Sinomenium acutum

Sinomenium acutum: A Comprehensive Reference

1. Identity and Botanical Classification

Taxonomic Names and Synonyms

Sinomenii Caulis (SC) — the pharmacopoeial designation for the drug — refers to the dried stems and rhizomes of Sinomenium acutum (Thunb.) Rehd. et Wils. and its variety Sinomenium acutum var. cinereum Rehd. et Wils. The plant is known by several synonymous names in TCM and the older botanical literature, including Menispermum acutum, Cocculus diversifolius, Qingfeng Teng, and Hanfang Ji.

The plant belongs to the genus Sinomenium and the family Menispermaceae. It includes Sinomenium acutum (Thunb.) Rehd. et Wils. and S. acutum var. cinereum (Diels) Rehd. et Wils., as recorded in the Pharmacopoeia of the People's Republic of China (PPRC).

Botanical Description and Geographic Distribution

Sinomenium acutum is a deciduous twining vine belonging to the Menispermaceae family, one of the most important and highly valued plant families in TCM for the treatment of rheumatalgia, rheumatism, and arthralgia. S. acutum has been widely used to treat arthromyodynia, rheumatism, and similar diseases for more than one thousand years, and has been reported to have anti-inflammatory, anti-arrhythmic, anti-rheumatic, anti-angiogenic, anti-anxiety, immunosuppressive, antihypertensive, and vasodilating effects. It grows over a vast geographical area in China.

The plant was first described by Alfred Rehder and Ernest Henry Wilson in Plantae Wilsonianae, published in 1913.

Common Names

The plant carries several common names across different languages and traditions: in Chinese medicine, it is most widely known as Qingfeng Teng (青風藤, literally "blue/green wind vine") or Qingteng. Among ethnic minorities in Guizhou province, it is known as "Gegenen," as documented in "Hmongb Medicine and Pharmacology."

Part Used and Pharmacopoeial Status

As a famous herb, SC is not only recorded in the Chinese Pharmacopoeia but also included in the pharmacopoeias of Japan, South Korea, and Europe, supporting its widespread international export.

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2. Traditional and Historical Use

Historical Documentation

SC was recorded in the earliest ancient Chinese medicine book, the Bencao Tujing. According to the theory of TCM, SC mainly targets the liver and spleen meridians. It was subsequently first recorded as an herbal medicine in the Ben-Cao-Gang-Mu (Compendium of Materia Medica).

Sinomenium acutum has been used for medicinal purposes in China for over 2,000 years, and has been recorded in ancient TCM books such as the Shen Nung Pen Ts'ao and Chin k'uei Yao Lueh.

Traditional Preparations and Indicated Conditions

The Compendium of Materia Medica recorded that Qingfengteng could be "steeped in medicinal wine for therapeutic use" to treat "rheumatic wandering arthritis (fengshi liuzhu), severe joint swelling (lijie hexi), numbness and itching (mabi saoyang), traumatic injuries with ulcerative swelling (sunshang chuangzhong)."

As a TCM for dispelling wind and dampness in China, it is widely distributed and has a long history of drug use. In China, Japan, and Korea, SA and sinomenine are used to treat neuralgia and rheumatoid arthritis with good reputation.

Originally extracted from Japanese Sinomenium acutum in the 1920s by Ishiwari, sinomenine is a strong histamine-releasing agent with a variety of pharmacological effects such as anti-inflammatory, immunosuppressive, analgesic, antihypertensive, and anti-arrhythmic effects.

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3. Phytochemistry: Key Constituents

Overview of Chemical Classes

At present, more than 210 natural compounds have been isolated from S. acutum, including alkaloids, lignans, triterpenoid saponins, steroids, and other structures. Previous phytochemical studies demonstrate that SA contains alkaloids, sterols, lipids, and some other components.

Sinomenine — The Principal Active Constituent

Sinomenine, the principal active constituent of S. acutum, belongs to the morphinan alkaloids. S. acutum has been utilized for millennia to alleviate various forms of rheumatic pain symptoms. The structurally diverse benzylisoquinoline alkaloids (BIAs) found in S. acutum are the primary contributors to its therapeutic efficacy, with sinomenine being the principal bioactive constituent.

Sinomenine (chemical structure: C₁₉H₂₃NO₄, MW 329.18) is a monomer alkaloid extracted from the TCM Sinomenium acutum, which has anti-inflammatory, analgesic, and immunomodulatory effects.

Sinomenine (7,8-didehydro-4-hydroxy-3,7-dimethoxy-17-methylmorphinane-6-one) is the main biomonomer alkaloid typically isolated from Sinomenium acutum, Rehder & E.H. Wilson.

Additional Alkaloids Identified

The plant produces a series of aporphine alkaloids, including dauriporphine, bianfugecine, dauriporphinoline, menisporphine, and magnoflorine; the morphinan alkaloid sinomenine; as well as the lignan (−)-syringaresinol and N-feruloyltyramine.

Alkaloids laudanosoline-1-O-xylopyranose, 6-O-methyl-laudanosoline-1-O-glucopyranoside, menisperine, sinomenine, laurifoline, magnoflorine, and norsinoacutin were identified in Sinomenium acutum (Qing Feng Teng in TCM). Thirteen isoquinoline alkaloids — for example, salutaridine, dauricumine, cheilanthifoline, dauriporphine, 8-demethoxycephatonine, and 7(R)-7,8-dihydrosinomenine — are isolated from the rhizome of S. acutum.

Metabolite profiling has identified structurally diverse BIAs in S. acutum, including the 1-benzylisoquinoline alkaloid (S)-norcoclaurine, the aporphine alkaloid magnoflorine, the morphinan alkaloid sinomenine, the protoberberine alkaloid tetrahydropalmatrubine, and the bisbenzylisoquinoline alkaloid fangchinoline.

Anti-Inflammatory Components

Identification of anti-inflammatory components in SA by spectro-effective relationship and chemometric methods showed that sinomenine, magnoflorine, menisperine, and cephalotenine were the main anti-inflammatory components of SA.

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4. Mechanisms of Action

Anti-Inflammatory Signaling

Sinomenine downregulates TNF-α and IL-1β through blocking the activity of nuclear factor-kappa B (NF-κB) in macrophages and synoviocytes. Sinomenine also inhibits the lipopolysaccharide-induced upregulation of IL-1α in vascular endothelial cells (VECs).

RA is treated with sinomenine based on the following main mechanisms: inhibiting the proliferation of inherent synovial cells and promoting their apoptosis; suppressing the activities of immunocytes such as lymphocytes, dendritic cells, and macrophages; as well as inducing balance through regulating the functions of the body's immune system; inhibiting the binding activity of NF-κB by up-regulating the expression of IκB-α, causing a decrease in the levels of inflammatory cytokines TNF-α and IL-1β, thereby relieving the local inflammatory reaction.

Furthermore, sinomenine reduces the synthesis of prostaglandin E2 (PGE2) induced by lipopolysaccharide-activated monocytes, through suppressing cyclooxygenase-2 (COX-2).

Sinomenine remarkably inhibited the chemotaxis and secretion function of LPS-stimulated macrophages. It also down-regulated both the protein levels of inflammatory cytokines (TNF-α, IL-1β, and IL-6) and the RNA and protein levels of the key factors (TLR4, MyD88, P-IκB) in the TLR4 pathway.

Immunosuppressive Properties

Pharmacological studies have highlighted sinomenine's anti-inflammatory and immunomodulatory capabilities, which include suppressing pro-inflammatory cytokines, inhibiting matrix metalloproteinase activity, and attenuating macrophage activation, thus helping to preserve joint structure and function.

Sinomenine hydrochloride has been shown to induce apoptosis in activated T-cells, which are implicated in the autoimmune response, thus helping to modulate the immune system.

The α7 Nicotinic Acetylcholine Receptor (Neuroimmune Axis)

The in vitro minimal effective concentration for sinomenine (≥250 μM) is hardly reached in either synovium or serum after oral administration at a therapeutic dose, raising questions about direct mechanisms. Recent findings suggest that the α7 nicotinic acetylcholine receptor (α7nAChR) might mediate sinomenine's inhibitory effect on macrophage activation. Orally administered sinomenine ameliorated the systemic inflammation of collagen-induced arthritis (CIA) rats; this effect was significantly diminished by either vagotomy or the antagonists of nicotinic acetylcholine receptors (especially the antagonist of α7nAChR). Sinomenine may bind to α7nAChR through interacting with the residues Tyr184 and Tyr191 in the binding pocket.

Anti-Oxidative and Nrf2 Signaling

Sinomenine can reduce oxidative stress and attenuate renal fibrosis by inhibiting Nrf2-mediated oxidative stress and TGF-β signaling. Its capacity to inhibit inflammatory mediators via NF-κB and Nrf2 signalling supports its application in rheumatic arthritis and cardiovascular protection.

Anti-Angiogenic Effects

In CIA mice, hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and angiopoietin 1 (ANG-1) were regulated by sinomenine to decrease angiogenesis.

Osteoclast Regulation

Sinomenine can attenuate osteoclastogenesis and osteolysis by downregulating TLR4/TRAF6 expression.

Cardiovascular Mechanisms

Sinomenine dilated norepinephrine-, KCl-, and PDB-induced vasoconstrictions. Pretreatment with nicardipine, staurosporine, L-NMMA, indomethacin, or propranolol significantly attenuated sinomenine-induced vasorelaxation. These results indicate that sinomenine causes vasorelaxation through inhibitions of Ca²⁺ current (ICa) and protein kinase C, β-adrenoceptor stimulation, and the activation of NO and PGI2 syntheses in endothelium.

Sinomenine inhibits VCAM-1 expression induced by TNF-α in vascular endothelial cells.

Histamine-Related Dual Regulation

The docking results suggest that sinomenine might exhibit dual regulatory effects in many processes such as COX-2 expression, NF-κB pathway activation, and degranulation of mast cells to release histamine, thereby exhibiting pro-inflammatory (adverse reactions) as well as anti-inflammatory effects.

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5. Scientific Evidence by Area of Use

5.1 Rheumatoid Arthritis (RA)

Regulatory Status

The Chinese government has approved the prescription medication sinomenine as an effective anti-inflammation drug for treating RA. Caulis Sinomenii was approved by the State Food and Drug Administration of China for treating RA almost 20 years ago. The Chinese patent medicine Zhengqing Fengtongning, produced from Caulis Sinomenii, has achieved efficacy in clinical practice.

Systematic Reviews and Meta-Analyses

A systematic review published in the NCBI DARE database assessed sinomenine versus non-steroidal anti-inflammatory drugs (NSAIDs) for RA. Ten trials (n=1,185, range 29 to 303 participants) were included: seven RCTs and three CCTs. Study duration ranged from one to six months. Two studies rated high quality and eight rated low quality. For patients treated with sinomenine, the number of improved patients was significantly greater compared with NSAIDs (OR 2.57, 95% CI 1.79 to 3.70; 10 studies), as was the number of rheumatoid-factor-disappeared patients (OR 1.93, 95% CI 1.19 to 3.13; four studies). There was no significant heterogeneity for these comparisons. Compared with NSAIDs, sinomenine was more effective in amelioration of morning stiffness (WMD −15.66, 95% CI −19.01 to −12.30; three studies), painful joints (WMD −1.40, 95% CI −2.69 to −0.11; three studies), and erythrocyte sedimentation rate (WMD −2.44, 95% CI −3.39 to −1.49; four studies).

Adverse events occurred less frequently in the digestive system during sinomenine treatment than during NSAID treatment (OR 0.04, 95% CI 0.01 to 0.23; three studies), but occurred more frequently in the dermatomucosal system with sinomenine treatment (OR 3.07, 95% CI 1.14 to 8.22; four studies). The review's authors noted that sinomenine may be a valuable remedy to clinically treat rheumatoid arthritis, although the current evidence needed to be further verified by more high-quality trials.

A multicriteria decision analysis (MCDA) of 44 RCTs found that sinomenine preparation alone offered less benefit than when combined with conventional drugs (benefit difference of 20, 95% CI 3.06 to 35.71), while the risk of the combination was significantly lower. The probability that the comprehensive benefit-risk score of the combined regimen is greater than that of sinomenine alone was 90.1%; the evaluation was found to be steady. The conclusion was that the benefit-risk of the combined application regimen is greater than that of sinomenine alone.

Comparison with Methotrexate (MTX)

Clinical randomized controlled trials have demonstrated that sinomenine exhibits efficacy comparable to MTX in the treatment of patients with RA, while presenting with fewer adverse effects. In a randomized controlled clinical trial, compared with RA patients treated with methotrexate and leflunomide (MTX + LEF), patients treated with methotrexate and sinomenine (MTX + SIN) gained similar medical benefits with fewer adverse events.

A randomized controlled trial of 80 patients showed that the efficacy of sinomenine in the treatment of RA was 82.6% compared to 70.8% for conventional drugs, and that sinomenine was effective in improving joint symptoms and laboratory parameters in RA patients.

Specific Clinical Trial (Immunological Parameters)

49 RA patients were randomly allocated to the experimental group (25 patients) and positive control group (24 patients); patients in each group received Zhengqing Fengtongning tablets (60–120 mg) orally twice a day and MTX (7.5–10 mg) plus folic acid tablets (5 mg) orally once a week. Combination use of Diclofenac Sodium Sustained Release tablets (75 mg) was allowed if necessary. The period of treatment for each group was three months.

Combination with MTX — Synovial and Bone Markers

The combination of sinomenine and methotrexate (MTX + SIN) could significantly inhibit the activation of synovial receptor activator of NF-κB ligand (RANKL) and osteopontin (OPN) production in collagen-induced arthritis rats.

Evidence Strength for RA: Moderate. Multiple RCTs and systematic reviews exist, but many included studies are of low-to-moderate methodological quality, conducted primarily in China, and of limited duration (one to six months). Larger, longer, international, double-blind trials are needed to fully confirm efficacy and long-term safety.

5.2 Osteoarthritis (OA)

Zhengqing Fengtongning release tablet (ZQFTN) is a proprietary Chinese medicine preparation of sinomenine, the main active component of Sinomenium acutum. It is used in China as a complementary and alternative medicine for knee osteoarthritis (KOA). A systematic review and meta-analysis assessing 18 studies included 1,512 participants (757 in the treatment group and 755 in the control group). Sinomenine can be used in the treatment of musculoskeletal diseases, neuropathy, cancer, and other diseases.

Evidence Strength for OA: Preliminary to moderate. The systematic review evidence base exists, but the underlying trials are mostly Chinese-language studies, and the methodological quality of individual studies is variable.

5.3 Ankylosing Spondylitis (AS)

A systematic review aimed to assess the effectiveness and safety of Zhengqing Fengtongning release tablets in treating ankylosing spondylitis, searching relevant electronic databases from inception to September 2017. The review encompassed Chinese and English databases, including Cochrane Library and PubMed, and examined sinomenine preparations against conventional pharmacotherapy.

Evidence Strength for AS: Preliminary. The available clinical studies are largely low-quality RCTs with small sample sizes; conclusions should be interpreted cautiously.

5.4 Gout and Urate-Lowering Therapy

Previous studies have found that Zhengqing Fengtongning sustained-release tablets (sinomenine) can improve inflammation in the acute phase of gout; the aim of a further registered clinical trial was to explore the efficacy and safety of sinomenine for prophylaxis of acute flares when initiating urate-lowering therapy. The design was a randomized, placebo-controlled, double-blinded trial of 210 gout patients, randomized 1:1 to test and control groups, with a 12-week intervention and 12-week follow-up.

Evidence Strength for Gout: Emerging. A registered RCT protocol has been published. Definitive efficacy data from fully reported high-quality trials are not yet available.

5.5 Renal / Nephroprotective Effects

In modern medicine, S. acutum is employed in formulations such as injections and extended-release tablets, effectively treating conditions like rheumatoid arthritis, chronic nephritis, and gout. Kidney disease is a chronic inflammatory disease with fibrosis being a common characteristic. Sinomenine has an anti-renal fibrosis effect. Sinomenine promotes TGF-β secretion to inhibit Th1 and Th2 immune responses, with the greatest impact on Th1. Th1 and Th2 cell regulation by sinomenine is a major mechanism underlying its function in nephritis. Research has been conducted on kidney disease treatment with sinomenine, predominantly focusing on three conditions: mesangial proliferative glomerulonephritis (MsPGN), IgA nephropathy, and diabetic nephropathy.

In experimental models, sinomenine significantly decreased albuminuria, BUN, Scr, β2-MG, and CIC to alleviate renal damage, and regulated the balance of Th1 and Th2, thereby down-regulating PD-L1 and TNF-α.

Evidence Strength for Nephroprotection: Preclinical and early clinical. The majority of supporting evidence is from animal models and small clinical studies. Robust RCT evidence in humans is lacking.

5.6 Cardiovascular Effects

Sinomenine and its derivatives play a significant role in cardiovascular and cerebrovascular protection, as well as organ protection. Sinomenine, a bioactive alkaloid derived from Sinomenium acutum, exhibits notable anti-inflammatory, antioxidant, and immunomodulatory properties, and has shown protective effects on the cardiovascular and nervous systems.

Evidence Strength for Cardiovascular Effects: Primarily preclinical (in vitro and animal models). Clinical evidence in humans is limited.

5.7 Neuroprotection and Neurological Conditions

A great deal of pharmacological and clinical research has been done on sinomenine, a main compound from SA, which mainly focuses on the immune system, cardiovascular system, and nervous system. Sinomenine and its derivatives have been demonstrated to possess multi-pharmacological effects such as antitumor, anti-inflammation, neuroprotection, and immunosuppressive properties. They exhibit anti-inflammatory and analgesic effects and are utilized in treating rheumatic arthritis. Moreover, they play a significant role in cardiovascular and cerebrovascular protection, as well as organ protection.

Evidence Strength for Neuroprotection: Preliminary (largely in vitro and animal studies). Translation to human clinical benefit remains to be established.

5.8 Anti-Cancer Properties

Sinomenine (SIN) is an alkaloid extract of Sinomenium acutum and exhibits a wide range of pharmacological activities such as immunosuppression, antirheumatic, antiangiogenic, and anti-inflammatory activities. In addition to anticancer effects, SIN was found to sensitize gastric cancer cells to 5-fluorouracil (5-FU) and induced apoptosis in vitro and in vivo. SIN also sensitized gastric cancer cells to cisplatin-induced apoptosis via the inactivation of PI3K/Akt/Wnt signaling pathways.

A comprehensive review evaluated sinomenine and its derivatives, highlighting a broad spectrum of pharmacological effects against breast, lung, liver, and prostate cancers, alongside anti-inflammatory and neuroprotective actions. Mechanistic investigations pinpointed modulation of PI3K/Akt/mTOR, NF-κB, MAPK, and JAK/STAT pathways as central to its antitumour efficacy, with observed IC50 values in the nanomolar range in prostate and breast cancer cell lines.

Evidence Strength for Anticancer Effects: Preclinical only (in vitro cell lines and animal models). No clinical trials in cancer patients have been reported at a sufficient scale to substantiate human benefit.

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6. Dosage Forms and Dosages Reported in Studies

Clinical Formulations

The primary clinical forms of sinomenine are sinomenine hydrochloride (SIN-HCl) tablets, enteric-coated tablets, and injections. At present, Zhengqing Fengtongning release tablets (ZQFTN), sinomenine tablets, and sinomenine hydrochloride injection are used clinically in China.

The sinomenine preparations (SP) include Zhengqing Fengtongning Conventional Tablet, Zhengqing Fengtongning Sustained Release Tablet, Zhengqing Fengtongning Enteric-Coated Tablet, Zhengqing Fengtongning Capsule, and Zhengqing Fengtongning Injection.

Doses Used in Identified Clinical Trials

• In a 49-patient RA clinical study, patients received Zhengqing Fengtongning tablets (60–120 mg) orally twice a day combined with MTX (7.5–10 mg) once weekly; combination use of diclofenac sodium sustained-release tablets (75 mg) was allowed if necessary. Treatment duration was 3 months.
• In clinical pharmacokinetic studies, oral administration of 80 mg sinomenine was performed in healthy volunteers.

Pharmacokinetic Parameters

In preclinical pharmacokinetic studies, the Tmax, T1/2, and oral bioavailability of rats after a single oral administration of 90 mg/kg sinomenine were 0.66 h, 5.5 h, and 79.6%, respectively, demonstrating fast oral absorption and high oral bioavailability.

In clinical contexts, sinomenine's oral bioavailability is described as hovering around 30%, a substantially lower value than observed in some animal studies. Sinomenine is prone to instability, decomposing easily under alkali, light, and heat, with a short half-life and low bioavailability.

In rats, at 45 min after oral dosage, the drug was found to distribute widely in the internal organs, with tissue concentrations (from highest to lowest) in the order: kidneys, liver, lungs, spleen and heart, brain, and testicles.

Studies on the metabolism and excretion of sinomenine found that sinomenine undergoes phase I biotransformation and active hepatobiliary excretion, mainly regulated by P-glycoprotein. Sinomenine can be metabolized to at least two metabolites in humans, in rats in vivo, and in human liver microsomes; the major metabolite was identified as N-demethylsinomenine.

Multi-Component Effects on Pharmacokinetics

The maximum concentration, the area under the concentration-time curve, clearance, and the apparent volume of distribution of sinomenine in the Sinomenium acutum extract statistically differed from those of sinomenine monomer (p < 0.05); however, the mean residence time, time of peak concentration, and half-life did not show significant differences between the two groups. An ever-increasing number of studies have indicated that the pharmacokinetics and therapeutic effects of the monomer in its pure form and as part of the herbal extract are different. In some situations these differences have been shown to be extensive and may lead to multi-component synergistic or inhibitory interactions.

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7. Body Systems and Health Areas

• Musculoskeletal / Rheumatological: The primary area of documented clinical use. As a TCM for dispelling wind and dampness, SA has a long history of use in rheumatological conditions. Indications include rheumatoid arthritis, osteoarthritis, gout, and ankylosing spondylitis.
• Immune System: A great deal of pharmacological and clinical research has been done on sinomenine, which mainly focuses on the immune system, cardiovascular system, and nervous system.
• Renal System: Research has focused on mesangial proliferative glomerulonephritis (MsPGN), IgA nephropathy, and diabetic nephropathy.
• Cardiovascular System: Sinomenine plays a significant role in cardiovascular and cerebrovascular protection.
• Nervous System: Sinomenine has shown protective effects on the nervous system, with preclinical evidence for neuroprotection and potential applications in neuroinflammatory conditions.
• Oncology (Preclinical): The findings indicate a broad spectrum of pharmacological effects, including antitumor, anti-inflammation, neuroprotection, and immunosuppressive properties.

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8. Safety, Adverse Effects, and Drug Interactions

Overview of Adverse Reactions

Due to the histamine release characteristics of sinomenine, its adverse reactions such as allergic reactions, gastrointestinal reactions, and circulatory systemic reactions have been drawing increasing attention.

Of 4,064 patients in seven hospitals who took Zhengqing Fengtongning (ZQFTN) sustained-release tablets, 193 experienced adverse drug reactions, with an incidence of adverse reactions of 4.75%. The adverse reactions principally involved the skin and digestive system, and the main clinical manifestations included allergic reactions and gastrointestinal reactions such as rash, itching, dizziness, headache, nausea, and vomiting, and decreased appetite.

Skin Reactions and Histamine Release

Sinomenine has some noticeable characteristics, which include a relatively short biological half-life, the potential of causing clinical adverse reactions such as rash and gastrointestinal reactions by promoting histamine release, and being unstable and easily decomposable under acid, alkali, light, or heat conditions.

The increased use of sinomenine has been accompanied by an increased incidence of adverse reactions, with clinical anaphylaxis receiving much research attention. N-Demethylsinomenine (M-3) is a major metabolite of sinomenine.

Hepatotoxicity

The non-negligible risk of toxicity is another major obstacle to the clinical translational use of sinomenine-based preparations. Dose-dependent hepatotoxicity and histamine release-induced adverse effects are particularly prominent, and are associated with the inhibition of CYP3A4 by the metabolite nortriptyline quinine leading to self-accumulation.

Hepatic and gastrointestinal disorders were the main adverse events identified in clinical comparisons; however, the ratio of patients suffering from hepatic disorder in the sinomenine group (1/38) was much lower than that in the MTX group (10/39) and the SIN+MTX group (8/36). Additionally, patients receiving a combination of sinomenine and MTX experienced reduced gastrointestinal side effects and liver toxicity compared to those treated with MTX+LEF.

Comparative Safety vs. Conventional Drugs

Adverse events occurred less frequently in the digestive system during sinomenine treatment than during NSAID treatment (OR 0.04, 95% CI 0.01 to 0.23; three studies), but occurred more frequently in the dermatomucosal system with sinomenine treatment (OR 3.07, 95% CI 1.14 to 8.22; four studies).

Long-Term Safety Gaps

Current clinical trials have a maximum duration of only 24 weeks, lacking assessment of bone metabolism effects for a period of ≥52 weeks and a two-year carcinogenicity study; preclinical trials of long-term biocompatibility and assessment of dynamic changes in the RA inflammatory microenvironment remain deficient.

Drug Interactions and CYP450

Inhibition or induction of cytochrome P450 isozymes is one of the major causes for clinical drug-drug interactions. Sinomenine can be metabolized to at least two metabolites in humans, in rats in vivo, and in human liver microsomes. At 50 μmol/L, sinomenine inhibited the activity of CYP2C19 in human microsomes; however, in vivo sinomenine at the normal clinical dose enhanced the elimination of mephenytoin.

Dose-dependent hepatotoxicity is associated with the inhibition of CYP3A4 by the metabolite nortriptyline quinine, leading to self-accumulation.

Pharmacopoeial and Regulatory Notes

SC is included in the pharmacopoeias of Japan, South Korea, and Europe, as well as in the Chinese Pharmacopoeia. A large retrospective study reported an adverse reaction rate of 4.75%, mainly involving the skin and its accessories (41.23%) and the gastrointestinal system (35.53%).

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9. Summary of Evidence

Sinomenium acutum and its principal alkaloid sinomenine represent one of the most extensively studied TCM compounds in East Asia, with a pharmacological profile spanning immunosuppressive, anti-inflammatory, analgesic, cardiovascular, neuroprotective, nephroprotective, and potential anticancer activities. More than 210 natural compounds have been isolated from S. acutum, including alkaloids, lignans, triterpenoid saponins, steroids, and other structures. The strongest clinical evidence is concentrated in rheumatoid arthritis, where multiple RCTs and several meta-analyses support efficacy, while the overall quality of the study base remains limited by short durations, small sample sizes, and predominantly single-country methodology. Other therapeutic areas — including osteoarthritis, gout, chronic nephritis, and cardiovascular disease — have emerging but incomplete clinical evidence. Anticancer and neuroprotective data remain predominantly preclinical.

References

• American Journal of Chinese Medicine — Sinomenium acutum: A Comprehensive Review of its Botany, Phytochemistry, Pharmacology and Clinical Application
• Pharmaceutical Biology (Taylor & Francis) — Sinomenium acutum: A review of chemistry, pharmacology, pharmacokinetics, and clinical use
• PubMed — Sinomenium acutum: a review of chemistry, pharmacology, pharmacokinetics, and clinical use (PMID 22775422)
• ScienceDirect Topics — Sinomenium acutum overview
• Scientific Reports — Metabolic profiling and transcriptome analysis of Sinomenium acutum (2025)
• PMC — Comparative Pharmacokinetics Study of Sinomenine in Rats (PMC6271545)
• PMC — Exploring the active ingredients and potential mechanisms of action of sinomenium acutum in rheumatoid arthritis (PMC10009275)
• Frontiers in Molecular Biosciences — Exploring the active ingredients and potential mechanisms of action of sinomenium acutum in RA via systems biology and network pharmacology
• bioRxiv — Genetic population variation and phylogeny of Sinomenium acutum in subtropical China
• ScienceDirect — Botany, ethnopharmacology, phytochemistry, pharmacological activities, toxicity, quality control, clinical application and novel preparations of Sinomenii Caulis: An updated review
• Frontiers in Cardiovascular Medicine — Sinomenine in Cardio-Cerebrovascular Diseases: Potential Therapeutic Effects and Pharmacological Evidences
• PMC — Sinoacutine inhibits inflammatory responses via NF-κB and JNK signaling (PMC8605577)
• PMC — Sinomenine Regulates Inflammatory Response and Oxidative Stress via NF-κB and Nrf2 Signaling Pathways (PMC6162969)
• PMC — Gut-Sourced Vasoactive Intestinal Polypeptide and the Anti-inflammatory Effect of Sinomenine in CIA (PMC6028598)
• Scientific Reports — Sinomenine treats rheumatoid arthritis by inhibiting MMP9 and inflammatory cytokines (2024)
• NCBI Bookshelf/DARE — Sinomenine versus NSAIDs for RA: a systematic review and meta-analysis
• PMC — Research progress in treatment of RA with Sinomenine and related formulations based on different administration routes (PMC12364828)
• PMC — Sinomenine ameliorates adjuvant-induced arthritis by inhibiting the autophagy/NETosis/inflammation axis (PMC9998614)
• PMC — Benefit-risk assessment of sinomenine preparations using MCDA for RA patients (PMC9901080)
• PMC — Research Advances and Prospects on Mechanism of Sinomenine on Histamine Release and Histamine Receptors (PMC6337707)
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• PMC — Cardiovascular Pharmacology of Sinomenine (PMC3155221)
• Frontiers in Immunology — Sinomenine Inhibits the Progression of Rheumatoid Arthritis by Regulating Inflammatory Cytokines and Monocyte/Macrophage Subsets
• PMC — Sinomenine Inhibits the Progression of RA by Regulating Cytokines and Monocyte/Macrophage Subsets (PMC6168735)
• Medicine (LWW) — Zhengqing Fengtongning sustained-release tablets prevents gout flares in ULT
• PMC — Zhengqing fengtongning sustained-release tablets prevents gout flares: RCT protocol (PMC9276265)
• PMC — The Efficacy and Safety of Zhengqing Fengtongning for Knee Osteoarthritis: Systematic Review and Meta-Analysis (PMC8794657)
• Evidence-Based Complementary and Alternative Medicine — Efficacy and Safety of Sinomenine Preparation for Ankylosing Spondylitis: Systematic Review and Meta-Analysis
• PubMed — The pharmacokinetics and tissue distribution of sinomenine in rats and its protein binding ability in vitro (PMID 16019035)
• ScienceDirect — The pharmacokinetics and tissue distribution of sinomenine in rats and its protein binding ability in vitro
• PMC — Investigation of preclinical pharmacokinetics of N-demethylsinomenine (PMC10359479)
• Frontiers in Medicine — Sinomenine in cerebral ischemia: mechanisms, delivery strategies, and the emerging multifunctional biomaterials of the bone–brain axis
• Molecules (MDPI) — Bioactivities and Mechanisms of Action of Sinomenine and Its Derivatives: A Comprehensive Review
• PMC — N-demethylsinomenine metabolite and sinomenine activate mast cells via MRGPRX2 and aggravate anaphylaxis (PMC11322065)
• PubMed — Effect of sinomenine on human cytochrome P450 activity (PMID 17292874)
• PMC — A systematic review: Sinomenine (PMC11098800)
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• Nature Index — Sinomenine Applications in Cancer and Inflammatory Disorders