and consistent communication about the compound.

Structural and Molecular Characteristics

Butylphthalide is an organic compound belonging to the benzofuranone class.[19] Its molecular structure consists of a phthalide core (a bicyclic structure containing a benzene ring fused to a lactone ring) with a butyl group attached at the 3-position of the furanone ring.

The elemental composition is defined by the chemical formula C12​H14​O2​.[1] This formula corresponds to an average molecular weight of approximately 190.24 g/mol, with various sources reporting values from 190.2384 to 190.242 g/mol.[3] The precise monoisotopic mass, critical for mass spectrometry analysis, is 190.099379692 Da.[6]

The two-dimensional structure and three-dimensional conformation of the molecule can be represented by standard chemical notations:

• SMILES (Simplified Molecular Input Line Entry System): CCCCC1C2=CC=CC=C2C(=O)O1 [19]
• InChI (IUPAC International Chemical Identifier): InChI=1S/C12H14O2/c1-2-3-8-11-9-6-4-5-7-10(9)12(13)14-11/h4-7,11H,2-3,8H2,1H3 [19]

These structural features, particularly the combination of an aromatic ring system and a flexible alkyl chain, are key determinants of its physicochemical properties and its interaction with biological targets.

Physical and Chemical Properties

Butylphthalide exists at room temperature as a colorless to pale yellow, oily liquid.[3] It is characterized by a faint, slightly aromatic odor, often described as having a warm, spicy, and herbaceous character reminiscent of celery, its natural source.[19]

Its solubility profile is a defining characteristic with significant biopharmaceutical implications. The compound is only slightly soluble in water but is readily soluble in various oils and organic solvents.[19] Quantitative solubility data indicates high solubility in ethanol, dimethyl sulfoxide (DMSO), and dimethylformamide (DMF), at concentrations of approximately 30 mg/mL or higher.[1] This poor aqueous solubility is a critical factor influencing its oral bioavailability and formulation design.

The lipophilicity of Butylphthalide is quantified by its partition coefficient (LogP), which has an experimentally determined value of 2.8.[19] This value indicates a strong preference for lipid environments over aqueous ones, classifying it as a highly lipophilic molecule.

Regarding stability, Butylphthalide is generally stable under ambient conditions, allowing for shipping at room temperature. However, for long-term preservation of its chemical integrity, storage at -20°C in a dry and dark environment is recommended.[1] Some sources also note that the compound is hygroscopic, meaning it can absorb moisture from the air, which should be considered during handling and storage.[26]

Table 2: Summary of Physicochemical Properties

Property	Description	Source(s)
Physical Form	Oily liquid, neat oil	24
Color	Colorless to pale yellow	24
Odor	Warm, spicy, herbaceous, celery-like	24
Water Solubility	Slightly soluble	19
Organic Solubility	Soluble in ethanol, DMSO, DMF (approx. 30 mg/mL)	1
LogP	2.8 (experimental)	19
Stability	Stable at ambient temperature; hygroscopic	1
Storage	Long-term: -20°C, dry, dark	24

The physicochemical profile of Butylphthalide provides a clear and direct link to its clinical and pharmacological characteristics. Its pronounced lipophilicity, evidenced by its oily nature and a LogP of 2.8, is the fundamental property that enables its therapeutic utility in central nervous system (CNS) disorders. This fat-solubility allows the molecule to readily diffuse across the lipid-rich blood-brain barrier, a critical step to reach its sites of action within the brain to treat conditions like ischemic stroke.[5] However, this same property creates a significant biopharmaceutical challenge. Its very low solubility in water leads to poor dissolution in the aqueous environment of the gastrointestinal tract, which in turn results in limited and variable oral bioavailability when administered in simple forms.[30] This solubility issue is the primary driver behind its formulation development. To overcome this limitation, the marketed oral product is a softgel capsule, which contains the oily drug in a solubilized form, enhancing its absorption.[16] Furthermore, this challenge has spurred research into more advanced drug delivery systems, such as liposomes, to further improve its oral absorption and brain accumulation.[30] Thus, the compound's chemical nature directly explains both its therapeutic strength—CNS penetration—and its pharmaceutical weakness—poor bioavailability—creating a clear rationale for its specific clinical formulation.

III. Comprehensive Pharmacological Profile

The therapeutic effects of Butylphthalide are rooted in a complex and multifaceted pharmacological profile. It does not conform to the traditional "one drug, one target" model; instead, it functions as a pleiotropic agent that simultaneously modulates multiple interconnected pathophysiological pathways. This section details its mechanism of action and its pharmacokinetic properties, providing a comprehensive view of how the drug interacts with and moves through the body.

Mechanism of Action: A Multi-Target Neuroprotective Agent

The neuroprotective efficacy of Butylphthalide in conditions like ischemic stroke arises from its ability to intervene at several critical points in the cascade of cellular injury. Its actions are not isolated but form a synergistic network that collectively preserves neuronal function and viability. Inflammation, oxidative stress, mitochondrial failure, and apoptosis are not independent events in an ischemic brain but are closely intertwined processes. Butylphthalide's strength lies in its capacity to disrupt this pathological network at multiple nodes. For instance, by preserving mitochondrial function, it directly reduces the generation of reactive oxygen species (ROS), thereby mitigating oxidative stress. This, in turn, prevents the activation of downstream apoptotic pathways that are triggered by both mitochondrial dysfunction and oxidative damage. Concurrently, its ability to improve cerebral microcirculation addresses the initial ischemic insult, reducing the primary trigger for this entire cascade. This multi-target engagement provides a more robust and comprehensive neuroprotective effect than would be achievable by targeting any single pathway alone, which helps explain its efficacy in complex, multifactorial diseases where single-target agents have often failed.

1. Enhancement of Cerebral Microcirculation and Hemodynamics

A primary and well-documented effect of Butylphthalide is its ability to restore and improve blood flow in the brain. In the context of ischemic stroke, it enhances cerebral blood flow, particularly in the ischemic penumbra—the area of salvageable tissue surrounding the core infarct.[5] This is achieved through several mechanisms. First, it acts as a vasodilator, promoting the relaxation of blood vessels. This effect is mediated by its ability to increase the production of two key endogenous vasodilators, nitric oxide (NO) and prostacyclin (

PGI2​), in cerebral vascular endothelial cells.[5] It further shifts the local vascular environment towards vasodilation by favorably modulating the ratio of vasodilator

PGI2​ to the potent vasoconstrictor and platelet aggregator thromboxane A2 (TXA2​).[5]

In addition to vasodilation, Butylphthalide possesses significant anti-thrombotic properties. It inhibits the aggregation of platelets induced by various agonists, including adenosine diphosphate (ADP), thrombin, and collagen.[5] A key molecular mechanism for this antiplatelet effect is the inhibition of cytosolic phospholipase A2 (

cPLA2​) phosphorylation. This action reduces the synthesis of TXA2​, thereby dampening platelet activation and aggregation and improving microcirculation.[5]

2. Protection of Mitochondrial Function

Mitochondria are central to cell survival and are particularly vulnerable to ischemic injury. Butylphthalide exerts profound protective effects on these organelles. It attenuates mitochondrial dysfunction by stabilizing the mitochondrial membrane potential, which is crucial for energy production and preventing the initiation of apoptosis.[5] The drug has been shown to improve the activity of key mitochondrial enzymes, including the ion pumps Na/K-ATPase and Ca-ATPase, as well as the components of the electron transport chain (complexes I–IV), thereby preserving cellular energy metabolism.[5]

Recent research has uncovered a more nuanced mechanism involving the regulation of mitochondrial dynamics. Butylphthalide promotes mitochondrial fusion—a process where individual mitochondria merge to share components and mitigate damage—through the activation of the AMPK/Mfn1 signaling pathway. This process helps maintain a healthy mitochondrial network under conditions of ischemic stress.[36] By stabilizing mitochondria, Butylphthalide also prevents the release of pro-apoptotic factors like cytochrome c into the cytoplasm, a critical step that commits the cell to the intrinsic pathway of apoptosis.[5]

3. Anti-Inflammatory and Antioxidant Effects

Ischemic injury triggers a robust inflammatory response and a surge of oxidative stress, both of which contribute significantly to secondary brain damage. Butylphthalide effectively counteracts these processes. It exhibits powerful antioxidant properties, reducing oxidative stress by decreasing the production of damaging ROS and lipid peroxidation products like malondialdehyde (MDA).[4] Concurrently, it boosts the brain's endogenous antioxidant defenses by increasing the activity of enzymes such as superoxide dismutase (SOD).[5]

Its anti-inflammatory actions are equally important. Butylphthalide suppresses neuroinflammation by inhibiting the activation of microglia and astrocytes, the primary immune cells of the CNS, which can become overactive and neurotoxic after injury.[32] It achieves this, in part, by downregulating the expression of key pro-inflammatory cytokines, including interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α). This effect is mediated through the inhibition of critical inflammatory signaling pathways, most notably the nuclear factor kappa B (NF-κB) pathway.[32]

4. Inhibition of Apoptosis and Regulation of Autophagy

Neuronal cell death following ischemia occurs largely through apoptosis, or programmed cell death. Butylphthalide is a potent inhibitor of this process.[5] By preserving mitochondrial integrity and reducing oxidative stress, it prevents the activation of the intrinsic apoptotic pathway. Furthermore, it directly interferes with the execution phase of apoptosis by reducing the activity of caspase-3, a key enzyme responsible for dismantling the cell.[28]

The drug also modulates autophagy, the cellular process of self-digestion that can be either protective or destructive depending on the context. Under severe ischemic stress, excessive autophagy can contribute to cell death. Butylphthalide helps to regulate this process, preventing it from becoming detrimental and thereby promoting cell survival.[38]

5. Promotion of Angiogenesis and Neurogenesis

Beyond protecting existing neurons, Butylphthalide also appears to promote long-term repair and recovery. It stimulates angiogenesis, the formation of new blood vessels, which is critical for restoring blood supply to damaged brain tissue. This is achieved by up-regulating the expression of key pro-angiogenic factors like Vascular Endothelial Growth Factor (VEGF).[37] Additionally, preclinical evidence suggests that Butylphthalide can enhance neurogenesis (the birth of new neurons) and synaptic plasticity, processes that are fundamental to the brain's ability to remodel itself and recover function after injury.[33]

Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of Butylphthalide describes its journey through the body and is characterized by rapid absorption, excellent brain penetration, extensive metabolism, and primarily renal excretion.

Absorption

Following oral administration, Butylphthalide is absorbed rapidly from the gastrointestinal tract. Peak plasma concentrations (Tmax​) are typically reached within 0.75 to 1.25 hours.[5] While its lipophilic nature facilitates passage across the gut wall, its poor aqueous solubility is a rate-limiting factor for dissolution and can lead to incomplete or variable absorption from simple formulations. This has necessitated the development of lipid-based formulations, such as the commercially available softgel capsules, to enhance its oral bioavailability.[30] Studies exploring advanced delivery systems like liposomes have shown the potential to achieve nearly complete oral absorption and significantly increase brain concentrations compared to standard suspensions.[30]

Distribution

A defining feature of Butylphthalide's pharmacokinetics is its ability to effectively distribute to its target site, the CNS. As a highly lipophilic, fat-soluble molecule, it readily crosses the blood-brain barrier.[5] Its main sites of distribution are the brain and adipose tissue, where it can accumulate due to its lipid-friendly properties.[5] This efficient brain penetration is a prerequisite for its efficacy in neurological disorders.

Metabolism

Butylphthalide undergoes extensive biotransformation in the human body, primarily in the liver.[3] Its metabolism is complex, involving multiple enzymatic pathways. Several cytochrome P450 (CYP450) isoenzymes play a role, with CYP3A4, CYP2E1, and CYP1A2 being particularly important for its initial oxidative metabolism.[44] In addition to CYP-mediated reactions, alcohol dehydrogenase and aldehyde dehydrogenase are also involved in the subsequent oxidation of its metabolites.[44]

The principal metabolic pathways include hydroxylation at various positions on the butyl side chain, further oxidation of these hydroxylated intermediates to ketones and carboxylic acids, and subsequent conjugation reactions, primarily with glucuronic acid, to form water-soluble compounds for excretion.[43] At least 23 distinct metabolites have been identified in human plasma and urine. The major circulating metabolites, which are present in significantly higher concentrations than the parent drug, are 3-hydroxy-NBP (M3-1), 10-hydroxy-NBP (M3-2), 10-keto-NBP (M2), and 11-carboxy-NBP (NBP-11-oic acid, M5-2).[3]

The pharmacokinetic profile of Butylphthalide is notable in that its major metabolites are not merely inactive byproducts but are present at substantially higher concentrations than the parent drug and are themselves biologically active. Following a standard oral dose, the systemic exposure (as measured by the area under the curve, or AUC) to these metabolites is several-fold higher than that of Butylphthalide itself. Specifically, AUC values for 10-Keto-NBP, 3-hydroxy-NBP, 10-hydroxy-NBP, and NBP-11-oic acid were found to be 1.6, 2.9, 10.3, and 4.1 times higher, respectively, than that of the parent NBP.[43] Crucially, studies have indicated that the biological activities of these metabolites are comparable to, or even greater than, that of NBP.[43] This finding has significant implications for understanding the drug's overall therapeutic effect. It suggests that the clinical efficacy observed is likely a composite effect of the parent compound and its pharmacologically active metabolites. This complicates direct pharmacokinetic-pharmacodynamic (PK/PD) modeling based solely on NBP concentrations and highlights the importance of factors that influence metabolism, such as genetic variations in CYP enzymes or co-administered drugs that inhibit or induce these enzymes. For example, the use of certain antibiotics was shown to alter gut microbiota, which in turn inhibited CYP3A1 activity and significantly increased systemic exposure to NBP.[45] This observation underscores that the overall "active moiety" is a combination of NBP and its metabolites, a critical consideration for both clinical use and future drug development.

Excretion

The metabolites of Butylphthalide are primarily eliminated from the body via the kidneys. Approximately 82% of an administered oral dose is recovered in the urine, almost entirely in the form of its various metabolites.[43] The major urinary metabolites are NBP-11-oic acid and the glucuronide conjugates of the mono-hydroxylated metabolites.[43]

Half-Life

The elimination half-life (t1/2​) of Butylphthalide is relatively long, supporting a dosing schedule of two to three times per day. Reported values vary slightly across studies and formulations, with a half-life of 11.84 hours cited in one review and a mean of 13.76 hours observed in a clinical study of an L-NBP tablet formulation.[5] This prolonged duration of action is beneficial for maintaining therapeutic concentrations over the dosing interval.

IV. Clinical Efficacy and Therapeutic Applications

The clinical utility of Butylphthalide has been extensively investigated, leading to its approval for acute ischemic stroke in China and prompting a wide range of studies into other neurological conditions. This section reviews the pivotal clinical evidence supporting its use, details common dosing regimens, and explores its emerging therapeutic applications.

Approved Indication: Acute Ischemic Stroke

The primary and most well-established clinical application of Butylphthalide is in the treatment of acute ischemic stroke. The racemic form, DL-3-n-butylphthalide (dl-NBP), was officially approved for this indication by the China Food and Drug Administration (now the NMPA) in 2002.[1] Since then, it has become a widely used neuroprotective agent in clinical practice throughout China, available in both intravenous and oral soft capsule formulations.[16]

A substantial body of evidence from numerous randomized controlled trials (RCTs) and subsequent meta-analyses has consistently demonstrated that NBP is both safe and effective for improving neurological recovery and functional outcomes in patients following an acute ischemic stroke.[11]

Pivotal Clinical Trial: The BAST Trial (NCT03539445)

The most definitive evidence for Butylphthalide's efficacy in the modern era of stroke care comes from the BAST (Butylphthalide for Acute Ischemic Stroke Patients Receiving Intravenous Thrombolysis or Endovascular Treatment) trial. This large-scale study was crucial because it evaluated NBP as an adjunct to current standard-of-care reperfusion therapies, a rigorous test where many other neuroprotective agents have previously failed.

• Study Design: The BAST trial was a multicenter, randomized, double-blind, placebo-controlled, Phase 3 clinical trial conducted across 59 medical centers in China.[10]
• Patient Population: The trial enrolled 1,216 adult patients diagnosed with acute ischemic stroke who presented with moderate to severe neurological deficits (National Institutes of Health Stroke Scale score ranging from 4 to 25) and were eligible for and received standard reperfusion therapy, either intravenous thrombolysis with rt-PA, endovascular treatment (thrombectomy), or both.[11]
• Intervention: Eligible patients were randomized in a 1:1 ratio to receive either Butylphthalide or a matching placebo. Treatment was initiated within 6 hours of symptom onset and continued for a total of 90 days. The regimen consisted of a sequential therapy approach: intravenous administration for the first 14 days, followed by oral soft capsules for the subsequent 76 days.[49]
• Primary Outcome: The primary efficacy endpoint was the proportion of patients achieving a favorable functional outcome at 90 days post-stroke. This was assessed using the modified Rankin Scale (mRS), a global scale of disability, with a favorable outcome defined as an mRS score of 0-2, depending on the baseline stroke severity.[12]
• Key Efficacy Results: The trial met its primary endpoint, demonstrating a statistically significant and clinically meaningful benefit for Butylphthalide. A favorable functional outcome at 90 days was achieved by 56.7% of patients in the Butylphthalide group, compared to only 44.0% in the placebo group. This corresponds to an odds ratio of 1.70, indicating that patients treated with NBP had a 70% higher odds of a favorable outcome.[11]
• Safety Results: The safety profile was comparable between the two groups. Serious adverse events within the 90-day period occurred in 10.1% of patients in the Butylphthalide group and 12.0% of patients in the placebo group, a difference that was not statistically significant.[11]
• Clinical Implication: The BAST trial provided high-level, Level 1 evidence confirming that adjunctive therapy with Butylphthalide is both effective and safe for patients with acute ischemic stroke receiving modern reperfusion treatments. This solidifies its role as a valuable neuroprotective agent in contemporary stroke management.

Dosing Regimens and Routes of Administration in Stroke Therapy

Clinical practice and major trials have established a consistent approach to dosing and administration for Butylphthalide in the setting of acute ischemic stroke, employing a sequential intravenous-to-oral therapy model to cover both the hyperacute and subacute phases of recovery.[47]

• Acute Phase (Initial 14 days): Treatment is initiated with intravenous administration to ensure rapid and complete bioavailability during the critical early period of injury. A standard regimen involves the infusion of Butylphthalide sodium chloride injection, typically 100 mL containing 25 mg of NBP, administered twice daily.[48]
• Continuation and Subacute Phase (Up to 90 days or longer): Following the initial intravenous course, patients are transitioned to oral therapy for continued neuroprotection and to support long-term recovery. The standard oral dose is 200 mg (administered as two 100 mg soft capsules) taken three times per day.[47]
• Secondary Prevention: Beyond the initial 90-day treatment period, longer-term administration is being investigated for its role in secondary stroke prevention. Studies have evaluated a regimen of 200 mg three times daily for up to 12 months to assess its efficacy in reducing the risk of recurrent stroke.[53]

Investigational and Emerging Applications

The therapeutic potential of Butylphthalide is not limited to acute stroke. Its unique multi-target mechanism of action, which addresses pathological processes common to a range of neurological disorders—such as inflammation, oxidative stress, mitochondrial dysfunction, and neuronal apoptosis—has prompted extensive research into its use for other conditions. This research reflects a strategic evolution in the drug's clinical positioning, expanding its application from an acute-phase treatment to a potential chronic therapy for a spectrum of neurovascular and neurodegenerative diseases. This trajectory began with its established use in acute stroke, then expanded to trials for secondary stroke prevention over several months. This was followed by investigations into its role in treating the chronic cognitive sequelae of stroke, such as vascular dementia. Most recently, its fundamental neuroprotective properties have led to its evaluation in primary neurodegenerative diseases like Alzheimer's disease and ALS, demonstrating a broadening scientific understanding of its therapeutic utility.

1. Vascular Dementia (VaD) and Post-Stroke Cognitive Impairment (PSCI)

One of the most promising areas of investigation for Butylphthalide is in the management of cognitive impairment of vascular origin. Numerous clinical studies, systematic reviews, and meta-analyses have provided evidence that NBP can improve cognitive function in patients with VaD and PSCI.[13] These studies consistently show improvements in scores on standardized cognitive assessments, such as the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA), as well as benefits in activities of daily living. This indication is currently under late-stage investigation; a large, multicenter Phase 3 trial (NCT03804229) is evaluating the efficacy and safety of NBP soft capsules for patients with mild to moderate VaD, though it is not currently recruiting.[58]

2. Amyotrophic Lateral Sclerosis (ALS)

In recognition of its potential to address the neurodegenerative processes in ALS, the U.S. FDA granted Butylphthalide an Orphan Drug Designation for the treatment of this condition on February 28, 2018.[15] This designation is intended to facilitate the development of drugs for rare diseases. The rationale is supported by preclinical data showing that NBP can attenuate glial activation and extend survival in animal models of ALS, suggesting a potential disease-modifying effect.[3]

3. Other Investigational Areas

The broad neuroprotective and vasculoprotective effects of Butylphthalide have led to its exploration in several other clinical contexts:

• Restenosis: It has been evaluated in clinical trials for its potential to prevent restenosis, the re-narrowing of an artery after an angioplasty procedure.[6]
• Cardiac Arrest: A randomized, double-blind, placebo-controlled trial (BNCA Trial, NCT06353334) is currently underway to evaluate the safety and efficacy of NBP in improving neurological outcomes in patients who have been successfully resuscitated after cardiac arrest.[60]
• Mild Cognitive Impairment (MCI): Recognizing its potential benefits in early-stage cognitive decline, a 12-month RCT (ChiCTR1800018362) is assessing its efficacy in patients diagnosed with MCI, a potential prodromal stage of Alzheimer's disease.[61]
• Cerebral Hemorrhage: While its antiplatelet effects would suggest caution, a recent meta-analysis has indicated potential benefits of NBP in treating intracerebral hemorrhage, possibly by improving local hemodynamics and reducing cerebral edema. This surprising finding warrants further dedicated research to clarify its role and safety in this setting.[63]

Table 3: Overview of Major Clinical Trials for Butylphthalide

Trial Identifier	Title/Purpose	Phase	Status	Indication(s)	Key Findings/Purpose
NCT03539445	Efficacy and Safety of Butylphthalide for Acute Ischemic Stroke Patients Receiving Intravenous Thrombolysis or Endovascular Treatment (BAST Trial)	3	Completed	Acute Ischemic Stroke	Showed NBP significantly improved 90-day functional outcomes vs. placebo.10
NCT05068349	Effectiveness and Safety of Butylphthalide in Patients With Ischemic Stroke	4	Recruiting	Ischemic Stroke, Vascular Disorders	To evaluate the effectiveness and safety of NBP in a real-world setting for various cerebrovascular conditions.64
NCT03906123	The Efficacy of DL-NBP in Patients With Mild Subcortical Ischemic Vascular Dementia	Not Available	Unknown	Subcortical Vascular Dementia	To assess the efficacy of NBP in treating mild vascular dementia.13
NCT06353334	Butylphthalide's Safety and Efficacy for Improving Neurological Function Prognosis in Patients With Cardiac Arrest (BNCA Trial)	Not Available	Not yet recruiting	Cardiac Arrest	To evaluate NBP's neuroprotective effects post-cardiac arrest.60
ChiCTR1800018362	Efficacy and safety of butylphthalide in patients with mild cognitive impairment (EBMCI study)	Not Available	Recruiting	Mild Cognitive Impairment (MCI)	To assess NBP's efficacy in improving cognitive function in MCI over 12 months.61
NCT03804229	Efficacy and Safety of Butylphthalide Soft Capsule for the Treatment of Vascular Dementia	3	Active, not recruiting	Vascular Dementia	To confirm the efficacy and safety of NBP soft capsules in patients with mild to moderate VaD.58

V. Safety, Tolerability, and Risk Profile

A comprehensive assessment of Butylphthalide's safety profile is essential for its responsible clinical use. Data from numerous clinical trials and pharmacovigilance databases provide a clear picture of its tolerability, common adverse effects, potential for drug interactions, and specific contraindications. Overall, Butylphthalide is considered to be generally well-tolerated, with a manageable side effect profile.

Adverse Events and Side Effect Profile

In large-scale clinical trials and meta-analyses, Butylphthalide has demonstrated a favorable safety profile, with the majority of reported adverse events being mild to moderate in severity.[1] The landmark BAST trial, for instance, found no significant difference in the rate of serious adverse events between the Butylphthalide group and the placebo group (10.1% vs. 12.0%).[11]

The most frequently observed adverse events associated with Butylphthalide treatment are:

• Elevated Liver Transaminases: The most common laboratory abnormality noted is a transient increase in liver enzymes (e.g., ALT, AST). The reported incidence varies widely across studies, ranging from 1.39% to as high as 17.53%. While often mild and reversible, this finding suggests that monitoring of liver function is prudent during therapy, particularly in patients with pre-existing hepatic conditions.[16]
• Gastrointestinal Discomfort: Symptoms such as nausea, vomiting, and diarrhea are among the most common patient-reported side effects. The incidence is generally low, reported in the range of 1.09% to 6.15%.[16]
• Neurological Effects: Some patients may experience headache, dizziness, or fatigue, which are generally mild and may be related to the drug's effects on the central nervous system.[17]
• Dermatological and Allergic Reactions: Skin rash is an infrequent adverse event, with an incidence reported between 0% and 1.96%.[16] More generalized allergic reactions, such as itching or swelling, are considered rare but possible.[17]

Drug-Drug Interactions

The primary and most clinically significant drug-drug interactions involving Butylphthalide are pharmacodynamic in nature and stem directly from its therapeutic mechanism of action. As a compound with inherent antiplatelet and anti-thrombotic properties, its co-administration with other drugs that affect hemostasis can lead to a synergistic or additive effect, thereby increasing the risk of bleeding. This is not an unexpected off-target effect but a predictable consequence of its intended pharmacology. The clinical implication is that while Butylphthalide can be used alongside other antithrombotic agents—as was done in the BAST trial where patients received reperfusion therapies—it necessitates heightened clinical vigilance for signs of bleeding.

The DrugBank database provides an extensive list of potential interactions, the vast majority of which are related to an increased risk of bleeding.[6] A summary of the most critical interactions is presented in the table below.

Table 4: Clinically Significant Drug Interactions with Butylphthalide

Interacting Drug/Class	Nature of Interaction	Clinical Recommendation
Antiplatelet Agents (e.g., Acetylsalicylic acid, Clopidogrel, Cilostazol, Anagrelide, Ticlopidine)	Increased antiplatelet activity; increased risk of bleeding.	Use with caution. Monitor closely for signs of bleeding, such as bruising, petechiae, or gastrointestinal hemorrhage.
Anticoagulants (e.g., Warfarin, Acenocoumarol, Apixaban, Rivaroxaban, Dabigatran)	Increased anticoagulant activity; significantly increased risk of bleeding.	Co-administration requires careful risk assessment and intensive monitoring. Monitor coagulation parameters (e.g., INR) and for any signs of hemorrhage.
Thrombolytic Agents (e.g., Alteplase, Reteplase, Tenecteplase)	Synergistic effect on fibrinolysis; significantly increased risk of bleeding, including intracranial hemorrhage.	Use in combination only under expert supervision in an acute care setting, as in post-thrombolysis stroke protocols.
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) (e.g., Aceclofenac, Diclofenac, Ibuprofen)	Increased risk of bleeding, particularly gastrointestinal bleeding, due to combined antiplatelet effects.	Avoid long-term concurrent use if possible. Advise patients to monitor for signs of GI bleeding.
Selective Serotonin Reuptake Inhibitors (SSRIs) (e.g., Citalopram, Desvenlafaxine)	SSRIs can impair platelet function; combined use may increase bleeding risk.	Use with caution and monitor for signs of abnormal bleeding.
Certain Chemotherapeutic Agents (e.g., Carmustine, Dacarbazine, Bendamustine)	Increased risk of bleeding due to drug-induced thrombocytopenia or direct effects on coagulation.	Monitor platelet counts and for signs of bleeding when used concomitantly.
Bile Acids (e.g., Cholic Acid, Deoxycholic acid)	The risk or severity of adverse effects can be increased.	Monitor for increased side effects.

Contraindications, Warnings, and Precautions

Based on its pharmacological profile and data from clinical trial exclusion criteria, several contraindications and warnings are in place for the use of Butylphthalide:

• Contraindications:
• Known hypersensitivity or allergy to Butylphthalide, its components, or to celery.[17]
• Pregnancy and lactation, due to a lack of safety data in these populations.[66]
• Warnings and Precautions:
• Bleeding Risk: Use with extreme caution in patients with a history of hemorrhagic diseases (e.g., intracranial hemorrhage), active bleeding, or known coagulation disorders.[11]
• Hepatic Impairment: Caution is advised in patients with severe liver dysfunction (e.g., alanine transaminase levels greater than three times the upper limit of normal), as the drug is extensively metabolized by the liver and impairment could lead to increased drug exposure and toxicity.[11]
• Renal Impairment: Use with caution in patients with severe kidney dysfunction (e.g., serum creatinine greater than two times the upper limit of normal), as renal excretion is the primary route of elimination for its metabolites.[11]
• Thrombocytopenia: Caution is warranted in patients with low platelet counts (e.g., <100x10⁹/L), as the drug's antiplatelet effect could exacerbate bleeding risk.[54]

Toxicological Data

Preclinical toxicology studies provide additional safety information. In animal models, Butylphthalide has a relatively low acute toxicity, with a reported oral median lethal dose (LD50) of 2,450 mg/kg in rats.[27] In hazard identification studies, it is classified as an irritant to the skin and eyes.[25]

VI. Regulatory and Commercial Landscape

The regulatory and commercial status of Butylphthalide is unique, reflecting its development path from a compound identified in traditional Chinese medicine to a modern pharmaceutical. Its market presence is currently concentrated in China, while its journey toward approval in Western markets is ongoing, marked by specific strategic designations and clinical trial programs.

Global Regulatory Status

The approval status of Butylphthalide varies significantly by region, highlighting different regulatory pathways and evidence requirements.

• China (NMPA): Butylphthalide is a fully approved and widely used medication in China. It received its initial approval from the China Food and Drug Administration (CFDA), now the National Medical Products Administration (NMPA), in 2002 for the treatment of ischemic stroke.[1] It is available by prescription in two primary formulations: an intravenous injection for acute hospital use and oral soft capsules for continued therapy.[31]
• United States (FDA): In the United States, Butylphthalide is an investigational drug and is not approved for marketing for any indication.[15] However, it has achieved two important regulatory milestones that support its continued development:

1. Orphan Drug Designation: On February 28, 2018, the FDA granted Orphan Drug Designation to DL-3-n-butylphthalide for the treatment of Amyotrophic Lateral Sclerosis (ALS).[15] This status provides incentives, such as tax credits and market exclusivity, to encourage the development of drugs for rare diseases.
2. Clinical Trials: The drug has been evaluated in FDA-regulated clinical trials. A Phase 2 trial (NCT02905565) assessing the safety and pharmacokinetics of NBP softgel capsules in patients with acute ischemic stroke was completed in August 2020.[72] The sponsoring company has also reported that a Phase 3 clinical trial for the soft capsules is underway in the US.[74]

• Europe (EMA): Butylphthalide is not approved for use in the European Union. A search of the European Medicines Agency's (EMA) database of centrally authorized products does not yield any results for the compound, nor is there evidence of its approval through national procedures in member states.[18] Its path to the European market would require a formal marketing authorization application supported by clinical trial data that meets EMA standards.

Commercialization and Manufacturing

The development, manufacturing, and commercialization of pharmaceutical-grade Butylphthalide are led by a single key entity, with a broader network of suppliers providing the compound for research purposes.

• Primary Developer and Manufacturer: The originator and primary global manufacturer of Butylphthalide is CSPC NBP Pharmaceutical Co., Ltd., a subsidiary of the CSPC Pharmaceutical Group, a major pharmaceutical enterprise based in China.[15] This company holds the key intellectual property, including numerous domestic and international patents, and is responsible for the production of the approved drug products.[74]
• Brand Names and Formulations: The drug is marketed by CSPC under the brand name NBP. It is also referred to by the trade name En Bi Pu.[23] The two main commercial formulations are:

1. NBP Soft Capsule: An oral formulation containing 100 mg of Butylphthalide per capsule.[31]
2. NBP Injection: An intravenous formulation supplied as a 100 mL vial containing 25 mg of Butylphthalide in sodium chloride solution.[31]

• Research-Grade Suppliers: For non-clinical and research applications, Butylphthalide is available from a variety of global chemical and life science supply companies. These include, but are not limited to, Sigma-Aldrich, Cayman Chemical, MedKoo, ChemFaces, and BioCrick.[1] Additionally, companies such as Manus Aktteva Biopharma in India are listed as global suppliers of the active pharmaceutical ingredient (API) for research and development purposes.[81]

VII. Synthesis and Future Directions

Butylphthalide has successfully transitioned from a natural product isolate to a clinically validated neuroprotective agent with a well-defined role in modern medicine. Its journey provides a compelling case study in drug development, and its future trajectory points toward an expanding role in the management of complex neurological diseases. This concluding section synthesizes the key findings of this report, offers an expert perspective on its current standing, and outlines promising directions for future research and clinical application.

Integrated Analysis and Expert Perspective

The cumulative evidence establishes Butylphthalide as a significant therapeutic agent, particularly in the context of acute ischemic stroke. Its approval and widespread use in China are supported by a robust foundation of clinical data, culminating in the high-quality evidence from the BAST trial. This trial's success is particularly noteworthy; in a field where dozens of neuroprotective agents have failed to show efficacy in rigorous clinical testing, Butylphthalide demonstrated a clear and significant improvement in functional outcomes when added to the best available standard of care, including thrombolysis and endovascular thrombectomy.

The key to its success likely lies in its multi-target mechanism of action. Ischemic brain injury is not a linear process but a complex cascade involving vascular collapse, energy failure, oxidative stress, inflammation, and programmed cell death. By simultaneously intervening in these interconnected pathways—improving microcirculation, preserving mitochondrial function, and providing antioxidant and anti-inflammatory effects—Butylphthalide offers a more comprehensive protective strategy than agents focused on a single molecular target.

Its safety profile is well-characterized and acceptable. The primary risk, an increased propensity for bleeding, is a predictable and manageable consequence of its therapeutic antiplatelet activity. Clinicians can mitigate this risk through careful patient selection and monitoring, particularly when Butylphthalide is used in combination with other antithrombotic drugs. The observed elevations in liver enzymes warrant routine monitoring but have not been associated with severe hepatotoxicity in major trials.

Emerging Research and Future Therapeutic Potential

While its role in acute stroke is established, the most exciting prospects for Butylphthalide lie in its potential to address other unmet needs in neurology. The current research landscape suggests a clear trajectory of expansion:

• Beyond Acute Stroke: The focus is shifting from solely treating the acute event to managing its long-term consequences and preventing recurrence. Ongoing and recently completed studies on its use in secondary stroke prevention and for treating post-stroke cognitive impairment (PSCI) and vascular dementia (VaD) are critical.[5] If positive, these findings could position Butylphthalide as a foundational chronic therapy for patients recovering from cerebrovascular events, aimed at preserving long-term cognitive health.
• Neurodegenerative Diseases: The mechanistic overlap between ischemic injury and chronic neurodegeneration—specifically the roles of mitochondrial dysfunction, oxidative stress, and neuroinflammation—provides a strong rationale for exploring Butylphthalide in these conditions. The FDA's Orphan Drug Designation for ALS is a significant validation of this potential.[5] Furthermore, the ongoing trial in Mild Cognitive Impairment (MCI) could establish a role for Butylphthalide in the early stages of the Alzheimer's disease continuum, a major area of unmet medical need.
• Novel Indications: Early-stage research is exploring entirely new applications. The investigation into its use for neuroprotection after cardiac arrest could extend its utility to another common cause of hypoxic-ischemic brain injury.[60] The preliminary findings in cerebral hemorrhage are counterintuitive but intriguing, and if validated, could dramatically reshape its clinical use.[63]
• Pharmaceutical Innovation: Future development will also likely involve pharmaceutical science. Advanced drug delivery systems, such as nanoformulations, are being explored to overcome the bioavailability challenges of this lipophilic compound and potentially enhance its brain penetration and efficacy.[30] In parallel, innovations in manufacturing, such as the adoption of greener and more efficient synthetic methods, will be crucial for ensuring a sustainable and cost-effective supply as its global demand potentially increases.[83]

Recommendations for Clinical Practice and Future Research

Based on the available evidence, the following recommendations can be made:

• For Clinical Practice:

1. Clinicians treating acute ischemic stroke, particularly in regions where the drug is approved, should recognize the strong evidence supporting the use of Butylphthalide as an adjunctive therapy to standard reperfusion treatments.
2. A high degree of vigilance is required for its primary safety risk: bleeding. A careful assessment of a patient's baseline bleeding risk and concurrent medications (especially anticoagulants, antiplatelets, and NSAIDs) is mandatory.
3. Routine monitoring of liver function tests is a prudent measure during the course of therapy.

• For Future Research:

1. Global Registration Trials: To make Butylphthalide accessible to patients worldwide, large-scale, multinational randomized controlled trials are needed. These studies should be designed to replicate the findings of the BAST trial in diverse patient populations to support marketing authorization applications to the US FDA and the EMA.
2. Long-Term Cognitive and Prevention Studies: The completion and publication of ongoing Phase 3 trials in vascular dementia and MCI are of high priority. Additionally, further research is needed to define the optimal duration of therapy for secondary stroke prevention and to establish its long-term impact on cognitive decline.
3. Translational and Mechanistic Studies: Further translational research is warranted to elucidate the precise contribution of Butylphthalide's active metabolites to its overall clinical effect. A deeper understanding of its PK/PD relationship, including the role of the metabolites, could lead to more personalized dosing strategies and the development of next-generation compounds.

In summary, Butylphthalide stands as a clinically proven neuroprotective agent with a bright future. Continued rigorous research and clinical development have the potential to expand its indications, solidify its place in the therapeutic armamentarium, and offer new hope for patients with a wide range of devastating neurological disorders.

Works cited

1. Butylphthalide | CAS#6066-49-5 | antioxidant - MedKoo Biosciences, accessed September 23, 2025, https://www.medkoo.com/products/7807
2. Butylphthalide - TargetMol, accessed September 23, 2025, https://www.targetmol.com/compound/butylphthalide
3. Butylphthalide - Wikipedia, accessed September 23, 2025, https://en.wikipedia.org/wiki/Butylphthalide
4. Research progress on pharmacology of butylphthalide and its derivatives - ResearchGate, accessed September 23, 2025, https://www.researchgate.net/publication/362124520_Research_progress_on_pharmacology_of_butylphthalide_and_its_derivatives
5. Application and prospects of butylphthalide for the treatment of neurologic diseases - PMC, accessed September 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6629339/
6. Butylphthalide: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 23, 2025, https://go.drugbank.com/drugs/DB12749
7. Dl-NBP (Dl-3-N-Butylphthalide) Treatment Promotes Neurological Functional Recovery Accompanied by the Upregulation of White Matter Integrity and HIF-1α/VEGF/Notch/Dll4 Expression - PMC, accessed September 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6993069/
8. A Study to Decipher the Potential Effects of Butylphthalide against Central Nervous System Diseases Based on Network Pharmacology and Molecular Docking Integration Strategy - PMC, accessed September 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8116153/
9. Dl-3-n-Butylphthalide (NBP)：A Promising Therapeutic Agent for Ischemic Stroke, accessed September 23, 2025, https://www.researchgate.net/publication/325741224_Dl-3-n-Butylphthalide_NBPA_Promising_Therapeutic_Agent_for_Ischemic_Stroke
10. Butylphthalide Completed Phase 3 Trials for Acute Ischemic Stroke Treatment - DrugBank, accessed September 23, 2025, https://go.drugbank.com/drugs/DB12749/clinical_trials?conditions=DBCOND0030034&phase=3&purpose=treatment&status=completed
11. Butylphthalide is an effective and safe neuroprotective agent for acute ischemic stroke– the BAST trial | 2 Minute Medicine, accessed September 23, 2025, https://www.2minutemedicine.com/butylphthalide-is-an-effective-and-safe-neuroprotective-agent-for-acute-ischemic-stroke-the-bast-trial/
12. Efficacy and Safety of Butylphthalide in Patients With Acute Ischemic Stroke: A Randomized Clinical Trial - PubMed, accessed September 23, 2025, https://pubmed.ncbi.nlm.nih.gov/37358859/
13. Subcortical Vascular Dementia Unknown Status Phase Trials for Butylphthalide (DB12749), accessed September 23, 2025, https://go.drugbank.com/indications/DBCOND0054605/clinical_trials/DB12749?phase=&status=unknown_status
14. Dl-3-n-Butylphthalide Alleviates Secondary Brain Damage and Improves Working Memory After Stroke in Cynomolgus Monkeys - AHA Journals, accessed September 23, 2025, https://www.ahajournals.org/doi/abs/10.1161/STROKEAHA.123.045037
15. Search Orphan Drug Designations and Approvals - FDA, accessed September 23, 2025, https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=623217
16. DL-3-n-butylphthalide for acute ischemic stroke: An updated systematic review and meta-analysis of randomized controlled trials - Frontiers, accessed September 23, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.963118/full
17. What is Butylphthalide used for? - Patsnap Synapse, accessed September 23, 2025, https://synapse.patsnap.com/article/what-is-butylphthalide-used-for
18. European Medicines Agency (EMA), accessed September 23, 2025, https://www.ema.europa.eu/en/medicines
19. Butylphthalide | C12H14O2 | CID 61361 - PubChem, accessed September 23, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Butylphthalide
20. Butylphthalide | C12H14O2 - ChemSpider, accessed September 23, 2025, https://www.chemspider.com/Chemical-Structure.55293.html
21. Butylphthalide - CAS Common Chemistry, accessed September 23, 2025, https://commonchemistry.cas.org/detail?cas_rn=6066-49-5
22. 3-n-Butylphthalide | CAS 6066-49-5 | SCBT - Santa Cruz Biotechnology, accessed September 23, 2025, https://www.scbt.com/p/3-n-butylphthalide-6066-49-5
23. Butylphthalide - CSPC Ouyi Pharmaceutical - AdisInsight - Springer, accessed September 23, 2025, https://adisinsight.springer.com/drugs/800044275
24. Butylphthalide 6066-49-5 wiki - Guidechem, accessed September 23, 2025, https://wap.guidechem.com/encyclopedia/3-n-butylphthalide-dic418736.html
25. 3-N-Butylphthalide = 98 HPLC 6066-49-5 - Sigma-Aldrich, accessed September 23, 2025, https://www.sigmaaldrich.com/US/en/product/sigma/smb00312
26. 3-N-Butylphthalide | 6066-49-5 - ChemicalBook, accessed September 23, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB5174179.htm
27. Safety Data Sheet - Cayman Chemical, accessed September 23, 2025, https://cdn.caymanchem.com/cdn/msds/30284m.pdf
28. PRODUCT INFORMATION - Cayman Chemical, accessed September 23, 2025, https://cdn.caymanchem.com/cdn/insert/30284.pdf
29. Application and prospects of butylphthalide for the treatment of ..., accessed September 23, 2025, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629339/
30. Full article: Rapid and improved oral absorption of N-butylphthalide by sodium cholate-appended liposomes for efficient ischemic stroke therapy - Taylor & Francis Online, accessed September 23, 2025, https://www.tandfonline.com/doi/full/10.1080/10717544.2021.2000678
31. Products > Innovative Drugs - CSPC Pharmaceutical Group Limited, accessed September 23, 2025, https://www.cspc.com.hk/en/products/innovative.php
32. DL-3-n-butylphthalide (NBP) alleviates poststroke cognitive impairment (PSCI) by suppressing neuroinflammation and oxidative stress - Frontiers, accessed September 23, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.987293/full
33. What is the mechanism of Butylphthalide? - Patsnap Synapse, accessed September 23, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-butylphthalide
34. Efficacy and safety of butylphthalide in secondary prevention of stroke: study protocol for a multicenter, real world, accessed September 23, 2025, https://d-nb.info/127222001X/34
35. 3-n-butylphthalide exerts neuroprotective effects by enhancing anti-ox - Dove Medical Press, accessed September 23, 2025, https://www.dovepress.com/3-n-butylphthalide-exerts-neuroprotective-effects-by-enhancing-anti-ox-peer-reviewed-fulltext-article-DDDT
36. Dl-3-n-butylphthalide attenuates cerebral ischemia/reperfusion injury in mice through AMPK-mediated mitochondrial fusion - Frontiers, accessed September 23, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1357953/full
37. A Brief Discussion of Mechanism of Butylphthalide in Treatment of Ischemic Cerebrovascular Disease and its Potential Clinical Applicationin Treatment of Multiple Sclerosis - MedCrave online, accessed September 23, 2025, https://medcraveonline.com/JCCR/a-brief-discussion-of-mechanism-of-butylphthalide-in-treatment-of-ischemic-cerebrovascular-disease-and-its-potential-clinical-applicationin-treatment-of-multiple-sclerosis.html
38. Neuroprotective mechanisms of 3‑n‑butylphthalide in neurodegenerative diseases (Review) - Semantic Scholar, accessed September 23, 2025, https://pdfs.semanticscholar.org/dfe1/10f109f1d198ba11e95b97ad4898fbabaca4.pdf
39. Neuroprotective mechanisms of 3-n-butylphthalide in neurodegenerative diseases - PMC, accessed September 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6873419/
40. Dl‑3n‑butylphthalide improves spatial learning and memory in rats with vascular dementia by reducing autophagy via regulation of the mTOR signaling pathway - Spandidos Publications, accessed September 23, 2025, https://www.spandidos-publications.com/10.3892/etm.2019.8402
41. Butylphthalide Combined With Conventional Treatment Attenuates MMP-9 Levels and Increases VEGF Levels in Patients With Stroke: A - Frontiers, accessed September 23, 2025, https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2021.686199/pdf
42. Pharmacokinetics, safety and tolerability of L-3-ν-butylphthalide tablet after single and multiple oral administrations in heal - SciELO, accessed September 23, 2025, https://www.scielo.br/j/bjps/a/L3HBWLmH6yXynhFyhyRPQ4q/?format=pdf&lang=en
43. (PDF) 3‐n‐Butylphthalide - ResearchGate, accessed September 23, 2025, https://www.researchgate.net/publication/316168877_3-n-Butylphthalide
44. (PDF) Metabolism and Pharmacokinetics of 3-n-Butylphthalide (NBP) in Humans: The Role of Cytochrome P450s and Alcohol Dehydrogenase in Biotransformation - ResearchGate, accessed September 23, 2025, https://www.researchgate.net/publication/233738566_Metabolism_and_Pharmacokinetics_of_3-n-Butylphthalide_NBP_in_Humans_The_Role_of_Cytochrome_P450s_and_Alcohol_Dehydrogenase_in_Biotransformation
45. Antibiotics affect the pharmacokinetics of n-butylphthalide in vivo by altering the intestinal microbiota | PLOS One - Research journals, accessed September 23, 2025, https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0297713
46. Pharmacokinetics, safety and tolerability of L-3-n-butylphthalide tablet after single and multiple oral administrations in healthy Chinese volunteers - SciELO, accessed September 23, 2025, https://www.scielo.br/j/bjps/a/L3HBWLmH6yXynhFyhyRPQ4q/?lang=en
47. Efficacy and safety of butylphthalide in secondary prevention of stroke: study protocol for a multicenter, real world trial based on Internet - PMC, accessed September 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9389750/
48. Ninety-day administration of dl-3-n-butylphthalide for acute ischemic stroke: A randomized, double-blind trial | Request PDF - ResearchGate, accessed September 23, 2025, https://www.researchgate.net/publication/256608854_Ninety-day_administration_of_dl-3-n-butylphthalide_for_acute_ischemic_stroke_A_randomized_double-blind_trial
49. Efficacy and safety of butylphthalide for patients who had acute ..., accessed September 23, 2025, https://bmjopen.bmj.com/content/11/5/e045559
50. Butylphthalide is an effective and safe neuroprotective agent for acute ischemic stroke– the BAST trial | 2 Minute Medicine | AccessObGyn, accessed September 23, 2025, https://obgyn.mhmedical.com/updatesContent.aspx?gbosId=628303
51. Effectiveness of butylphthalide on cerebral autoregulation in ischemic stroke patients with large artery atherosclerosis (EBCAS study): A randomized, controlled, multicenter trial - PubMed Central, accessed September 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10581234/
52. Efficacy and safety of 3‐n‐butylphthalide combined with endovascular treatment in acute ischemic stroke due to large vessel occlusion - PMC, accessed September 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9627349/
53. Efficacy of butylphthalide in preventing cognitive decline in ischaemic stroke survivors: a 12-month prospective following-up study, accessed September 23, 2025, https://svn.bmj.com/content/early/2025/01/24/svn-2024-003611
54. Long-Term Benefits of N-Butylphthalide in Preventing Ischemic Stroke R | TCRM, accessed September 23, 2025, https://www.dovepress.com/long-term-benefits-of-n-butylphthalide-in-preventing-ischemic-stroke-r-peer-reviewed-fulltext-article-TCRM
55. Efficacy of butylphthalide soft capsules in patients with vascular dementia and the relevant antioxidative mechanism - e-Century Publishing Corporation, accessed September 23, 2025, https://e-century.us/files/ijcem/12/7/ijcem0089329.pdf
56. Butylphthalide combined with donepezil for the treatment of vascular dementia: a meta-analysis - PMC, accessed September 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10981252/
57. Efficacy and Safety of DL-3-n-Butylphthalide in the Treatment of Poststroke Cognitive Impairment: A Systematic Review and Meta-Analysis - Frontiers, accessed September 23, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.810297/full
58. Efficacy and Safety of Butylphthalide Soft Capsule for the Treatment of Vascular Dementia | Clinical Research Trial Listing - CenterWatch, accessed September 23, 2025, https://www.centerwatch.com/clinical-trials/listings/NCT03804229/efficacy-and-safety-of-butylphthalide-soft-capsule-for-the-treatment-of-vascular-dementia
59. BUTYLPHTHALIDE - precisionFDA, accessed September 23, 2025, https://precision.fda.gov/ginas/app/ui/substances/803d541b-26bb-44ed-9c2b-488f2781444d
60. Study Details | Butylphthalide's Safety and Efficacy for Improving Neurological Function Prognosis in Patients With Cardiac Arrest (BNCA Trial) | ClinicalTrials.gov, accessed September 23, 2025, https://clinicaltrials.gov/study/NCT06353334
61. Efficacy and safety of butylphthalide in patients with mild cognitive impairment: a multicentre, randomised, double-blind, placebo-controlled trial (EBMCI study) - PubMed, accessed September 23, 2025, https://pubmed.ncbi.nlm.nih.gov/39002963/
62. Efficacy and safety of butylphthalide in patients with mild cognitive impairment: a multicentre, randomised, double-blind, placebo-controlled trial (EBMCI study) | BMJ Open, accessed September 23, 2025, https://bmjopen.bmj.com/content/14/7/e082404
63. Effects of Dl-3-n-butylphthalide on neurological function, hemodynamics and Hcy concentration in cerebral hemorrhage: a systematic review and meta-analysis - Frontiers, accessed September 23, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1360932/full
64. Butylphthalide Recruiting Phase 4 Trials for Vascular Disorders / Infarction Cerebral / Central Nervous System Disorder / Infarction, Brain / Nervous System Diseases / Stroke / Cerebral Ischemia Treatment - DrugBank, accessed September 23, 2025, https://go.drugbank.com/drugs/DB12749/clinical_trials?conditions=DBCOND0038937%2CDBCOND0031659%2CDBCOND0158720%2CDBCOND0125631%2CDBCOND0028057%2CDBCOND0020609%2CDBCOND0059255&phase=4&purpose=treatment&status=recruiting
65. What are the side effects of Butylphthalide? - Patsnap Synapse, accessed September 23, 2025, https://synapse.patsnap.com/article/what-are-the-side-effects-of-butylphthalide
66. Celery Uses, Benefits & Dosage - Drugs.com, accessed September 23, 2025, https://www.drugs.com/npp/celery.html
67. Efficacy and safety of 3‐n‐butylphthalide for the treatment of cognitive impairment: A systematic review and meta‐analysis, accessed September 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9532910/
68. pmc.ncbi.nlm.nih.gov, accessed September 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9532910/#:~:text=Of%20these%2C%20five%20studies%2014,%3D%200.31%3B%20Figure%206C)..&sa=D&source=editors&ust=1758626266091947&usg=AOvVaw3fS-qdYWa6hXwIe3M2AE3y)
69. Efficacy and safety of butylphthalide for patients who had acute ischaemic stroke receiving intravenous thrombolysis or endovascular treatment (BAST trial): study protocol for a randomised placebo-controlled trial - PMC, accessed September 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8154958/
70. Investigation of the Impact Factors and Efficacy of N-Butylphthalide (NBP) on Functional Outcomes Following Mechanical Thrombectomy in Stroke Patients - PMC, accessed September 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11895694/
71. butylphthalide - Drug Central, accessed September 23, 2025, https://drugcentral.org/drugcard/5257
72. Study Details | NCT02905565 | NBP in Adult Patients With Acute Ischemic Stroke (AIS), accessed September 23, 2025, https://www.clinicaltrials.gov/study/NCT02905565
73. Study Details | NCT02905565 | NBP in Adult Patients With Acute Ischemic Stroke (AIS), accessed September 23, 2025, https://clinicaltrials.gov/study/NCT02905565
74. CSPC NBP PHARMACEUTICAL CO., LTD., accessed September 23, 2025, https://en.e-cspc.com/our-members/cspc-nbp-pharmaceutical-co-ltd.html
75. DL-3-n-butylphthalide for acute ischemic stroke: An updated systematic review and meta-analysis of randomized controlled trials - PubMed, accessed September 23, 2025, https://pubmed.ncbi.nlm.nih.gov/36120291/
76. EMA's CHMP Recommends 13 New Medicines for Approval - BioPharm International, accessed September 23, 2025, https://www.biopharminternational.com/view/ema-s-chmp-recommends-13-new-medicines-approval-0
77. National registers of authorised medicines | European Medicines Agency (EMA), accessed September 23, 2025, https://www.ema.europa.eu/en/medicines/national-registers-authorised-medicines
78. CSPC Pharmaceutical Group - Wikipedia, accessed September 23, 2025, https://en.wikipedia.org/wiki/CSPC_Pharmaceutical_Group
79. 3-n-Butylphthalide | CAS:6066-49-5 | Manufacturer ChemFaces, accessed September 23, 2025, https://www.chemfaces.com/natural/3-n-Butylphthalide-CFN90235.html
80. 3-n-Butylphthalide | CAS:6066-49-5 | Miscellaneous | High Purity | Manufacturer BioCrick, accessed September 23, 2025, https://www.biocrick.com/3-n-Butylphthalide-BCN2381.html
81. Butylphthalide (CAS No.: 6066-49-5) - Manus Aktteva Biopharma LLP, accessed September 23, 2025, https://www.manusaktteva.com/api/Butylphthalide
82. Application and prospects of butylphthalide for the treatment of neurologic diseases | Chinese Medical Journal - MedNexus, accessed September 23, 2025, https://mednexus.org/doi/abs/10.1097/CM9.0000000000000289
83. Dl-3-N-Butylphthalide Market Size & Share 2025-2030, accessed September 23, 2025, https://www.360iresearch.com/library/intelligence/dl-3-n-butylphthalide