Nafamostat: A Comprehensive Monograph on a Multifaceted Serine Protease Inhibitor with a Uniquely Constrained Pharmacokinetic Profile

1.0 Executive Summary

Nafamostat is a synthetic, broad-spectrum serine protease inhibitor characterized by a significant dichotomy: its profound and wide-ranging biochemical potency is sharply constrained by an ultrashort biological half-life. This pharmacokinetic profile is not a limitation but rather the defining feature that dictates its clinical utility, safety profile, and the challenges associated with expanding its therapeutic applications. For over three decades, Nafamostat has been a standard-of-care agent in Japan and South Korea for the management of acute pancreatitis, disseminated intravascular coagulation (DIC), and, most notably, as a regional anticoagulant for extracorporeal circuits such as those used in hemodialysis and continuous renal replacement therapy (CRRT). In this latter role, its rapid enzymatic hydrolysis in the bloodstream is a distinct advantage, localizing its potent anticoagulant effects to the external circuit and minimizing the risk of systemic hemorrhage compared to conventional anticoagulants like heparin.

Despite this established niche, Nafamostat's broader potential has been largely unfulfilled. Its powerful anti-inflammatory, antithrombotic, and neuroprotective properties, demonstrated in preclinical models, have not translated into approved systemic therapies. The investigation of Nafamostat as a repurposed drug for COVID-19 serves as a critical case study. Despite exhibiting one of the most potent in vitro antiviral activities against SARS-CoV-2 by inhibiting the host protease TMPRSS2, clinical trials yielded inconclusive or negative results. This disconnect is primarily attributable to its pharmacokinetic limitations; the intravenously administered drug is likely cleared from circulation before it can achieve sustained, therapeutic concentrations in target tissues like the lungs.

The safety profile of Nafamostat is favorable in the context of bleeding risk but is associated with rare but serious adverse events, including hyperkalemia, anaphylaxis, and agranulocytosis, which require careful clinical monitoring. Its drug interaction profile is dominated by pharmacodynamic concerns, particularly with other agents affecting hemostasis. This report provides a comprehensive analysis of Nafamostat, detailing its chemical properties, complex pharmacology, and the pivotal role of its pharmacokinetics. It concludes that Nafamostat is a highly effective therapeutic for a narrow range of acute, localized conditions and that its future in systemic disease depends entirely on overcoming its inherent instability through innovative formulation science and drug delivery technologies.

2.0 Introduction and Historical Context

The development and clinical integration of Nafamostat are rooted in the specific therapeutic challenges and pharmaceutical research priorities of Japan in the latter half of the 20th century. Its history reveals a drug engineered for acute, hospital-based interventions where rapid, potent, and highly controllable protease inhibition is paramount.

2.1 Synthesis and Early Development

Nafamostat, known initially by its developmental code FUT-175, was first synthesized by Fujii and colleagues in Japan in the early 1980s.[1] It was designed as a synthetic, small-molecule, broad-spectrum inhibitor of serine proteases, a class of enzymes central to numerous physiological and pathological processes, including digestion, blood coagulation, and inflammation.

2.2 First Market Approval and Indication Expansion

Following its development, Nafamostat was brought to the Japanese market by Japan Tobacco in 1986.[2] The initial regulatory approval was for the treatment of acute inflammatory conditions, specifically acute pancreatitis.[2] This indication was based on the drug's potent ability to inhibit trypsin, a pancreatic serine protease whose premature activation within the pancreas is a key trigger in the pathophysiology of the disease.

The clinical utility of Nafamostat was quickly recognized to extend beyond pancreatitis. In 1989, its approval in Japan was expanded to include two critical hematological conditions: disseminated intravascular coagulation (DIC) and its use as an anticoagulant during hemodialysis.[3] This established the dual therapeutic identity of Nafamostat, positioning it as a vital agent for managing both uncontrolled inflammation and dysregulated coagulation.

2.3 Geographically Constrained Clinical Use

For more than three decades, the clinical application of Nafamostat has been largely confined to a few Asian countries, with Japan and South Korea being the primary markets where it is considered a standard-of-care agent for its approved indications.[5] This geographically concentrated history of use has provided a deep reservoir of real-world clinical data on its efficacy and safety, albeit within a specific patient population and healthcare context. The drug's development trajectory, originating from a need to manage acute, life-threatening hospital-based conditions, fundamentally shaped its formulation as an intravenous agent with a short, controllable duration of action, a characteristic that continues to define its clinical profile today.

3.0 Chemical and Physical Properties

A precise understanding of Nafamostat's chemical and physical characteristics is fundamental to appreciating its formulation, mechanism of action, and inherent instability. As a basic compound, it is almost exclusively formulated as a salt to enhance its aqueous solubility and stability for clinical use.

3.1 Nomenclature and Identifiers

Nafamostat is identified by a variety of chemical names and registry numbers, which can differ based on whether the reference is to the free base or one of its salt forms.

• Drug Name: Nafamostat
• DrugBank ID: DB12598
• Type: Small Molecule
• Synonyms: Nafamostatum, FUT-175, 6-Amidino-2-naphthyl 4-guanidinobenzoate, p-Guanidinobenzoic acid ester with 6-hydroxy-2-naphthamidine.[5]

3.2 Chemical Structure and Salt Forms

The parent molecule, Nafamostat free base, is an ester composed of a guanidinobenzoate group and an amidino-naphthol group. Due to its basic nature, it is formulated with acids to form salts suitable for intravenous administration.[5]

• Nafamostat (Free Base):
• CAS Number: 81525-10-2 [9]
• Molecular Formula: C19​H17​N5​O2​ [11]
• Molecular Weight: 347.37 g/mol [11]
• IUPAC Name: (6-carbamimidoylnaphthalen-2-yl) 4-(diaminomethylideneamino)benzoate [9]
• Nafamostat Mesylate (Dimethanesulfonate): This is the most common salt form used in clinical practice and research.
• CAS Number: 82956-11-4 [10]
• Molecular Formula: C21​H25​N5​O8​S2​ (or C19​H17​N5​O2​⋅2CH4​O3​S) [10]
• Molecular Weight: 539.58 g/mol [10]
• Nafamostat Hydrochloride: Another salt form, though less commonly referenced.
• CAS Number: 80251-32-7 [10]

3.3 Physical and Chemical Properties

Nafamostat mesylate is a solid powder with specific solubility characteristics that dictate its preparation for clinical use.

• Appearance: Crystalline solid powder.[11]
• Solubility: The mesylate salt is soluble in water (up to 25 mg/mL) and Dimethyl sulfoxide (DMSO) (up to 50 mg/mL). It is sparingly soluble in aqueous buffers unless first dissolved in DMSO.[11]
• Storage and Stability: For long-term preservation, the powder is stored at -20°C. Aqueous solutions are unstable and are not recommended for storage for more than one day.[11]

The distinction between the free base and its salt forms is critical, as the molecular weight and formula differ substantially, impacting dosage calculations and experimental concentrations. The following table provides a consolidated reference for these key identifiers.

Table 1: Chemical and Physical Identifiers of Nafamostat and its Mesylate Salt

Property	Nafamostat (Free Base)	Nafamostat Mesylate	Source(s)
CAS Number	81525-10-2	82956-11-4	9
Molecular Formula	C19​H17​N5​O2​	C19​H17​N5​O2​⋅2CH3​SO3​H	11
Molecular Weight	347.37 g/mol	539.58 g/mol	10
IUPAC Name	(6-carbamimidoylnaphthalen-2-yl) 4-(diaminomethylideneamino)benzoate	6-Amidino-2-naphthyl 4-guanidinobenzoate dimethanesulfonate	10
SMILES	C1=CC(=CC=C1C(=O)OC2=CC3=C(C=C2)C=C(C=C3)C(=N)N)N=C(N)N	CS(=O)(=O)O.CS(=O)(=O)O.NC(=N)c1ccc2cc(OC(=O)c3ccc(N=C(N)N)cc3)c(C)cc2c1 (Representative)	11
InChIKey	MQQNFDZXWVTQEH-UHFFFAOYSA-N	SRXKIZXIRHMPFW-UHFFFAOYSA-N	10
Solubility	10 mM in DMSO	Soluble in Water (25 mg/mL), DMSO (50 mg/mL)	11

4.0 Pharmacology: A Detailed Examination of Mechanism of Action

Nafamostat's diverse therapeutic effects are derived from its function as a potent, broad-spectrum inhibitor of serine proteases. Its mechanism is not merely one of simple competitive inhibition; rather, it acts as a slow tight-binding substrate, a mode of action that results in highly effective and sustained inactivation of its target enzymes. This broad inhibitory profile allows it to modulate several critical physiological and pathological cascades simultaneously.

4.1 Core Inhibitory Mechanism

Nafamostat functions by mimicking the natural peptide substrates of serine proteases that cleave after lysine or arginine residues.[9] It binds to the enzyme's active site, where the catalytic serine residue (Ser195) attacks the ester bond of Nafamostat. This process forms a stable, covalent acyl-enzyme intermediate.[9] While this bond is technically reversible, its formation and dissociation are slow, effectively trapping the enzyme in an inactive state and preventing it from processing its physiological substrates.[9] This "slow tight-binding" mechanism is the molecular basis for its potent, broad-spectrum inhibitory activity.

4.2 Inhibition of the Coagulation and Fibrinolytic Systems

The primary clinical application of Nafamostat as an anticoagulant is a direct result of its comprehensive inhibition of key enzymes within the coagulation and fibrinolytic cascades.

• Key Targets: Nafamostat potently inhibits multiple serine proteases essential for blood clotting, including thrombin (the final enzyme in the common pathway), Factor Xa (at the convergence of the intrinsic and extrinsic pathways), and Factor XIIa (initiating the intrinsic pathway).[5] It also inhibits plasmin, the primary enzyme responsible for breaking down fibrin clots.[13]
• Therapeutic Effect: By directly inhibiting thrombin, Nafamostat prevents the conversion of soluble fibrinogen into insoluble fibrin polymers, which form the meshwork of a blood clot.[9] Its action on upstream factors like Xa and XIIa serves to block the amplification of the coagulation cascade. This multi-target inhibition provides robust anticoagulant activity, which is crucial for preventing thrombosis in extracorporeal circuits and managing the pathological coagulation seen in DIC.[5]

4.3 Modulation of Inflammatory Pathways

Nafamostat's efficacy in treating acute pancreatitis and other systemic inflammatory conditions stems from its ability to suppress key enzymatic drivers of inflammation.

• Key Targets: It is a powerful inhibitor of trypsin, the pancreatic protease whose aberrant activation within the pancreas initiates a cascade of autodigestion and severe inflammation that characterizes acute pancreatitis.[13] Beyond the pancreas, it inhibits plasma kallikrein, a central component of the contact (kallikrein-kinin) system which generates the potent inflammatory mediator bradykinin, and C1 esterase, an early component of the classical complement pathway.[5]
• Therapeutic Effect: In pancreatitis, the inhibition of trypsinogen activation to trypsin effectively halts the disease-initiating step.[13] Its broader anti-inflammatory effects are mediated by the suppression of the kallikrein-kinin and complement systems, which contribute to vasodilation, increased vascular permeability, and recruitment of inflammatory cells. Furthermore, studies have shown that Nafamostat can inhibit the production of nitric oxide (NO) and pro-inflammatory cytokines such as Interleukin-6 (IL-6) and Interleukin-8 (IL-8) in response to inflammatory stimuli like lipopolysaccharide (LPS).[5] This demonstrates an ability to modulate inflammatory signaling at the cellular level.

The interconnectedness of the systems that Nafamostat targets is a crucial aspect of its pharmacology. Coagulation and inflammation are not separate processes but are deeply intertwined in a phenomenon known as thromboinflammation, which is a hallmark of severe conditions like sepsis and DIC. For instance, thrombin is not only a pro-coagulant enzyme but also a potent pro-inflammatory signaling molecule. By inhibiting a network of targets at the intersection of these pathways, Nafamostat can act as a master regulator of these complex, multi-system disorders. This lack of specificity, while potentially problematic for highly targeted therapies, is an advantage in acute, systemic "storms" of coagulation and inflammation.

4.4 Neuroprotective and Cellular Mechanisms

Beyond its approved indications, preclinical research has uncovered potential neuroprotective roles for Nafamostat, suggesting its utility in neurological insults like ischemic stroke.

• NMDA Receptor Antagonism: In vitro experiments on primary rat cortical neurons demonstrated that Nafamostat provides potent and concentration-dependent protection against neuronal death induced by N-methyl-D-aspartate (NMDA), a key mediator of excitotoxic brain injury. Its neuroprotective efficacy was found to be statistically equivalent to that of MK-801, a well-characterized NMDA receptor antagonist.[10]
• Thrombin Inhibition in the Central Nervous System: In animal models of middle cerebral artery occlusion (MCAO), a model for ischemic stroke, Nafamostat treatment significantly reduced brain thrombin expression and activity. This antithrombin effect was associated with reduced neuronal damage, suggesting that its anticoagulant properties contribute directly to its neuroprotective effects in the brain.[5]
• Antioxidant and Endothelial Protection: Nafamostat has demonstrated cellular protective effects beyond its protease inhibition. It can suppress the production of reactive oxygen species (ROS) induced by tumor necrosis factor-alpha (TNF-α) in vascular endothelial cells.[5] It also promotes endothelium-dependent vasorelaxation through the Akt-eNOS signaling pathway.[10] These actions may help protect the integrity of the blood-brain barrier and mitigate the broader cellular damage caused by ischemia-reperfusion injury.[10]

4.5 Antiviral Mechanism: Inhibition of TMPRSS2

The scientific rationale for investigating Nafamostat as a treatment for COVID-19 was based on its potent inhibition of a specific host cell protease essential for viral entry.

• Key Target: Nafamostat is a powerful inhibitor of Transmembrane Protease, Serine 2 (TMPRSS2).[13] TMPRSS2 is a serine protease expressed on the surface of host cells, particularly in the respiratory epithelium.
• Mechanism of Action: Coronaviruses, including SARS-CoV and SARS-CoV-2, utilize their spike (S) protein to bind to the host cell's ACE2 receptor. Following binding, the S protein must be cleaved, or "primed," by a host protease to activate its fusogenic potential and allow the viral and host cell membranes to fuse, enabling the viral genome to enter the cell.[6] TMPRSS2 is the primary protease responsible for this critical priming step at the cell surface. By potently inhibiting TMPRSS2, Nafamostat effectively blocks this essential gateway for viral entry, thereby preventing infection.[13] In vitro studies confirmed this mechanism and showed that Nafamostat was significantly more potent in this regard than the related compound, camostat mesylate.[26]

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

The pharmacokinetic profile of Nafamostat is the single most critical factor governing its clinical use, efficacy, and limitations. Its journey through the body is characterized by rapid and extensive metabolism, which is both its greatest therapeutic advantage for certain indications and its most significant barrier for others.

5.1 Administration and Bioavailability

• Route of Administration: Nafamostat is administered exclusively by continuous intravenous (IV) infusion.[9] This route is mandated by its poor oral absorption and rapid systemic clearance.
• Oral Bioavailability: The drug is not suitable for oral administration. Preclinical studies in rats revealed an extremely low oral bioavailability, ranging from just 0.95% to 1.59%.[22] This is attributed to its high polarity, which limits gastrointestinal permeability, and its inherent instability, which leads to degradation before it can be absorbed systemically.

5.2 Metabolism and Half-Life: The Defining Characteristic

The metabolism of Nafamostat is the central feature of its pharmacokinetics, defining its therapeutic window and applications.

• Primary Metabolic Pathway: The chemical structure of Nafamostat contains an ester linkage that is highly susceptible to hydrolysis. This ester bond is essential for its pharmacological activity as a protease inhibitor.[22] The drug is rapidly and extensively cleaved by carboxylesterases and arylesterases, which are ubiquitous enzymes found in high concentrations in the blood (particularly within erythrocytes), plasma, and various tissues, especially the liver.[5]
• Metabolites: This hydrolysis breaks Nafamostat down into two primary metabolites: p-guanidinobenzoic acid (PGBA) and 6-amidino-2-naphthol (AN). Both of these metabolites are pharmacologically inactive as protease inhibitors.[5]
• Half-Life (t1/2​): The most clinically relevant pharmacokinetic parameter of Nafamostat is its ultrashort elimination half-life. This rapid clearance necessitates continuous infusion to maintain steady-state therapeutic concentrations.
• In human systemic circulation, the half-life is consistently reported to be very brief, approximately 8 minutes.[5]
• A more detailed compartmental analysis in human subjects following a 2-hour IV infusion reported a terminal half-life of approximately 23 minutes in blood, while plasma half-life values from the same study were longer, around 2 hours.[14] The discrepancy may reflect different analytical methods or compartmental modeling assumptions.
• The extremely short half-life is the key to its function as a regional anticoagulant. The drug exerts its effect within the extracorporeal circuit but is so rapidly cleared upon returning to the patient's systemic circulation that it does not cause significant systemic anticoagulation, thereby reducing the risk of bleeding complications.[30] This stands in stark contrast to agents like unfractionated heparin, which has a much longer half-life of about 60 minutes and produces systemic effects.[30]

5.3 Distribution and Excretion

• Distribution: Pharmacokinetic analyses in humans suggest that Nafamostat's distribution can be described by a two-compartment model.[30] The drug has been observed to accumulate in the kidneys.[5] Preclinical data from rats showed a relatively low steady-state volume of distribution ( Vss​) of approximately 0.99 L/kg, indicating that the drug does not distribute extensively into deep tissues.[22]
• Excretion: The inactive metabolites, PGBA and AN, are cleared from the body primarily through renal excretion.[5]
• Special Populations: The liver is a major site of esterase activity. In patients with severe liver dysfunction, the metabolism of Nafamostat may be impaired. This can lead to the detection of parent drug in the intracorporeal circulation during CRRT, a situation not typically seen in patients with normal liver function. Consequently, dosage adjustments and careful monitoring may be required in this patient population.[32]

5.4 Analytical Challenges

The profound chemical instability of Nafamostat in biological matrices poses a significant challenge for accurate pharmacokinetic analysis.

• Standard blood collection and processing can lead to substantial ex vivo degradation of the drug, resulting in artificially low or unmeasurable concentrations.[22]
• Reliable quantification requires specialized sample handling, including the use of collection tubes containing esterase inhibitors (e.g., sodium fluoride), immediate cooling to 4°C, and acidification of the plasma sample to inhibit enzymatic hydrolysis during storage and processing.[22]
• It is plausible that some clinical trials, particularly early investigations for COVID-19, may have reported unmeasurable plasma concentrations due to a failure to implement these stringent stabilization procedures, confounding the interpretation of pharmacokinetic and pharmacodynamic relationships.[29]

The pharmacokinetic parameters in humans demonstrate a linear, dose-proportional relationship, where increases in dose lead to proportional increases in peak concentration and overall exposure, as summarized in the table below.

Table 2: Summary of Key Human Pharmacokinetic Parameters

Parameter	Dose (Single IV Infusion)	Matrix	Value	Source(s)
Cmax​	10 mg	Plasma	14.49 ng/mL	14
	20 mg	Plasma	40.4 ng/mL	14
	40 mg	Plasma	60.43 ng/mL	14
AUC	10 mg	Plasma	1,655.84 ng·min/mL	14
	20 mg	Plasma	3,571.14 ng·min/mL	14
	40 mg	Plasma	6,880.46 ng·min/mL	14
t1/2​	40 mg	Blood	23.1 min	14
	10 mg	Plasma	112.42 min	14
	20 mg	Plasma	128.19 min	14
	40 mg	Plasma	122.91 min	14
Systemic Half-Life	Continuous Infusion	Systemic Circulation	~8 min	5

6.0 Approved and Investigational Clinical Applications

The clinical utility of Nafamostat is distinctly divided between its established, regulator-approved roles in Asia and a wide range of investigational applications where its therapeutic potential is still being explored. This division is largely dictated by its pharmacokinetic profile, with approved uses leveraging its localized action and investigational uses facing the challenge of achieving systemic exposure.

6.1 Established (Approved) Indications in Asia

In Japan, South Korea, and China, Nafamostat is an integral part of the therapeutic armamentarium for several acute, critical care conditions.

• Acute Pancreatitis: Nafamostat is approved for improving the acute symptoms of various forms of pancreatitis, including acute pancreatitis, acute exacerbations of chronic pancreatitis, post-operative acute pancreatitis, and pancreatitis following endoscopic retrograde cholangiopancreatography (ERCP).[2] Its efficacy is attributed to the potent inhibition of trypsin and other proteases that drive the pancreatic inflammatory cascade.
• Disseminated Intravascular Coagulation (DIC): It is a first-line or alternative therapy for DIC, a life-threatening syndrome of systemic activation of coagulation.[2] Its ability to inhibit multiple factors in the coagulation cascade and the fibrinolytic system makes it particularly useful for managing the complex hemostatic derangements of DIC, especially in patients with sepsis or hematological malignancies.[21]
• Regional Anticoagulation for Extracorporeal Circuits: This represents one of its most important and widespread applications. Its ultrashort half-life makes it an ideal regional anticoagulant, preventing clot formation within external medical circuits while minimizing systemic effects in the patient.
• Continuous Renal Replacement Therapy (CRRT) and Hemodialysis: Nafamostat is frequently used to maintain the patency of the dialysis circuit, particularly in patients with acute kidney injury who have a high risk of bleeding, for whom systemic anticoagulants like heparin would be hazardous.[5] Clinical studies have demonstrated that Nafamostat prolongs the functional lifespan of the dialysis filter and is associated with a lower incidence of bleeding events compared to heparin.[30]
• Extracorporeal Membrane Oxygenation (ECMO): In patients requiring ECMO for cardiac or respiratory support, Nafamostat serves as a safe and effective alternative to heparin for circuit anticoagulation, especially in those with bleeding tendencies or contraindications to heparin.[5]

6.2 Investigational Applications

The broad-spectrum activity of Nafamostat has prompted investigation into numerous other therapeutic areas, though these remain unproven in late-stage clinical trials.

• Oncology: A growing body of preclinical evidence suggests Nafamostat possesses anti-cancer properties.
• Mechanism: It is hypothesized to inhibit tumor growth, invasion, and metastasis by inhibiting tumor-associated proteases like matrix metalloproteinases (MMPs) and urokinase-type plasminogen activator (uPA), and by suppressing angiogenesis through the downregulation of vascular endothelial growth factor (VEGF).[2] It may also enhance anti-tumor immunity by reversing immune resistance.[2]
• Tumor Types: Promising anti-tumor effects have been observed in experimental models of various malignancies, including pancreatic, colorectal, gastric, and triple-negative breast cancer.[2] A Phase I/II clinical study in patients with unresectable pancreatic cancer showed that Nafamostat combined with gemcitabine was safe and demonstrated a favorable response rate.[38]
• Neuroprotection: Preclinical data support a potential role for Nafamostat in mitigating brain injury.
• Ischemic Stroke: In animal models, Nafamostat has been shown to reduce cerebral infarct size and improve functional outcomes. These effects are attributed to its ability to inhibit thrombin in the brain and protect the blood-brain barrier.[5]
• Viral Infections: Its ability to inhibit host proteases required for viral entry has made it a candidate for various viral diseases.
• Coronaviruses: The discovery of its potent inhibition of TMPRSS2 was first made in the context of Middle East Respiratory Syndrome Coronavirus (MERS-CoV), predating the COVID-19 pandemic.[26]
• Dengue Hemorrhagic Fever: Nafamostat inhibits tryptase, a protease implicated in the capillary leakage that causes severe hemorrhagic fever and shock in dengue infections, suggesting a potential therapeutic application.[9]
• Cystic Fibrosis: There is a theoretical rationale for its use in cystic fibrosis. By potentially decreasing the activity of the epithelial sodium channel (ENaC), which is hyperactive in this disease, Nafamostat could help to increase airway surface liquid and improve mucus clearance.[13]

The stark contrast between Nafamostat's established and investigational uses highlights its core challenge. Its approved indications all involve localized action—either within a contained organ like the pancreas or an external medical device—where its rapid systemic clearance is a benefit. Conversely, its investigational applications in cancer and neuroprotection require sustained systemic distribution to distant tissues, a goal that is fundamentally at odds with its inherent pharmacokinetic instability. Therefore, advancing Nafamostat into these new therapeutic areas will depend less on proving its pharmacological mechanism and more on developing novel formulations or stable analogs capable of overcoming this pharmacokinetic barrier.

7.0 Safety and Tolerability Profile

The safety profile of Nafamostat is best understood as a trade-off. It mitigates the significant and predictable risk of systemic bleeding associated with traditional anticoagulants like heparin, but it introduces a different spectrum of risks, including rare but serious idiosyncratic reactions and a specific metabolic disturbance.

7.1 Overall Safety Assessment

For its approved indications, particularly as a regional anticoagulant, Nafamostat is generally considered to have a favorable safety profile. Its principal advantage is a significantly reduced risk of systemic bleeding complications compared to agents like heparin or low-molecular-weight heparin (LMWH).[30] This superior safety with respect to hemorrhage is a direct consequence of its ultrashort half-life, which confines its anticoagulant activity primarily to the extracorporeal circuit. Meta-analyses of its use in blood purification therapies have confirmed that Nafamostat is associated with a significantly lower risk of bleeding complications compared to conventional anticoagulant therapies.[35]

7.2 Serious Adverse Events

Despite its advantages, Nafamostat is associated with several potentially life-threatening adverse events that necessitate vigilant clinical monitoring.

• Hyperkalemia: This is a well-documented and mechanistically understood risk. While the reported incidence is low (e.g., 0.7% in one study) [14], its potential for cardiac toxicity makes it clinically significant.
• Mechanism: The drug and its metabolites inhibit the amiloride-sensitive sodium channel (ENaC) in the epithelial cells of the renal collecting ducts. This channel is crucial for sodium reabsorption, which in turn drives potassium secretion into the urine. By blocking this channel, Nafamostat inhibits potassium excretion, leading to its accumulation in the blood.[5]
• Clinical Management: Regular monitoring of serum potassium levels is essential, especially in patients with underlying renal impairment, those receiving prolonged infusions, or those taking other medications that can elevate potassium (e.g., ACE inhibitors, potassium-sparing diuretics).
• Anaphylaxis and Hypersensitivity Reactions: Severe, immediate-type allergic reactions, including anaphylactic shock, have been reported.[3] Symptoms can range from mild skin rashes and itching to severe systemic reactions involving fever, shivering, chills, profound hypotension, tachycardia, and gastrointestinal distress.[3] This risk requires close observation of the patient, particularly at the beginning of the infusion.
• Agranulocytosis: A rare but severe adverse event characterized by a drastic reduction in neutrophils, a type of white blood cell, has been associated with Nafamostat use.[5] This condition leaves patients highly susceptible to life-threatening infections. Periodic monitoring of complete blood counts may be warranted during extended courses of therapy.
• Cardiac Arrest: There have been reports of cardiac arrest in patients receiving Nafamostat during dialysis, potentially precipitated by sudden clinical deterioration, such as acute dyspnea.[5]

7.3 Common Adverse Events

More frequently encountered adverse events are typically less severe but can impact patient comfort and require management.

• Infusion Site Reactions: Phlebitis, or inflammation of the vein at the infusion site, is a common complication. In one clinical trial for COVID-19, phlebitis was observed in approximately 50% of patients treated with Nafamostat.[43] Local pain, erythema, and swelling are also common.[19]
• Gastrointestinal Disturbances: Nausea, vomiting, and abdominal pain are frequently reported, though they are usually mild to moderate in severity.[19]
• Hypotension: The drug can exert vasodilatory effects, which may lead to a drop in blood pressure, causing symptoms such as dizziness and lightheadedness.[42]
• Hematological Effects: Mild and transient reductions in platelet counts (thrombocytopenia) or white blood cell counts (leukopenia) can occur.[19]

7.4 Contraindications and Precautions

While there are no absolute contraindications listed in some analyses beyond hypersensitivity [45], prudent clinical practice and exclusion criteria from clinical trials suggest specific situations where Nafamostat should be avoided or used with extreme caution.

• Absolute Contraindication: A history of known hypersensitivity or anaphylactic reaction to Nafamostat or any of its excipients is an absolute contraindication to its use.[19]
• Precautions and Relative Contraindications:
• Active Bleeding: The drug should not be used in patients with severe active bleeding.[34]
• Severe Coagulopathy: Caution is advised in patients with pre-existing severe coagulopathies, such as an international normalized ratio (INR) >2.5 or a platelet count <20,000/mm3.[46]
• Concomitant Anticoagulation: Co-administration with other systemic anticoagulants or potent antiplatelet agents requires a careful risk-benefit analysis and intensive monitoring.[19]
• Pregnancy and Lactation: Use in pregnant or lactating women is generally avoided due to a lack of safety data.[36]

8.0 Clinically Significant Drug-Drug Interactions

The drug-drug interaction profile of Nafamostat is overwhelmingly dominated by pharmacodynamic interactions that amplify its effects on hemostasis. Due to its unique and rapid metabolism, clinically significant pharmacokinetic interactions are rare.

8.1 Pharmacodynamic Interactions (Increased Bleeding Risk)

The most critical interactions are those involving concomitant use of other medications that impair blood clotting. The additive or synergistic effects can dramatically increase the risk of serious bleeding and hemorrhage. Close monitoring is essential when Nafamostat is combined with any of the following drug classes.

• Other Anticoagulants: Co-administration with other anticoagulants, such as heparin, warfarin, direct oral anticoagulants (DOACs) like apixaban and rivaroxaban, or direct thrombin inhibitors like argatroban, can lead to a profound anticoagulant effect and a high risk of bleeding.[5]
• Antiplatelet Agents: Drugs that inhibit platelet function, including aspirin, P2Y12 inhibitors (e.g., clopidogrel, ticagrelor), and glycoprotein IIb/IIIa inhibitors (e.g., abciximab), disrupt primary hemostasis. When used with Nafamostat, which disrupts secondary hemostasis (the coagulation cascade), the overall ability to form a clot is severely impaired.[5]
• Nonsteroidal Anti-inflammatory Drugs (NSAIDs): Common NSAIDs like ibuprofen, naproxen, and diclofenac possess antiplatelet activity and can cause gastrointestinal mucosal injury. This combination of effects significantly increases the risk of gastrointestinal bleeding when used with an anticoagulant like Nafamostat.[5]
• Thrombolytic Agents: The combination of Nafamostat with thrombolytic (fibrinolytic) agents such as alteplase (tPA), reteplase, or streptokinase is extremely hazardous. Thrombolytics actively dissolve existing clots, and their co-administration with a potent anticoagulant can lead to severe and uncontrollable hemorrhage.[5]

8.2 Pharmacokinetic Interactions

Nafamostat's susceptibility to pharmacokinetic interactions is minimal. Its metabolic fate is determined by rapid hydrolysis via high-capacity esterase enzymes in the blood and tissues, not by the cytochrome P450 (CYP) enzyme system, which is the source of most clinically significant drug-drug interactions.[22] This metabolic pathway is so efficient that it effectively preempts any significant metabolism by CYP enzymes. Consequently, Nafamostat is not expected to be a victim or perpetrator of interactions involving CYP inhibitors or inducers. While some databases may list potential interactions mediated by drug transporters or other minor pathways, their clinical relevance is likely negligible in the face of its overwhelming and rapid hydrolytic clearance. Therefore, when assessing interaction risk, clinicians should focus almost exclusively on pharmacodynamic effects related to hemostasis.

Table 3: Clinically Significant Drug-Drug Interactions with Nafamostat

Interacting Drug Class	Example Drugs	Mechanism of Interaction	Clinical Effect	Management Recommendation
Anticoagulants	Heparin, Warfarin, Apixaban, Rivaroxaban, Argatroban	Pharmacodynamic	Potentiated anticoagulant effect; significantly increased risk of severe bleeding and hemorrhage.	Concomitant use is generally avoided or requires intensive monitoring of coagulation parameters (e.g., aPTT, INR) and clinical signs of bleeding.
Antiplatelet Agents	Aspirin, Clopidogrel, Ticagrelor, Prasugrel	Pharmacodynamic	Additive impairment of hemostasis (inhibition of both platelets and coagulation cascade); increased risk of bleeding.	Use with extreme caution. Requires careful risk-benefit assessment and close monitoring for bleeding.
NSAIDs	Ibuprofen, Naproxen, Diclofenac, Ketorolac	Pharmacodynamic	Increased bleeding risk due to antiplatelet effects and potential for gastrointestinal mucosal injury.	Avoid concomitant use if possible, especially for prolonged periods. Monitor for signs of gastrointestinal bleeding.
Thrombolytic Agents	Alteplase (tPA), Reteplase, Streptokinase	Pharmacodynamic	Synergistic effect on hemostasis (inhibition of new clot formation and dissolution of existing clots); high risk of severe, life-threatening hemorrhage.	Concomitant use is generally contraindicated.

9.0 Regulatory Landscape and Global Status

The regulatory status of Nafamostat is characterized by a stark geographical divide. It is a long-established and widely used medication in several Asian countries, yet it remains an investigational drug in the United States and Europe, a situation that reflects differing historical medical practices and modern regulatory strategies.

9.1 Approvals in Asia

• Japan: Nafamostat received its first approval in Japan on March 30, 1989.[4] It is licensed and widely prescribed for a range of indications, including acute pancreatitis, disseminated intravascular coagulation (DIC), and as a regional anticoagulant for extracorporeal circulation procedures like hemodialysis.[3] A multitude of generic and branded versions are available on the Japanese market.[48] Notable brand names include Futhan (Torii Yakuhin), Buipel (Takeda Teva Pharma), Coahibitor (AY Pharma), Famoset (Towa Yakuhin), Nafatat (Nichi-Iko), Naotamin (Asahi Kasei Pharma), and Ronastat (Koa Isei).[49]
• South Korea: The drug is also approved and integrated into standard clinical practice for similar indications as in Japan, including the management of pancreatitis and as a crucial anticoagulant for CRRT and ECMO circuits.[6]
• China: Nafamostat is utilized in clinical practice, particularly as an anticoagulant for patients on ECMO and CRRT.[30]

9.2 Status in the United States and Europe

In Western markets, Nafamostat has not undergone the traditional regulatory approval process for any therapeutic indication and is not commercially available. However, it has gained recognition through specific regulatory designations that may pave the way for future approval in niche applications.

• United States (Food and Drug Administration - FDA):
• Nafamostat is not an FDA-approved drug.
• It was granted Orphan Drug Designation on May 11, 2020, for the treatment of pancreatic cancer.[4] This designation provides developmental incentives, such as tax credits and market exclusivity, for drugs intended to treat rare diseases.
• In a novel regulatory approach, a specific lyophilized formulation of Nafamostat, known as Niyad™, has been granted Breakthrough Device Designation by the FDA.[51] This designation is for its use as a regional anticoagulant for the extracorporeal circuit in patients undergoing renal replacement therapy who are at high risk of bleeding. This strategy cleverly leverages the drug's key pharmacokinetic feature—its rapid systemic clearance—to argue that its primary function is localized to the medical device (the circuit), thus allowing it to be potentially regulated as a device rather than a systemic drug. This could represent a more streamlined pathway to the US market for this specific application.
• European Union (European Medicines Agency - EMA):
• Nafamostat is not approved for marketing in the EU.
• Similar to the US, it has received Orphan Drug Designation from the EMA, recognizing its potential for treating a rare condition.[4]

The divergence in regulatory status highlights a key dynamic in global pharmaceuticals. A drug that has been a generic staple in Asia for decades has had little commercial incentive for sponsors to fund the expensive and lengthy process of seeking a New Drug Application (NDA) in the West. The "Breakthrough Device" strategy for Niyad™ in the US represents a potential turning point, not for Nafamostat as a systemic therapeutic, but as a specialized tool for extracorporeal circuit management, effectively turning its greatest pharmacokinetic liability into a regulatory asset.

10.0 Special Focus: The Repurposing of Nafamostat for COVID-19

The emergence of the COVID-19 pandemic in 2020 triggered an urgent global search for effective treatments, with drug repurposing at the forefront of this effort. Nafamostat quickly emerged as one of the most promising candidates based on a powerful preclinical rationale, but its journey through clinical trials provides a sobering case study on the complexities of translating in vitro activity into in vivo efficacy.

10.1 The Preclinical Rationale: A "Perfect Storm" of Activity

Nafamostat was identified as a leading candidate for COVID-19 due to a compelling combination of antiviral and host-modulating activities.

• Potent Antiviral Activity: The primary rationale was its potent inhibition of the host cell protease TMPRSS2. In vitro studies using human lung cell lines demonstrated that Nafamostat could block SARS-CoV-2 entry at extremely low concentrations.[6] Its potency was striking, with a half-maximal inhibitory concentration ( IC50​) reported to be 0.0022 µM, making it appear hundreds of times more potent than remdesivir (IC50​ 1.3 µM) and roughly ten times more potent than its structural analog, camostat mesylate, in these cellular assays.[6]
• Dual Mechanism of Action: Beyond its direct antiviral effect, Nafamostat's established therapeutic profile was seen as a major advantage. Severe COVID-19 is characterized by a profound thrombo-inflammatory state, often leading to complications like DIC, pulmonary embolism, and a "cytokine storm." It was hypothesized that Nafamostat's proven antithrombotic and anti-inflammatory properties could provide a dual benefit: blocking viral entry while simultaneously mitigating the life-threatening systemic complications of the disease.[6]

10.2 Overview of Major Clinical Trials

This strong preclinical promise led to the rapid initiation of numerous clinical trials worldwide. However, the results from these studies were varied and, in aggregate, failed to provide a clear signal of clinical benefit.

Table 4: Overview of Major COVID-19 Clinical Trials for Nafamostat

Trial Identifier/Registry No.	Country/Region	Phase	Patient Population	Key Findings/Conclusion	Source(s)
NCT04623021	Russia	II	Hospitalized patients with moderate-to-severe pneumonia requiring high-flow oxygen or non-invasive ventilation.	No significant difference in primary endpoint (time to clinical improvement). A post-hoc analysis suggested benefit in a small subgroup of high-risk patients (NEWS ≥7).	7
RACONA Study (NCT04352400)	Italy	II/III	Hospitalized patients with COVID-19.	Trial struggled with recruitment (only 15 patients randomized). Insufficient to assess efficacy but showed a good safety profile.	39
jRCTs031200026	Japan	Multicenter RCT	Patients with mild, early-onset COVID-19 (Omicron strains).	Nafamostat treatment was associated with a significant, dose-dependent reduction in viral load. No serious adverse events were observed.	43
DEFINE Trial	United Kingdom	Ib/IIa	Hospitalized patients with COVID-19 pneumonitis.	No evidence of anti-inflammatory, anticoagulant, or antiviral activity. The Nafamostat group experienced more adverse events and a longer hospital stay.	57

10.3 Synthesis of Evidence and The Pharmacokinetic Barrier

When synthesized, the clinical evidence for Nafamostat in COVID-19 is inconclusive and often contradictory.[23] While an exploratory study in mild, early-onset disease suggested an effect on viral load [44], larger studies in more severe disease failed to show a benefit in primary clinical outcomes like time to recovery or mortality.[55] The DEFINE trial was overtly negative.[57]

The most compelling explanation for this stark disconnect between profound in vitro potency and the lack of clear in vivo efficacy lies in the drug's pharmacokinetics. The therapeutic target for antiviral action, TMPRSS2, is located on lung epithelial cells. To be effective, intravenously administered Nafamostat must survive transit in the bloodstream, distribute from the capillaries into the lung tissue, and accumulate at the cell surface at a concentration sufficient to inhibit the enzyme. Given its ultrashort half-life of approximately 8 minutes due to rapid enzymatic degradation in the blood, it is highly improbable that sustained, therapeutic concentrations were ever achieved at the site of viral replication.[29] The drug was likely metabolized and inactivated long before it could exert a meaningful clinical effect in the lungs. This pharmacokinetic failure, rather than a failure of the drug's mechanism of action, is the most logical reason for the disappointing clinical trial results.

11.0 Future Directions and Expert Conclusion

Nafamostat is a molecule of significant pharmacological power whose clinical identity has been forged by the constraints of its own chemistry. Its journey from a niche therapeutic in Asia to a globally investigated candidate for a pandemic disease has provided invaluable lessons in drug development, highlighting the inseparable link between a drug's mechanism of action and its pharmacokinetic behavior.

11.1 Consolidated Expert Assessment

Nafamostat is a highly effective and established therapeutic for a well-defined set of acute, localized, or extracorporeal conditions. In its role as a regional anticoagulant for CRRT and ECMO, its combination of potent, broad-spectrum protease inhibition and rapid systemic clearance represents a near-ideal profile, offering a clear safety advantage over systemic anticoagulants like heparin by dramatically reducing the risk of patient hemorrhage. Its utility in acute pancreatitis and DIC further solidifies its value in managing conditions characterized by acute, runaway enzymatic cascades.

However, the very chemical instability that makes it an excellent regional agent acts as a formidable barrier to its development for systemic diseases. The extensive and ultimately inconclusive clinical investigation for COVID-19 starkly illustrated this limitation. Despite being one of the most potent in vitro inhibitors of a key viral entry mechanism, its inability to achieve sustained therapeutic concentrations in target tissues rendered it clinically ineffective for this indication. Nafamostat should therefore be viewed not as a failed drug, but as a highly successful niche therapeutic whose limitations are as instructive as its successes.

11.2 Future Research and Development

The future of Nafamostat and its therapeutic class lies in two primary areas: optimizing its current applications and overcoming the central pharmacokinetic challenge to unlock its systemic potential.

• Optimization of Current Use: While established, the use of Nafamostat can be further refined. Prospective studies are needed to develop evidence-based dosing and monitoring strategies, particularly in special populations such as patients with severe hepatic impairment, where metabolism may be altered, and in pediatric patients, where data is scarce.[32] Establishing the most reliable pharmacodynamic marker for its anticoagulant effect (e.g., activated partial thromboplastin time vs. activated clotting time) is a clinical priority.[30]
• Overcoming the Pharmacokinetic Barrier: The key to expanding Nafamostat's therapeutic reach into areas like oncology, neuroprotection, and systemic inflammatory or viral diseases lies in innovative pharmaceutical science. Future research must focus on strategies to stabilize the molecule and control its delivery.
• Development of Stabilized Analogs: Medicinal chemistry efforts could focus on designing next-generation analogs that retain the essential pharmacophore for protease inhibition but modify the labile ester bond to be more resistant to hydrolysis. This could create a molecule with a longer systemic half-life, suitable for treating systemic diseases.
• Novel Drug Delivery Systems: A more immediate path forward involves advanced formulation technology. Encapsulating Nafamostat in delivery vehicles such as liposomes or nanoparticles could protect it from premature enzymatic degradation in the bloodstream and potentially target its delivery to specific tissues, such as tumors or inflamed lungs.[60] Such an approach could finally bridge the gap between Nafamostat's known pharmacological power and its unrealized systemic therapeutic potential.

In conclusion, Nafamostat remains a valuable clinical tool for its approved indications. It also serves as a powerful archetype in pharmacology, demonstrating that a drug's ultimate clinical value is determined not by its potency in a test tube, but by its ability to reach the right target, at the right concentration, for the right amount of time in vivo. The future of this potent protease inhibitor will be defined by the ability of scientists to master its delivery.

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