Dichroa

Dichroa (Dichroa febrifuga Lour.): A Comprehensive Reference

1. Identity: Botanical Classification, Natural Source, and Common Preparations

1.1 Taxonomy and Nomenclature

Dichroa febrifuga Lour. is a member of the genus Dichroa in the family Hydrangeaceae, growing in grove-shaded and humid mountainous areas, mainly distributing in Sichuan, Guizhou, Hunan, and Hubei of China. The species name febrifuga means "medicine used to reduce fever," referring to its use in treating high fever, particularly related to malaria. The plant's applications in this regard are known from the Himalayas, Malaysia, and China.

Common names include blue evergreen hydrangea, Chinese quinine, and fever-flower. In Chinese herbal medicine, it is called chang shan (root) and shu chi (leaf). In Vietnam, the local people call it "thuong son." In pharmacopoeial literature, the drug derived from the root is referred to as Radix Dichroae or Changshan.

Chang Shan (Dichroa febrifuga) should not be confused with Hai Zhou Chang Shan (Clerodendrum trichotomum), which belongs to an entirely different plant family (Lamiaceae/Verbenaceae). Hai Zhou Chang Shan is used to treat hypertension and has completely different chemistry and indications. The two share the name "Chang Shan" but are unrelated botanically and pharmacologically.

1.2 Botanical Description

Dichroa febrifuga Lour. is a deciduous shrub in the Hydrangeaceae (formerly placed in Saxifragaceae) family, growing 0.4 to 2 meters tall. Branchlets are often fleshy, terete or slightly 4-angular, usually purplish. Leaf blades are papery, 6–25 × 2–10 cm, with a denticulate or serrulate margin. Corymbose panicles are terminal, 3–20 cm long. Flowers are bluish, about 8 mm in diameter, with 4–6 calyx lobes and 4–6 petals. Stamens number 10–20, styles 4–6. Berries are 3–7 mm in diameter, and blue when ripe.

Dichroa is prevalent in China (in the provinces of Anhui, Fujian, Gansu, Guangdong, Guangxi, Guizhou, Hubei, Hunan, Jiangxi, Shaanxi, Sichuan, Taiwan, and Xizang). It is also found growing wild in Bhutan, Cambodia, northern India, Laos, Myanmar, Nepal, Sikkim, Thailand, and Vietnam.

1.3 Parts Used and Common Preparations

Changshan (Radix Dichroae) is the dry root of Dichroa febrifuga Lour., collected in the fall. It is officially listed in the Chinese Pharmacopoeia and used as an antimalarial agent.

The roots are usually dug up in autumn, stripped of any loose fibrous material, then dried and cut into slices. Authentic Chang Shan can be identified by its characteristic chicken-bone-like twisted root morphology, hard woody texture with powdery fracture, and yellowish-white cross-section with distinct radial lines.

Shu Qi (蜀漆), the leaf and young branch of the same plant, is a related but distinct medicinal product with stronger emetic properties. The leaf preparation has historically been used in addition to the root, though the root (Radix Dichroae) is the primary form in modern Chinese medicine practice.

Preparations described in the literature include aqueous decoctions (boiling dried root slices in water), powdered dried root, and aqueous extracts. According to the Pharmacopoeia of China (2020 version), D. febrifuga is one of the common Chinese herbal medicines in folk use, which can be used to treat malaria and eliminate phlegm.

2. Traditional and Historical Use

2.1 Origins in Chinese Medicine

The traditional herbal medicine Dichroa febrifuga (changshan) has been used in East Asia to treat malaria for nearly two thousand years. It was first recorded in the Treatise on Cold Diseases and Miscellaneous Diseases (Shanghan zabing lun) by Zhang Zhongjing (150/154–215/219 CE).

As a typically toxic medicine, D. febrifuga can be traced back to Shennong's Materia Medica (Shennong Bencao Jing), the earliest extant medicine monograph in China. It was recorded that its roots used as medicine were named "HengShan," and its twigs and leaves were called "ShuQi."

The roots of Dichroa febrifuga Lour., family Hydrangeaceae, known as Chang shan, and the leafy tops, known as Shu chi, have been used for the treatment of malaria in China for at least two thousand years. Their use for medicinal purposes in China was first mentioned in the Herbal of the Emperor Shen-Nung, the written version of which dates back at least to the Han Dynasty (206 BCE to 220 CE), and they have since been used along with several other medicinal substances such as betel nut, turtle shell, and ginger for mitigating fever and for treatment of malaria.

2.2 Use Across Cultures and Time Periods

Throughout history, they have been used in numerous countries around the world, including China, Korea, and Vietnam, to alleviate symptoms such as fever brought on by malaria infection.

The roots of Dichroa febrifuga Lour. have been used as a traditional antimalarial drug and also used in the treatment of productive cough and unstable fever caused by infection in China and Korea. This plant has a wide application as a complementary therapeutic agent in Korea for the treatment of unstable fever caused by infection.

In Nepal, the juice extracted from the leaves has been used to treat coughs, colds, and bronchitis, and the root sap is used as a remedy for fever and indigestion.

2.3 Wartime Medical Use

During the last World War, owing to the scanty supply of quinine, preparations containing Chang shan were used to take the place of quinine in some parts of China, and later it was found that Chang shan used alone was as efficacious against malaria as when used in combination with other substances.

In the 1940s, the Republic of China supported a national project related to the discovery of febrifugine (C₁₆H₁₉N₃O₃). In a 1943 report, it was recorded that a crude extract of this root had been effectively used on clinical cases of tertian malaria.

2.4 Traditional Preparation Methods and Indications

In Chinese medicine, roots used in TCM are described as inducing vomiting of phlegm and slobber, removing heat, and controlling malaria. Dichroa root is associated with the Heart, Liver, and Lung meridians, and has bitter, spicy, cold, and slightly toxic properties. It has been used for centuries to help treat malaria, often as part of a formula that includes tsaoko, anemarrhena, and areca seed.

3. Phytochemistry: Key Constituents and Active Compounds

3.1 Overview of Chemical Classes

Thirty chemical compounds, including alkaloids, terpenoids, flavonoids, and other kinds, were isolated and identified from D. febrifuga. The plant is rich in quinazolone alkaloids, coumarins, steroids, polyphenols, and other chemical components.

3.2 Febrifugine and Isofebrifugine

Febrifugine is a benzopyrimidine or quinazoline-based natural compound and is a well-recognized antimalarial agent in ancient Chinese medicine. It is present in the dry roots of the Chinese herb Dichroa febrifuga.

Febrifugine has a molecular weight of 301.34, molecular formula C₁₆H₁₉N₃O₃, and a melting point of 145–146 °C. Studies demonstrated that the activity of this plant is predominantly attributed to febrifugine, an active quinazoline-type alkaloid.

Early isolation work identified multiple related alkaloids. An alkaloidal fraction of the root exhibited marked anti-malarial activity, and among the initial alkaloids isolated, an active alkaloid called dichroine B was identified, with additional alkaloids eventually resolved from the original fractions. With the probable exception of dichroine-A, all these alkaloids are more or less effective against P. gallinaceum infection in chicks, with antimalarial activity in the descending order: dichroines-γ, dichroin-β, dichroidine, and quinazolone.

3.3 Halofuginone: The Synthetic Derivative

Halofuginone (HF) is a racemic halogenated derivative of febrifugine, synthesized in a search for a less-toxic form of this plant bioactive. Halofuginone is a clinically active derivative of febrifugine, first isolated from the Chinese herb Dichroa febrifuga. The beneficial biological effects of halofuginone on various diseases, including parasitic diseases, cancer, fibrosis, and autoimmune disorders, have been established. Halofuginone has reduced toxic side effects compared to febrifugine, an advantage that has led to the commercial availability of halofuginone-based antiparasitic drugs and completed early human clinical trials for the treatment of tumors and fibrosis.

3.4 Additional Identified Compounds

Compounds isolated from the leaves of Dichroa febrifuga include hydrangenoside C, isoarborinol, and methyl 1,3,4,6-tetra-O-acetyl-fructofuranoside. One constituent of this plant, changrolin (4-[3,5-bis{(N-purrolidinyl)-methyl}-4-hydroxyanilino]-quinazoline), has been used as an anti-arrhythmic drug.

Febrifugine was isolated from the roots and leaves of Dichroa febrifuga Lour. Subsequently, it was also isolated from the leaves of certain Hydrangea species.

4. Mechanisms of Action

4.1 Inhibition of Prolyl-tRNA Synthetase (ProRS / EPRS)

Febrifugine is an antimalarial, the active component of the Chinese herb Chang Shan. Recent studies indicate that its mechanism of action is as an inhibitor of prolyl-transfer RNA synthetase (ProRS).

Halofuginone (HF) binds glutamyl-prolyl-tRNA synthetase (EPRS), inhibiting prolyl-tRNA synthetase activity; this inhibition is reversed by the addition of exogenous proline or EPRS. Febrifugine, one of the fifty fundamental herbs of traditional Chinese medicine, had been characterized for its therapeutic activity while its molecular target had remained unknown until this work. Febrifugine derivatives have been used to treat malaria, cancer, fibrosis, and inflammatory disease.

Using an integrated chemogenomics approach combining drug resistance selection, whole-genome sequencing, and an orthogonal yeast model, researchers demonstrated that the cytoplasmic prolyl-tRNA synthetase (PfcPRS) of the malaria parasite Plasmodium falciparum is a biochemical and functional target of febrifugine and its synthetic derivative halofuginone. Febrifugine is the active principle of a traditional Chinese herbal remedy for malaria. Treatment with febrifugine derivatives activated the amino acid starvation response in both P. falciparum and a transgenic yeast strain expressing PfcPRS.

The mechanism by which halofuginone and other febrifugine analogs inhibit the amino acid starvation response is by binding to glutamyl-prolyl-tRNA synthetase and inhibiting prolyl-tRNA synthetase activity, by simultaneously occupying two different substrate binding sites on prolyl-transfer RNA synthetase. Only the 2R,3S isomer of halofuginone, which matches the absolute configuration of febrifugine, exhibits biological activity.

4.2 Inhibition of NF-κB, MAPK, and Akt Signaling

Aqueous extract of Dichroa febrifuga (AEDF) inhibited the production of IL-1β and IL-6, NF-κB activation, IκB-α degradation, and IKK, Akt, ERK1/2, and JNK activities in LPS-stimulated mouse peritoneal macrophages. These results suggest that AEDF inhibits proinflammatory cytokine production in LPS-stimulated macrophages, and that these effects are mediated by inhibition of the IKK/IκB/NF-κB pathway and the phosphorylation of Akt, ERK1/2, and JNK.

In an in vivo rat model of LPS-induced sepsis, Western blot analysis showed that the level of NF-κBp65 was markedly up-regulated and IκB-α was down-regulated by LPS challenge. However, AEDF at 100 mg/kg inhibited induction of NF-κBp65 and degradation of IκB-α in the liver of LPS-challenged rats.

4.3 TGF-β / Smad3 Signaling and Antifibrotic Mechanisms

One described mode of halofuginone action is inhibition of Smad3 phosphorylation downstream of the TGF-β signaling pathway, resulting in inhibition of fibroblast-to-myofibroblast transition and fibrosis.

Halofuginone inhibited TGF-β-dependent Smad3 phosphorylation, causing a reduction in fibroblast differentiation, reduction in the levels of extracellular matrix (ECM) proteins, and inhibition of fibrosis and tumor growth.

4.4 Th17 Cell Differentiation and Amino Acid Response Pathway

Halofuginone was shown to inhibit the differentiation of T helper 17 (TH17) cells, which are associated with autoimmune diseases. The demonstration that halofuginone inhibits prolyl-tRNA synthetase activity explains the observed activation of the amino acid response pathway in TH17 cells and identifies amino acid restriction pathways as potential drug targets in inflammatory disease.

Inhibition of EPRS underlies the broad bioactivities of this family of natural products. This work both explains the molecular mechanism of a promising family of therapeutics, and highlights the amino acid response (AAR) pathway as an important drug target for promoting inflammatory resolution.

5. Scientific Evidence by Area of Use

5.1 Antimalarial Activity

Preclinical and Historical Clinical Evidence

Febrifugine is the active principal isolated from the Chinese herb chang shan (Dichroa febrifuga Lour.), which has been used as an antimalarial in Chinese traditional medicine for more than 2,000 years. However, intensive study of the properties of febrifugine has been hindered for decades due to its side effects.

In 1945, when Plasmodium gallinaceum became available for testing, crude extracts of both the root and the leaves of the herb were found to be effective for chicks infected with P. gallinaceum, with the leaves being about five times as active as the roots.

Workers in the United States isolated two alkaloids from the roots, one of which had activity against Plasmodium lophurae in ducks 100 times that of quinine. Hewitt et al. (1952) reported that febrifugine was approximately 100 times more effective than quinine in counteracting P. lophurae infection in ducks.

Although febrifugine has good antiparasitic activity at 2.5 mg per day orally, an emetic action limited its further use as an antimalarial drug.

A febrifugine structure-based computer search of the Walter Reed Chemical Information System identified 10 analogs that inhibited parasite growth in vitro, with 50% inhibitory concentrations ranging from 0.141 to 290 ng/ml. The host macrophages (J744 cells) were 50 to 100 times less sensitive to the febrifugine analogs than the parasites.

Neither febrifugine nor any of its direct derivatives could be used clinically in the treatment of malaria on account of their toxicity. A 1950 human study (cited in PMC literature as Coatney et al., J Natl Malar Soc, 1950) conducted a trial of febrifugine, an alkaloid obtained from Dichroa febrifuga Lour., against the Chesson strain of Plasmodium vivax — this early human-malaria study reported antimalarial efficacy but also confirmed the dose-limiting gastrointestinal toxicity that has prevented further clinical development of the parent compound.

Evidence strength: The antimalarial activity of febrifugine is well-established in animal models and early clinical observation, and has a clear mechanistic basis (PfcPRS inhibition). However, due to its toxicity profile, febrifugine itself has not progressed to modern controlled clinical trials. Evidence remains primarily preclinical for the crude extract and isolated alkaloid in humans.

5.2 Anti-Inflammatory Activity

In Vitro and Animal Studies

Researchers evaluated the anti-inflammatory effect and underlying molecular mechanism of aqueous extract of Dichroa febrifuga (AEDF) in C57BL/6 mouse peritoneal macrophages. The effect of AEDF on proinflammatory cytokine (IL-1β and IL-6) production was analyzed by ELISA and real-time RT-PCR. The effects of AEDF on NF-κB/IκB-α/IKK were measured by reporter assay, EMSA, Western blotting, and kinase assay. The effects of AEDF on Akt and MAPKs activity were assayed by Western blotting. Results: AEDF inhibited the production of IL-1β and IL-6, NF-κB activation, IκB-α degradation, and IKK, Akt, ERK1/2, and JNK activities in LPS-stimulated mouse peritoneal macrophages.

Hydrangenoside C, isoarborinol, and methyl 1,3,4,6-tetra-O-acetyl-fructofuranoside were isolated from the leaves of Dichroa febrifuga. The anti-inflammatory property of these isolates was assessed using an in vivo assay of an edema mouse model induced by carrageenan. Of the three, isoarborinol inhibited the edema effectively and dose-dependently, similarly to diclofenac, while no obvious activity was observed for the other two. In silico results demonstrated that isoarborinol enables binding to 5-LOX and PLA2 via generating hydrogen bonds.

Evidence strength: Anti-inflammatory activity is supported by multiple in vitro and animal studies identifying plausible mechanisms. No controlled human trials have been conducted specifically for inflammatory conditions. Evidence is therefore preliminary and preclinical.

5.3 Antiparasitic Activity (Beyond Malaria)

Many studies have investigated the bioactivities of halofuginone, an analog of febrifugine, which has been approved for drugs for malaria, coccidiosis in broiler chickens and growing turkeys, and protozoan parasites in cattle.

Research has summarized advances in determining the mechanism of action of halofuginone, focusing on its antiprotozoal role in malaria, cryptosporidiosis, coccidiosis, toxoplasmosis, and leishmaniasis.

A 2020 in vitro study investigated the antischistosomal potential of febrifugine: Reports on the antischistosomal effect of several antimalarial drugs such as artesunate, mefloquine, and amodiaquine suggest that febrifugine, which exerts an antimalarial effect, can also be expected to possess antischistosomal potential. This study was in vitro only, and results require in vivo and clinical confirmation.

Evidence strength: For halofuginone-derived veterinary antiparasitic uses, evidence is well-established and the compound is commercially approved for animal use. For febrifugine itself against non-malarial parasites, evidence is primarily in vitro or in experimental animal models.

5.4 Antifibrotic Activity

An additional mechanism for the halofuginone-dependent inhibition of fibrosis involves selective prevention of the development of Th17 cells, by activation of the amino acid starvation response. Halofuginone treatment reduced the severity and incidence of autoimmune encephalomyelitis associated with Th17 cells characterized by production of interleukin-17 (IL-17), which promotes fibrosis by both exacerbating the upstream inflammatory response and regulating the downstream activation of fibroblasts.

The beneficial biological effects of halofuginone on various diseases including parasitic diseases, cancer, fibrosis, and autoimmune disorders have been investigated. Halofuginone has reduced toxic side effects compared to febrifugine, an advantage that has led to the commercial availability of halofuginone-based antiparasitic drugs for animal use, and to human clinical trials for the treatment of tumors and fibrosis.

In the last two decades, HF has gained attention and progressed to Phase 2 clinical trials for its potential as a therapeutic in cancer and fibrosis.

Evidence strength: Antifibrotic effects of halofuginone (the synthetic derivative) are supported by multiple mechanistic and animal studies, and early-phase human trials have been conducted, primarily for oncology and fibrosis. Evidence for the crude plant extract itself for fibrosis in humans is absent from the peer-reviewed literature.

5.5 Antitumor Activity

Febrifugine, derived from the roots and leaves of Dichroa febrifuga and Hydrangea, has been employed for approximately 2,000 years in treating malaria-induced fever. Studies indicate febrifugine's efficacy in impeding angiogenesis, inhibiting neovascularization processes, restraining uncontrolled cell proliferation, and inducing apoptosis, showcasing promising antitumor activity.

A robust inhibitory effect of febrifugine was observed on T24 bladder cancer cells, though its inhibitory effect on non-cancer cells was comparatively weak, indicating promising anticancer activity for bladder cancer. Hematoxylin and eosin staining and immunohistochemical detection of animal tissues confirmed that febrifugine inhibited the growth of bladder cancer transplanted tumors.

HF (halofuginone) possesses broad pharmacological activities, including anti-fibrotic, anti-viral, anti-inflammatory, immunomodulatory, cardioprotective, and anticancer activities. Studies have shown that HF not only shows good antitumor inhibition in a variety of cancers, such as breast cancer, colon cancer, lung cancer, prostate cancer, brain tumor, liver cancer, bladder cancer, and pancreatic cancer, but the preponderance of this evidence derives from preclinical investigations.

In vivo, oral treatment with halofuginone at concentrations of 0.1–0.4 mg/kg per day significantly reduced brain tumor growth and angiogenesis in a metastatic brain tumor model in rats.

Halofuginone extract inhibits the growth of breast cancer cells and induces the generation of reactive oxygen species (ROS) and apoptosis. In addition, HF significantly reduces the migration and invasion of MCF-7 and MDA-MB-231 human breast cancer cells after TPA stimulation. Matrix metalloproteinase-9 plays a critical role in tumor metastasis; Western blot analysis and gelatin zymography showed that HF suppresses MMP-9 expression and activity in a concentration-dependent manner.

HF inhibited proliferation, induced G0/G1 phase arrest, and promoted apoptosis in lung cancer cells in a dose-dependent manner. Halofuginone is a febrifugine-derivative alkaloid extracted from Dichroa febrifuga. It has been reported that HF possesses marked antimalarial, anti-coccidial, and anticancer activities.

Evidence strength: Antitumor activity is supported by a range of preclinical (in vitro and animal) studies for both febrifugine and halofuginone. Halofuginone entered early-phase clinical trials in oncology (Phase 2). No large controlled clinical trials of the crude Dichroa plant extract or raw febrifugine in cancer patients have been reported in the accessible peer-reviewed literature. All claims for antitumor benefit remain preliminary and investigational.

5.6 Autoimmune and Immunomodulatory Activity

Halofuginone, a widely studied derivative of febrifugine, inhibits the development of Th17-driven autoimmunity in a mouse model of multiple sclerosis by activating the amino acid response pathway (AAR).

HF was reported to inhibit TH17 cell differentiation by activating the amino acid response pathway, through inhibiting human prolyl-transfer RNA synthetase (ProRS) to cause intracellular accumulation of uncharged tRNA.

Evidence strength: Immunomodulatory and anti-autoimmune effects are well-characterized at the mechanistic level in experimental models for halofuginone. Direct human clinical evidence for Dichroa extract or febrifugine in autoimmune disease has not been established.

6. Body Systems and Health Areas of Association

• Immune system and infectious disease: Primary traditional and pharmacological focus — antimalarial, antiparasitic (anti-coccidial, antischistosomal), antipyretic.
• Respiratory system: The roots have been used as a traditional antimalarial drug and also used in the treatment of productive cough and unstable fever caused by infection in China and Korea.
• Hepatic and gastrointestinal system: Used in traditional formulas to clear phlegm-heat; simultaneously recognized as a source of hepatotoxic risk via its alkaloids.
• Cardiovascular system: One constituent, changrolin (4-[3,5-bis{(N-purrolidinyl)-methyl}-4-hydroxyanilino]-quinazoline), has been used as an anti-arrhythmic drug.
• Connective tissue and fibrosis: Via the TGF-β/Smad3 pathway; halofuginone has been studied for scleroderma, graft-versus-host disease, and pulmonary fibrosis.
• Oncology: Multiple cancer cell lines investigated in preclinical studies; early-phase clinical trials conducted for halofuginone.
• Immune-mediated inflammatory disease: Via TH17 suppression and NF-κB inhibition.

7. Dosage Forms and Reported Dosages

The typical dosage of dichroa root is between 5 and 10 grams, taken with hot water as a decoction.

In the context of the 2009 in vitro and macrophage study, AEDF at 100 mg/kg inhibited induction of NF-κBp65 and degradation of IκB-α in the liver of LPS-challenged rats — this is an animal-study dose and does not correspond directly to a human therapeutic dose.

In reported early clinical pharmacology studies, febrifugine has good antiparasitic activity at 2.5 mg per day orally. However, this dose was accompanied by limiting emetic toxicity.

In vivo animal studies of halofuginone used oral doses of 0.1–0.4 mg/kg per day in a rat brain tumor model.

No well-controlled human clinical dose-finding studies for Dichroa febrifuga crude extract exist in the modern peer-reviewed literature. Dosing references in the acupuncture and TCM literature reflect traditional practice rather than controlled trial data.

8. Safety Considerations and Toxicology

8.1 General Toxicity Profile

Dichroa febrifuga Lour. is a toxic but extensively used traditional Chinese medicine with a remarkable effect, commonly called "Changshan" in China. Alkaloids, as the material basis of its efficacy, are also the source of its toxicity. The plant can cause multiple organ damage, including liver, kidney and heart, and cause adverse reactions such as nausea and vomiting, abdominal pain and diarrhea.

The adverse effects of febrifugine include diarrhoea, vomiting, and liver toxicity. Although febrifugine has good antiparasitic activity at 2.5 mg per day orally, an emetic action limited its further use as an antimalarial drug.

Febrifugine is an alkaloid isolated from Dichroa febrifuga Lour. as the active component against Plasmodium falciparum. Adverse side effects have precluded febrifugine as a potential clinical drug.

8.2 Emetic Properties and Traditional Management

Because it can cause strong nausea and vomiting, it is used with caution, typically in processed form and only in robust patients, never in the weak or elderly. Methods to reduce toxicity include structural modification, traditional processing, and dosage form changes.

8.3 Documented Fatal and Serious Adverse Event

A suspected fatal case of D. febrifuga poisoning has been reported in China. The patient had a history of rheumatic heart disease. She developed nausea and repeated vomiting after consuming 10 g of dried roots as TCM. She later developed cardiogenic shock and succumbed despite supportive treatment.

8.4 Organ-Level Toxicity

It has been confirmed that the alkaloids are both the basis of efficacy and the source of toxicity, capable of causing multiple organ damage including liver, kidney, and heart. The compound has been associated with strong liver toxicity and nauseating effects.

8.5 Differential Toxicity of Halofuginone vs. Febrifugine

Halofuginone, the synthetic derivative of febrifugine from Chang Shan, has been examined as an antiprotozoal agent. Halofuginone has reduced toxic side effects compared to the parent compound and has progressed to commercial veterinary use and human clinical trials for tumors and fibrosis. The mechanism of action involves inhibition of prolyl-tRNA synthetase and its efficacy extends to malaria, coccidiosis, cryptosporidiosis, toxoplasmosis, and leishmaniasis.

8.6 Cautions for Specific Populations

Traditional Chinese medicine texts and the clinical toxicology literature consistently identify certain contraindications. Chang Shan is used with caution, typically in processed form and only in robust patients, never in the weak or elderly. The suspected fatal case involved a patient with pre-existing cardiac disease, highlighting heightened risk in individuals with cardiovascular compromise. The emetic property is particularly relevant for patients with esophageal, cardiac, or gastric conditions. Given the evidence for multi-organ alkaloid toxicity, including liver, kidney, and heart, the plant requires cautious use with attention to baseline organ function. This alkaloid has potent antimalarial properties; however, its clinical usage is impeded by the presence of adverse effects and toxicity associated.

References

• Zhang et al. (2024). Dichroa febrifuga Lour.: A review of its botany, traditional use, phytochemistry, pharmacological activities, toxicology, and progress in reducing toxicity. Journal of Ethnopharmacology. PubMed PMID: 38537842
• Characterization of the first chloroplast genome of Dichroa febrifuga and its phylogenetic analysis. Mitochondrial DNA Part B: Resources (2021)
• Pham TV et al. (2023). The anti-inflammatory activity of the compounds isolated from Dichroa febrifuga leaves. Saudi Journal of Biological Sciences. PMID: 36910464
• Jang CS et al. (1948). Pharmacology of Ch'ang Shan (Dichroa febrifuga), a Chinese Antimalarial Herb. Nature, 161, 400–401
• Park et al. (2009). Dichroa febrifuga Lour. inhibits the production of IL-1beta and IL-6 through blocking NF-kappaB, MAPK and Akt activation in macrophages. Journal of Ethnopharmacology. PMID: 19607899
• Choi BT et al. (2003). Anti-inflammatory effects of aqueous extract from Dichroa febrifuga root in rat liver. Acta Pharmacologica Sinica. PMID: 12546719
• Keller TL et al. (2012). Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase. Nature Chemical Biology. PMC3281520
• Bhatt et al. (2015). The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs. Science Translational Medicine. PMID: 25995223
• Jiang S et al. (2005). Antimalarial Activities and Therapeutic Properties of Febrifugine Analogs. Antimicrobial Agents and Chemotherapy, 49(3), 1169–1176
• Discovery of anticancer function of Febrifugine in bladder cancer cells. Toxicology and Applied Pharmacology (2024)
• Halofuginone for cancer treatment: A systematic review of efficacy and molecular mechanisms. Biomedicine & Pharmacotherapy (2022)
• Pines M & Spector I (2014). Halofuginone for fibrosis, regeneration and cancer in the gastrointestinal tract. World Journal of Gastroenterology. PMC4209542
• Mitsui Y et al. (2020). In vitro effects of febrifugine on Schistosoma mansoni adult worms. Tropical Medicine and Health. PMC7271449
• Pines M & Spector I (2015). Halofuginone — The Multifaceted Molecule. Molecules, 20(1), 573–594
• Halofuginone Sensitizes Lung Cancer Organoids to Cisplatin via Suppressing PI3K/AKT and MAPK Signaling Pathways. Frontiers in Cell and Developmental Biology (2021)
• Halofuginone inhibits growth and migration of breast cancer cells. International Journal of Oncology (2014)
• Hospital Authority Hong Kong: Toxic Plant — Dichroa febrifuga 常山
• Me & Qi: Chang Shan (Dichroa root) — TCM Herb Reference
• Acupuncture Today: Dichroa Root (chang shan)
• ScienceDirect Topics: Febrifugine — overview
• Pham TV et al. (2023). The anti-inflammatory activity of the compounds isolated from Dichroa febrifuga leaves. PMC9999195