Triptolide in the treatment of psoriasis and other immune-mediated inflammatory diseases

Rui Han; Martin Rostami-Yazdi; Sascha Gerdes; Ulrich Mrowietz

doi:10.1111/j.1365-2125.2012.04221.x

. 2012 Feb 20;74(3):424–436. doi: 10.1111/j.1365-2125.2012.04221.x

Triptolide in the treatment of psoriasis and other immune-mediated inflammatory diseases

Rui Han ^1,^*,^†, Martin Rostami-Yazdi ^1,^†, Sascha Gerdes ¹, Ulrich Mrowietz ¹

PMCID: PMC3477344 PMID: 22348323

Abstract

Apart from cancer chronic (auto)immune-mediated diseases are a major threat for patients and a challenge for physicians. These conditions include classic autoimmune diseases like systemic lupus erythematosus, systemic sclerosis and dermatomyositis and also immune-mediated inflammatory diseases such as rheumatoid arthritis and psoriasis. Traditional therapies for these conditions include unspecific immunosuppressants including steroids and cyclophosphamide, more specific compounds such as ciclosporin or other drugs which are thought to act as immunomodulators (fumarates and intravenous immunoglobulins). With increasing knowledge about the underlying pathomechanisms of the diseases, targeted biologic therapies mainly consisting of anti-cytokine or anti-cytokine receptor agents have been developed. The latter have led to a substantial improvement of the induction of long term remission but drug costs are high and are not affordable in all countries. In China an extract of the herb Tripterygium wilfordii Hook F. (TwHF) is frequently used to treat autoimmune and/or inflammatory diseases due to its favourable cost–benefit ratio. Triptolide has turned out to be the active substance of TwHF extracts and has been shown to exert potent anti-inflammatory and immunosuppressive effects in vitro and in vivo. There is increasing evidence for an immunomodulatory and partly immunosuppressive mechanism of action of triptolide. Thus, compounds such as triptolide or triptolide derivatives may have the potential to be developed as a new class of drugs for these diseases. In this review we summarize the published knowledge regarding clinical use, pharmacokinetics and the possible mode of action of triptolide in the treatment of inflammatory diseases with a particular focus on psoriasis.

Keywords: anti-inflammatory disease, psoriasis, triptolide

Introduction

Psoriasis is an immune-mediated inflammatory disease of the skin affecting 2–3% of Caucasian and 0.123% of the Chinese population [1, 2]. It negatively affects patients' health-related quality of life (HRQoL) and results in a significant socioeconomic burden. Traditional therapies include non-specific immunosuppressants, such as steroids and cyclophosphamide, and more specific compounds such as ciclosporin or other drugs which are thought to act as immunomodulators (fumarates and intravenous immunoglobulins). With increasing knowledge about the underlying pathomechanisms of the diseases targeted biologic therapies mainly consisting of anti-cytokine or anti-cytokine receptor agents have been developed. The latter have lead to a substantial improvement of the induction of long term remission but drug costs are high and cannot be covered in all countries.

Extracts of the herb Tripterygium wilfordii Hook F. (TwHF), also known as ‘Lei Gong Teng’, are used as one of the most common systemic treatments for inflammatory and (auto)immune disorders in China mainly due to their favourable cost–benefit ratio. TwHF has been used for centuries in traditional Chinese medicine to treat a variety of immunological disorders, including rheumatoid arthritis, immune complex nephritis and systemic lupus erythematosus. Originally, an extract obtained by boiling the root or leaves of TwHF in water (decoction) was used for systemic treatment. Since a number of adverse effects were observed during therapy the extraction method was changed [3]. With the aim to reduce toxicity an ethyl acetate extract and a chloroform–methanol extract (T2) were developed in the 1970s [4]. Both of these preparations are commercially available in China and have been used extensively meanwhile.

The extracts of TwHF contain more than 70 ingredients including diterpenoids, triterpenoids, sesquiterpenoids, β-sitosterol, dulcitol and glycosides [5]. Triptolide (C₂₀H₂₄O₆, chemical structure see Figure 1) turned out to be the most potent bioactive substance in the TwHF extracts. It has been shown to possess potent anti-inflammatory and immunosuppressive properties in vitro as well as in different animal models in numerous preclinical studies [6–10]. Besides its use for the treatment of psoriasis, it has been shown that triptolide inhibits experimental autoimmune uveoretinitis and prolongs allograft survival [11, 12]. Moreover, it has been demonstrated that a succinyl derivative of triptolide, PG490-88, can prevent graft vs. host disease [13]. In addition to its anti-inflammatory and immunosuppressive activities, triptolide also exhibits potent anti-tumour and anti-leukaemic activities [14–16].

Application of triptolide

Clinical use of triptolide

Empirically it was found that a dosage of 0.8–1.5 mg kg⁻¹ of T2 (equivalent to approximately 66 µg triptolide) given up to three times a day was safe and effective for the treatment of inflammatory and autoimmune diseases. With improvement of the disease the dose can be reduced stepwise by 10 mg day⁻¹ (equivalent to approximately 33 µg triptolide). In previous clinical practice treatment is stopped after a period of 3 months. If indicated it is usually resumed after a break of 1 to 2 months. However, continuous long term therapy is also used. Complete blood count, liver and kidney function and ECG are commonly monitored every 2 weeks. Treatment should be stopped if haemoglobin is lower than 60 g l⁻¹, white blood cells are less than 3.5 × 10⁹ l⁻¹, platelets are less than 100 × 10⁹ l⁻¹ or abnormal ECG, liver or kidney function is noticed [17].

Clinical studies using triptolide

During the past three decades, more than a thousand patients with different autoimmune and inflammatory diseases have been treated with extracts of TwHF in China in clinical trials and practice. It has been reported that rheumatoid arthritis [18–22], systemic lupus erythematosus (SLE) [23–26], systemic scleroderma [27], ankylosing spondylitis [28, 29], psoriatic arthritis [30, 31], Behçet's disease [32–34], polymyositis [35], Henoch-Schonlein purpura [36, 37], reactive status of leprosy [38–40], chronic lymphocytic thyroiditis [41], chronic nephrotic syndrome [42, 43], IgA nephropathy [44–46] as well as adult and childhood nephritis [47] were treated successfully [48]. Triptolide was also used for prevention of graft rejection after kidney transplantation [49]. Furthermore, triptolide was effective in the treatment of a variety of skin diseases such as psoriasis [30, 31], allergic contact dermatitis, polymorphous light eruption, erythema multiforme, atopic dermatitis and pemphigus [50–52]. Randomized, double-blind, placebo controlled clinical trials in the US have confirmed the efficacy in the treatment of rheumatoid arthritis [53–55]. Most clinical studies used the T2-extract of TwHF in which the content of triptolide is defined as 33 µg triptolide per 20 mg tablet.

Clinical studies with triptolide in psoriasis

Psoriasis is one of the primary indications for triptolide in China. It is important to emphasize that although efficacy of triptolide has been claimed in the above mentioned various dermatological conditions most of these claims have been derived from uncontrolled clinical trials or retrospective reports. Nevertheless, the reports are from multiple medical centres including more than a thousand patients. Some patients have been followed up for more than 10 years. As the incidence of psoriasis in China is rather low, the number of patients recruited in a local hospital is limited and therefore some clinical trials were performed including different clinical variants of psoriasis like plaque psoriasis, pustular psoriasis, erythrodermic psoriasis and psoriatic arthritis. In a literature search including the databases Medline, The Cochrane Library, China BioMedical Literature on disc (CBMdsic), National Science and Technology Library (NSTL), Vip and all Chinese medical journals only 10 randomized or quasi-randomized controlled trials of T2 or other extracts of TwHF with psoriasis patients were found. Nine of these studies were performed using a group of patients who received a comparator drug and only one was designed with a placebo group [56–65]. These studies have all been performed in China and are summarized in Table 1. A meta-analysis of all clinical trials demonstrates a statistically significant improvement of the disease after treatment with TwHF extracts [66].

Table 1.

Overview of all published randomized or quasi-randomized clinical trials in which psoriasis patients were treated with extracts of Tripterygium wilfordii Hook F

Trials	Method	Trial group					Control group					Intervention measures		PASI effective rate	Grades of evidence
Trials	Method	Cases	Age interval (years)	Age (mean SD) (years)	PASI before (mean ± SD)	PASI after treatment (mean ± SD)	Cases	Age interval (years)	Age (mean ± SD)	PASI before (mean ± SD)	PASI after treatment (mean ± SD)	trial group	control group	PASI effective rate	Grades of evidence
*He et al. [56]*	Quasi- random sampling	45	17–68	33.7 ± 4.1			43	17–68	33.7 ± 4.1			T2 20 mg × 3 day⁻¹,	Azithromycin 500 mg day⁻¹,	88.9% vs. 41.9%,	B
												4 weeks	2 weeks	P ≤ 0.05
												Azithromycin 500 mg day⁻¹, 2 weeks
*Hang et al. [57]*	Simple random sampling	28	16–45	26.7 ± 2.3	9.27 ± 4.12	2.02 ± 0.07	30	16–60	28.6 ± 14.2	10.27 ± 4.47	5.64 ± 2.46	T2 10 mg × 4 day⁻¹, Ampepitidium et Elementum 1.8 g × 2 day⁻¹, 8 weeks	Ampepitidium et Elementum 3 g × 2 day⁻¹, 8 weeks	89.3% vs. 40%, P≤ 0.01	B
*Ma et al. [58]*	Simple random sampling, double-blind	50	16–50	28.0 ± 2.3	9.4 ± 3.8	2.2 ± 0.01	50	16–65	29.5 ± 13.2	11.0 ± 4.51	9.52 ± 2.61	TwHF 3 g day⁻¹,	Indigo 20 mg × 3 day⁻¹,	84% vs. 64%,	A2
*Ma et al. [58]*	Simple random sampling, double-blind	50	16–50	28.0 ± 2.3	9.4 ± 3.8	2.2 ± 0.01	50	16–65	29.5 ± 13.2	11.0 ± 4.51	9.52 ± 2.61	4 weeks	4 weeks	P≤ 0.001	A2
*Yang et al. [59]*	Simple random sampling	54	16–62	31.6 ± 3.2			48	16–62	31.6 ± 3.2			T2 20 mg × 3 day⁻¹+	Erythromycin	74.1% vs. 50%,	B
												Erythromycin 0.25 g × 4 day⁻¹+	0.25 g × 4 day⁻¹+	P≤ 0.01
												Glycyrrhizin 150 mg ×× 3 day⁻¹,	Glycyrrhizin
												6 weeks	150 mg × 3 day⁻¹,
													6 weeks
*Chen et al. [60]*	Simple random sampling	37	15–73				34	15–73				T2 20 mg × 3 day⁻¹	Ampepitidium et Elementum 3 g × 2 day⁻¹	78.38% vs. 79.41%,	B
*Chen et al. [60]*	Simple random sampling	37	15–73				34	15–73				T2 20 mg × 3 day⁻¹	Ampepitidium et Elementum 3 g × 2 day⁻¹	Not significant	B
*Zhang et al. [61]*	Random number table, double-blind	25	16–45	26.7 ± 12.3	9.07 ± 4.23	2.12 ± 0.07	27	16–60	28.6 ± 14.2	10.04 ± 4.47	9.64 ± 2.46	TwHF 18 g day⁻¹,	Placebo	96% vs. 11%,	A2
*Zhang et al. [61]*	Random number table, double-blind	25	16–45	26.7 ± 12.3	9.07 ± 4.23	2.12 ± 0.07	27	16–60	28.6 ± 14.2	10.04 ± 4.47	9.64 ± 2.46	4 weeks	4 weeks	P≤ 0.001	A2
*Feng et al. [62]*	Simple random sampling	56	16–63				33	18–57				T2 20 mg × 3, 10 weeks	Ampepitidium et Elementum 3 g × 2 day⁻¹	96.43% vs. 87.88%,	B
*Feng et al. [62]*	Simple random sampling	56	16–63				33	18–57				T2 20 mg × 3, 10 weeks	10 weeks	Not significant	B
*Huang et al. [63]*	Quasi- random sampling	52	17–64	36.7 ± 18.2			43	18–67	34.7 ± 19.3			T2 10 mg × 3 day⁻¹, 60 days	Ampepitidium et Elementum 3 g × 2 day⁻¹	71.15% vs. 46.51%, P≤ 0.01	B
*Huang et al. [63]*	Quasi- random sampling	52	17–64	36.7 ± 18.2			43	18–67	34.7 ± 19.3			T2 10 mg × 3 day⁻¹, 60 days	60 days	71.15% vs. 46.51%, P≤ 0.01	B
*Lu et al. [64]*	Simple random sampling	98	13–59				66	13–59				T2 20 mg 3 day⁻¹+	Bimolane 0.2 g × 2 day⁻¹+ Folic acid 5 mg × 2 day⁻¹, 8 weeks	92.9% vs. 71.2%,	B
*Lu et al. [64]*	Simple random sampling	98	13–59				66	13–59				Bimolane 0.2 g × 2 day⁻¹+ Folic acid 5 mg × 2 day⁻¹, 8 weeks		P ≤ 0.05	B
*Shen et al. [65]*	Simple random sampling	112	14–73	43.52			96	12–75	45.68			decoction of TwHF,	Halcinonide ointment, 4 weeks	86.6% vs. 39.6%, P≤ 0.05	B
*Shen et al. [65]*	Simple random sampling	112	14–73	43.52			96	12–75	45.68			Halcinonide ointment, 4 weeks	Halcinonide ointment, 4 weeks	86.6% vs. 39.6%, P≤ 0.05	B

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In one clinical trial a TwHF extract was used in comparison with placebo in a randomized, double-blind trial in 61 patients with plaque psoriasis [61]. Patients received 18 g day⁻¹ of a TwHF ethanol extract for 4 weeks. The psoriasis area and severity index (PASI) decreased from initially 9.1 to 4.2 in comparison with the placebo group in which the PASI remained almost stable after 2 weeks of treatment. In three patients the skin was completely cleared. Analysis after 4 weeks of treatment showed a further decrease of PASI to 2.1 with almost no change in the placebo group. In 64% of the patients a PASI100 could be observed. Two patients in the treatment arm discontinued the study due to severe GI reactions and four patients developed moderate GI reactions which could be treated with metoclopramide. One woman had a delayed menstrual cycle which normalized after treatment was stopped.

Another double-blind, randomized clinical study involved 100 patients with psoriasis vulgaris [58]. Fifty patients received a TwHF ethanolic extract (18 g daily orally), another 50 patients were treated with an equal dose of an extract of indigo naturalis (a dark blue plant used to treat psoriasis in traditional Chinese medicine). PASI decreased significantly from 9.4 to 4.3 (indigo naturalis: from 11.0 to 9.5) after 2 weeks of treatment. In 12 patients the skin was completely cleared. Analysis after 4 weeks of treatment showed further significant improvement of PASI to 2.2 in the treatment group whereas the PASI in the placebo group remained almost stable. In 64% of patients receiving the TwHF extract but only in 28% of the indigo group a PASI100 was observed. GI reactions were seen in two patients who could be treated symptomatically.

In three of the listed studies drug combinations were used. Two studies used a combination of triptolide with macrolide antibiotics such as azithromycin and erythromycin. In a quasi-randomized, open-label study 131 patients with guttate or plaque psoriasis participated [56]. In the first treatment group patients received 20 mg T2 orally three times daily for 4 weeks followed by 2 weeks of i.v. administration of azithromycin (500 mg day⁻¹). The second treatment group received T2 only and patients in the control groups received azithromycin. A reduction of the PASI of more than 60% was seen in 88.9% of patients in the first treatment group and in 40.0% of patients psoriasis was totally cleared. Patients treated with T2 only showed a 60% reduction of PASI in 67.4% of patients in comparison with 41.9% of patients treated with azithromycin. The most common adverse event under T2 treatment was nausea. In four cases irregular menstruation developed and in two cases leukocytopenia was observed. All these side effects were reversible within 2 weeks after treatment had been stopped.

In a further randomized trial 54 psoriasis patients were treated with T2 (20 mg, three times daily orally) combined with erythromycin (0.25 g four times daily) and glycyrrhizin (150 mg three times daily) [59]. In this study 74.1% of patients in the treatment group showed a reduction of PASI of 60% compared with 50% in the control group after 6 weeks of treatment. The short term and long term (over 1 year) recurrence rate in both groups showed no significant difference. Adverse reactions included slight dizziness (one case), menoxenia (one case) and elevated aminotransferases (one case). Adverse events were reversible 2 weeks after treatment was stopped.

Plaque psoriasis, pustular or erythrodermic psoriasis or psoriatic arthritis were included in a randomized trial in 164 patients [64]. Patients were randomized to receive T2 (20 mg three times daily), bimolane (0.2 g twice a day) and folic acid (5 mg twice a day) in the treatment group or only bimolane and folic acid in the control group. Bimolane is a member of a bis (2,6-dioxopiperazine) class of drugs and has been widely used in China as an anti-neoplastic agent and for the treatment of psoriasis. Folic acid is given to patients to reduce the likelihood of oral ulcers and blood count abnormalities similar to the use with methotrexate. After 8 weeks 92.9% of patients in the treatment group showed a PASI75 response compared with 71.2% in the control group. Total skin clearance occurred in 50% and 31.8% of the patients, respectively. Two patients in the treatment group in comparison with five patients in the control group relapsed 4 weeks after discontinuing treatment.

Another medication named Di Yin Pian, or Ampepitidium et Elementum, is also widely used to treat psoriasis in China. This was used as a comparator in four clinical trials with triptolide. One randomized trial involved 158 patients with plaque psoriasis, pustular or erythrodermic psoriasis and psoriatic arthritis [60]. Patients were randomized into three groups receiving T2 (20 mg three times daily orally), or Ampepitidium et Elementum (3 g twice daily orally), or a combination of T2 and Ampepitidium et Elementum. A reduction in PASI of 70% was achieved by 78.4% of the patients receiving T2, similar to the patients receiving Ampepitidium et Elementum (79.4%). A significant improvement of 95.4% reaching a PASI70 was seen in the combination group. In the T2 group only 8.1% of the patients showed GI adverse events, much less than in the other groups (85%).

Another randomized study included 58 patients with plaque psoriasis and was carried out over 8 weeks [57]. Participants in the treatment group received T2 (10 mg orally four times daily) and Ampepitidium et Elementum (1.8 g orally twice a day). In the control group Ampepitidium et Elementum was administered (3 g twice a day). Improvement in PASI (from 9.3 ± 4.1 to 4.3 ± 1.1) occurred after 4 weeks with T2 therapy. In the control group the PASI dropped from 10.3 ± 4.5 to 7.5 ± 1.3. After 8 weeks PASI70 was seen in 89.3% of the patients in the treatment group compared with only 40% in the control group. Only one patient in the treatment group developed menoxenia and two patients developed GI reactions. Side effects were reversible.

Another clinical trial in 2004 included 89 patients with plaque psoriasis [62]. Participants were randomly assigned to receive T2 (20 mg three times daily orally) and Ampepitidium et Elementum (3 g twice daily orally) as the treatment group, or the same dose of Ampepitidium et Elementum as the control group. Total skin clearance occurred in 48.2% of the patients in the treatment group after 10 weeks, which was significantly higher when compared with 18.2% of the patients in the control group.

The same treatment as mentioned above was used in a study including 95 patients with plaque psoriasis [63]. After 9 weeks of treatment 71.2% of the patients in the treatment group showed a reduction of PASI of 60% as compared with 46.5% in the control group. Three patients in the treatment group developed GI reactions at day 8, two patients developed leukocytopenia (≤4.0 × 10⁹ l⁻¹) and in one patient elevated alanine transaminases occured. In all patients adverse effects were reversible after reducing the dose of T2.

In a further study a decoction prepared from roots of TwHF was used in a randomized study involving 208 patients with plaque psoriasis [65]. One hundred and two patients received 50 ml of the decoction per day as oral treatment together with halcinonide ointment for external use once a day. As a control group 96 patients received only halcinonide ointment once a day. The study ended after 4 weeks. In 86.6% of the treatment group a reduction of PASI of 60% was observed and 45.5% of the patients achieved a PASI100. In comparison, 39.6% of the patients in the control group showed a reduction of PASI of 60%. Adverse reactions included tolerable GI reaction (11 cases), delayed menstrual period (three cases), and mild leukocytopenia (one case).

The design of numerous of the studies which have been published and discussed may not meet state-of-the-art criteria for clinical trials today. Proper definition of the selected population such as moderate-to-severe psoriasis and the inclusion only of plaque psoriasis following standard definitions were not performed. In addition, significant improvement of PASI in patients with only mild forms of psoriasis may bias a favourable efficacy outcome. Another drawback for a better understanding of the benefit–risk profile of triptolide is the lack of long term trials or even reports of open studies running for more than 1 year. On the background of published data to date it is difficult to judge the full potential of this drug for use in psoriasis.

These shortcomings may lead to the design of a head-to-head trial with methotrexate as the active comparator in a defined patient population with plaque psoriasis in order to gain further insight into the potential benefits and risks of the use of triptolide for this indication. Such a trial should be performed in Asians and Caucasians.

Mode of action of triptolide

The C-14 beta-hydroxyl and gammabutyrolactone moieties of the triptolide molecule were shown to be crucial for its anti-inflammatory properties and also for cytotoxicity [67]. Molecular biological research of the past decades indicates that the MAP kinase pathways as well as the transcription factor nuclear factor-kappa B (NF-κB) are the major targets regulating inflammatory responses in various cells in vivo and in vitro[68–72].

In mice, triptolide acts on the tumour necrosis factor α (TNF-α)/tumour necrosis factor receptor 2 pathway of lymphocytes in the colon inhibiting the activation of NF-κB as well as the expression of interferon (IFN) -γ[39]. Triptolide can inhibit TNF-α, interleukin (IL)-1β, IL-6 and IL-8 production in human bronchial epithelial cells and also staphylococcal exotoxin-stimulated T-cell proliferation and expression of Il-1β, IL-6, TNF, IFN-γ, monocyte chemotactic protein (MCP) -1, macrophage inflammatory protein (MIP) -1α and MIP-1β released from peripheral blood mononuclear cells (PBMCs) [73]. By attenuating the transcription at the purine-box/antigen receptor response element, triptolide reduced IL-2 production and release from Jurkat T cells [74]. Recently it was found that triptolide inhibited the differentiation of murine CD4⁺ T cells into Th17 cells in a dose dependent manner [75]. Triptolide decreased the transcription level of Il-17 mRNA and IL-6-induced phosphorylation of STAT3, a key signalling molecule involved in the development of Th17 cells.

Expression of prostaglandin E₂ in lymphocytes is also suppressed by triptolide [9].

The T2 extract also inhibited the production of the immunoglobulins IgM, IgG and IgA by stimulated B-lymphocytes [76].

Accessory cells, in particular professional APCs such as dendritic cells (DCs), are another target of the immunosuppressive activity of triptolide. Triptolide inhibited the differentiation, maturation, trafficking and function of immature DCs [77, 78]. High concentrations (≥20 ng ml⁻¹) of triptolide induced apoptosis in DCs through sequential p38 MAP kinase phosphorylation and caspase 3 activation [14]. DC-mediated chemo-attraction of neutrophils and T cells has also been shown to be inhibited by triptolide through decreased STAT3 phosphorylation and NF-κB activation [79]. Triptolide prevented the differentiation of immature monocyte-derived DCs (MoDCs) by down-regulation of CD1a, CD40, CD80, CD86, and HLA-DR expression, and by reducing the capacity of MoDCs to stimulate lymphocyte proliferation in the allogeneic mixed lymphocyte reaction (MLR).

However, expression of surface CD14 and phagocytic capacity of MoDCs were increased by triptolide [77]. Interestingly, modulation/suppression of T-cell functions and inhibition of dendritic cell differentiation together with unaffected phagocytic function of monocytes has previously been observed for dimethylfumarate (DMF), a compound which is used to treat psoriasis systemically in Germany and which is under development for multiple sclerosis in phase III clinical trials [80]. Although treatment with fumarates and triptolide can lead to lymphocytopenia, a significantly increased risk for severe infections has not been observed even during long term use with fumarates [81]. This may at least in part be due to the fact that both drugs do not interfere with the phagocytic capacity of cells of the monocytic lineage.

In host defense against intracellular pathogens and malignancies Il-12, produced by APCs, plays an important role. Il-12 and IL-23 are strongly associated with the pathogenesis of psoriasis [82]. Triptolide was shown to reduce the IFN-γ-induced CD80 and CD86 expressions and inhibit Il-12 and IL-23 expression in DCs and in THP-1 cells, a human monocytic cell line [78, 83, 84]. Recently, it was shown that triptolide inhibited Il-12/IL-23 expression in APCs via CCAAT/enhancer-binding protein alpha [85], which provided mechanistic insights into the immunomodulatory capacity of triptolide.

In addition, triptolide was shown to suppress pro-inflammatory responses by attenuating various intracellular signalling pathways including the toll like receptor (TLR) signalling. It was reported that treatment of mouse macrophages with triptolide suppressed inflammation by down-regulating TLR gene expression [86].

Triptolide also blocks the production of two chemokines, IL-8 and MCP-1, in cultured human corneal fibroblasts stimulated with pro-inflammatory cytokines [68]. Expression of intracellular adhesion molecule 1 (ICAM-1) and of matrix metalloproteinase 9 (MMP-9) in psoriatic lesions decreased after topical treatment with TwHF [87].

Hyperproliferation of keratinocytes is characteristic for psoriasis. Triptolide is able to modulate the production of several mediators in keratinocytes. It could inhibit CXCL11/I-TAC secretion induced by IFN-γ and TNF-α and thereby decrease the infiltration of Th1 cells in the skin [88]. High concentrations of T2 down-regulated NF-κB expression in keratinocytes, which may regulate immune and inflammatory responses in the skin [49].

However, despite intensive research the precise mode of action of triptolide regarding its molecular target(s) still remains unclear. In an array study triptolide treatment modulated the expression of 22.5% of 195 immune signalling genes, the spectrum of which is already beyond the spectrum of genes controlled by NF-κB or AP-1. Recently, Vispe et al. found that triptolide inhibits both total RNA and mRNA neosynthesis by up to 80% by using [³H]-uridine incorporation [89]. It has been suggested that triptolide could reduce the level of RNA polymerase I and II in cancer cells [90], which may explain the broad spectrum of genes whose expression are influenced upon triptolide treatment.

Pharmacokinetics

A well designed pharmacokinetic study on triptolide metabolism in humans after systemic administration has not yet been published. A plasma peak concentration of 0.15 mg l⁻¹ has been reported from only one clinical study [91].

In beagle dogs the maximum plasma concentration (C_max) after i.v. administration of 0.05 mg kg⁻¹ triptolide was 28.0 ± 11.8 ng ml⁻¹ (Table 2).

Table 2.

Pharmacokinetic parameters in dogs or rats after oral or i.v. administration of triptolide

Route of administration	Dose (mg kg⁻¹)	C_max (µg l⁻¹)	t_max (min)	t_1/2 (min)
Beagle dogs [125]
Intragastric	0.05	35 ± 8	30 ± 6	150 ± 42
Intragastric	0.08	64 ± 16	30 ± 12	156 ± 60
Intragastric	0.10	74 ± 7	30 ± 18	144 ± 72
i.v.	0.05	28.0 ± 11.8	57.6 ± 18	150 ± 56
Rats [92]
Oral	0.6	254 ± 47.34	11.00 ± 2.24	21.70 ± 3.00
Oral	1.2	446.65 ± 112.86	10.00 ± 0.00	16.81 ± 5.24
Oral	2.4	537.33 ± 143.34	10.00 ± 0.00	20.40 ± 3.75
i.v.	0.6			15.10 ± 4.44

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C_max maximum concentration, t_max time to maximum concentration; t_1/2 elimination half-life.

In rats, the kinetics of triptolide fulfilled the criteria of a one compartment model after i.v. administration. Bioavailability after oral administration of 0.6 mg kg⁻¹ was 72.1%. Less than 1% triptolide was excreted in the bile, urine or faeces within 48 h. After oral application of 1.2 mg kg⁻¹ triptolide to rats tic, somnolence, kolyphremia and anorexia were observed from 4 to 24 h post dose and some of the animals died [92].

Toxicological data after application of purified triptolide are not available. They are only reported for the ethyl acetate and the T2 extract of TwHF.

Variation of the LD₅₀ results is due to the fact that extracts were prepared from the root, stem or leaf of TwHF. Furthermore, the duration of extraction plays a crucial role regarding the final concentration of triptolide [93]. For the ethyl acetate extract the LD₅₀ in mice is 608–858 mg kg⁻¹. Orally administrated concentrations from 1/16 to 1/4 of the mean LD₅₀ dose in rats over a time period of 6 months revealed pathological changes mainly in the lymphatic and reproductive systems [94]. For T2 the LD₅₀ in mice is reported to be 159.7 mg kg⁻¹. In mice, rats and dogs treated with doses from 1/4 to 1/24 of the LD₅₀ for 80 days, pathological changes were mainly observed in the testes [3]. After i.v. injection of triptolide to mice a LD₅₀ of 0.8 mg kg⁻¹ was determined [95].

Adverse effects

The major side effects of TwHF extracts are gastrointestinal (GI) complaints, in particular diarrhoea, skin rash and pigmentation, decrease in white and red blood cells and platelets and malfunction of the male and female reproductive system [18, 19, 96–99]. GI adverse events were usually observed in the beginning of treatment and were dose dependent. They often caused early discontinuation of treatment [100].

Skin rashes and hyperpigmentation are often seen but are not regarded as a reason to stop treatment.

Treatment with triptolide is often associated with dysmenorrhea and irregular menstruation [98, 100–105]. Administration of triptolide (40 mg daily for 1 month) can cause reversible sterility in men, with a 50% reduction of sperm motility. The long term administration (over 2 months) of triptolide or an extract of TwHF can lead to severe reduction of both sperm counts and motility. This effect was first noted in the treatment of Chinese men with TwHF extracts with a daily dose of 20 mg to 30 mg to treat rheumatoid arthritis and psoriasis who became sterile within 2 months. In these patients testosterone and LH concentrations as well as libido and sexual potency were unchanged [106]. This effect led to the investigation of triptolide as a contraceptive for men [107]. However, as infertility was not reversible in rats the interest in triptolide has dropped for this application [108].

An adverse effect on renal function such as a decrease of creatinine clearance in elderly patients is documented [104]. There is at least one report in which induction of hypertension by triptolide has been described [53].

There is one case report about a young man who developed profuse vomiting, diarrhoea, leukopenia, renal failure, profound hypotension and shock after oral administration of the extract [109]. Therapeutic concentrations showed a haematotoxic effect leading to bone marrow suppression [110].

Abnormal development of mouse embryos has been observed in vitro[111] and human occipital meningoencephalocele of a newborn associated with use of the extract by the mother has been reported [112].

Up to 6% of patients treated with TwHF extracts developed leukopenia. The immunosuppressive effects of TwHF may also render patients susceptible to infectious diseases like upper respiratory tract infections [113]. Most adverse events were reversible either spontaneously or after dose adjustment. Interestingly, the side effect-related withdrawal rate for T2 in a 3 month trial was only 2.9% [18].

Treatment-related death has rarely been seen and has occurred mostly in patients who either received an overdose due to self-prepared decoctions or alcoholic extracts of TwHF (tincture). Causes of death were myocardial damage, renal failure, low volume shock or severe intestinal tract disturbances [114].

Outlook

One clinical trial compared purified triptolide (0.5–0.75 mg day⁻¹) with an ethyl alcohol extract (120 mg day⁻¹) in the treatment of rheumathoid arthritis. Significant improvement of the disease in both groups was seen. However, adverse effects were observed more frequently and were more pronounced in the group treated with purified triptolide [115].

Efforts have been made to reduce the toxicity of triptolide by chemical modification. Among these derivatives, tripchlorolide and tripbromolide were reported to exert inhibitory activities on antibody formation in mice. Furthermore, in vitro proliferation of murine lymphocytes was inhibited. However, these derivatives were not as potent as triptolide experimentally [116]. In view of this, several triptolide derivatives with improved water solubility have been developed, like PG490-88, LLDT-8 and F60008.

PG490-88 is a water-soluble 14-succinyl sodium salt of triptolide which was synthesized in early 2000 (Figure 2). This compound is a prodrug of triptolide and is metabolized to triptolide after absorption into the blood. Its anti-inflammatory effects were demonstrated to be comparable with triptolide. An early study showed that intraperitoneal injection of PG490-88 at a dose of 0.25 mg kg⁻¹ day⁻¹ for 2 weeks could attenuate inflammation and fibrosis in the bleomycin model of mouse lung fibrosis [117]. Pan et al. showed that oral administration of PG490-88 could prolong graft survival time from 7 days to 19 days using a rat model of kidney transplantation [118]. The anti-cancer property of this prodrug has been successfully tested in a phase I study for the treatment of solid tumours [119].

Chemical structure of PG490-88. Formula C₂₄H₂₈O₉Na. Molecular weight 483.47

A clinical phase I trial with F60008, another synthetic derivative of triptolide, showed three complete remissions out of 26 patients with acute myeloid leukaemia [120]. However, a phase I study of F60008 in the Netherlands for the treatment of solid tumours (colorectal carcinoma, oesophageal carcinoma, gastrointestinal stromal tumour and others) showed high inter-individual variability [121].

LLDT-8 is a C14-hydroxyl substituted derivative of triptolide, and its anti-inflammatory effect has been extensively studied in China (Figure 3). It was demonstrated to protect mice against experimental bleomycin-induced lung fibrosis by suppressing the production of TNF-α, IL-4 and transforming growth factor (TGF)-β and by infiltration of neutrophils and lymphocytes into the bronchoalveolar space [122]. Of note, a mechanistic study showed LLDT-8 primarily targeted the activated T cells. It suppressed the ovalbumin-specific T cell proliferation and inhibited T cell-derived IFN-γ production by reducing the gene expressions of the IFN-γ pathway [123]. A recent study showed that LLDT-8 could significantly suppress mixed lymphocyte reaction as well as IL-2 and TNF-α released from activated peripheral blood mononuclear cells [124]. Clinical studies with LLDT-8 in rheumatoid arthritis are now being performed in China.

The structure of (5R)-5-hydroxytriptolide (LLDT-8). Formula C₂₀H₂₄O₇. Molecular weight 376.39

Conclusions

The pathogenesis of psoriasis is unknown, although it is generally accepted that this chronic inflammatory skin disorder is a complex cutaneous immune reaction with a major inflammatory component involving elements of the innate and adaptive immune system and abnormal keratinocyte proliferation/differentiation. Activation of antigen-presenting cells leads to the preferential development of Th1- and Th17-type T cells that migrate into and proliferate within the skin. Several mediators have been identified that orchestrate many of the changes typical of psoriasis, including Il-12 and IL-23, TNF-α and IFN-γ. Present studies of triptolide have shown inhibitory effects on the differentiation of DCs as well as Th1 and Th17 cells. Furthermore, triptolide decreased concentrations of Il-12, IL-23, TNF-α and IFN-γ. Despite several unknown aspects of the treatment with triptolide, there is strong evidence that triptolide is an effective therapy for immune-mediated inflammatory diseases such as psoriasis.

When the efficacy of triptolide, mainly using the T2 extract, is compared to currently registered drugs or to UV treatment for psoriasis triptolide was superior to methotrexate. Although no formal registries or post-marketing data are available for the use of triptolide in psoriasis or autoimmune diseases the common use of this drug provides a reasonable background of information not only on efficacy but also on safety. Triptolide is used for short term induction therapy and thus data on long term effects including efficacy, safety and tolerability are lacking.

Triptolide can be regarded as a model substance from which to develop new chemically modified compounds for the treatment of diseases mentioned above. Such drug-modelling may also overcome the adverse effects which triptolide has on fertility in males.

Competing Interests

There no competing interests to declare.

REFERENCES

1.Raychaudhuri SP, Farber EM. The prevalence of psoriasis in the world. J Eur Acad Dermatol Venereol. 2001;15:16–7. doi: 10.1046/j.1468-3083.2001.00192.x. [DOI] [PubMed] [Google Scholar]
2.Yip SY. The prevalence of psoriasis in the Mongoloid race. J Am Acad Dermatol. 1984;10:965–8. doi: 10.1016/s0190-9622(84)80314-x. [DOI] [PubMed] [Google Scholar]
3.Tao X, Lipsky PE. The Chinese anti-inflammatory and immunosuppressive herbal remedy Tripterygium wilfordii Hook F. Complementary and alternative therapies for rheumatic diseases II. Rheum Dis Clin North Am. 2000;26:29–50. doi: 10.1016/s0889-857x(05)70118-6. [DOI] [PubMed] [Google Scholar]
4.Gutian Hospital and Beisha Hospital FP. Report on the therapeutic effect of the herbal medicine Tripterygium wilfordii Hook F on reactive status of leprosy [in Chinese] Pi Fu Bing Fang Zhi Tong Xun. 1972;2:29–30. [Google Scholar]
5.Chen BJ. Triptolide, a novel immunosuppressive and anti-inflammatory agent purified from a Chinese herb Tripterygium wilfordii Hook F. Leuk Lymphoma. 2001;42:253–65. doi: 10.3109/10428190109064582. [DOI] [PubMed] [Google Scholar]
6.Asano K, Matsuishi J, Yu Y, Kasahara T, Hisamitsu T. Suppressive effects of Tripterygium wilfordii Hook F, a traditional Chinese medicine, on collagen arthritis in mice. Immunopharmacol. 1998;39:117–26. doi: 10.1016/s0162-3109(98)00006-x. [DOI] [PubMed] [Google Scholar]
7.Chang ML, Yang LL, Chang DM, Kuo SY, Chu SJ. The influence of Chinese traditional medicine on the production and activity of interleukin 1 (IL-1) [in Chinese] Zhonghua Min Guo Wei Sheng Wu Ji Mian Yi Xue Za Zhi. 1993;26:15–24. [PubMed] [Google Scholar]
8.Chang DM, Chang WY, Kuo SY, Chang ML. The effects of traditional antirheumatic herbal medicines on immune response cells. J Rheumatol. 1997;24:436–41. [PubMed] [Google Scholar]
9.Tao X, Schulze-Koops H, Ma L, Cai J, Mao Y, Lipsky PE. Effects of Tripterygium wilfordii Hook F extracts on induction of cyclooxygenase 2 activity and prostaglandin E2 production. Arthritis Rheum. 1998;41:130–8. doi: 10.1002/1529-0131(199801)41:1<130::AID-ART16>3.0.CO;2-4. [DOI] [PubMed] [Google Scholar]
10.Ho LJ, Chang DM, Chang ML, Kuo SY, Lai JH. Mechanism of immunosuppression of the antirheumatic herb TWHf in human T cells. J Rheumatol. 1999;26:14–24. [PubMed] [Google Scholar]
11.Wu Y, Wang Y, Zhong C, Li Y, Li X, Sun B. The suppressive effect of triptolide on experimental autoimmune uveoretinitis by down-regulating Th1-type response. Int Immunopharmacol. 2003;3:1457–65. doi: 10.1016/S1567-5769(03)00144-9. [DOI] [PubMed] [Google Scholar]
12.Kupchan SM, Court WA, Dailey RG, Jr, Gilmore CJ, Bryan RF. Triptolide and tripdiolide, novel antileukemic diterpenoid triepoxides from Tripterygium wilfordii. J Am Chem Soc. 1972;94:7194–5. doi: 10.1021/ja00775a078. [DOI] [PubMed] [Google Scholar]
13.Chen BJ, Chen Y, Cui X, Fidler JM, Chao NJ. Mechanisms of tolerance induced by PG490-88 in a bone marrow transplantation model. Transplantation. 2002;73:115–21. doi: 10.1097/00007890-200201150-00022. [DOI] [PubMed] [Google Scholar]
14.Liu Q, Chen T, Chen H, Zhang M, Li N, Lu Z, Ma P, Cao X. Triptolide (PG-490) induces apoptosis of dendritic cells through sequential p38 MAP kinase phosphorylation and caspase 3 activation. Biochem Biophys Res Commun. 2004;319:980–6. doi: 10.1016/j.bbrc.2004.04.201. [DOI] [PubMed] [Google Scholar]
15.Jiang XH, Wong BC, Lin MC, Zhu GH, Kung HF, Jiang SH, Yang D, Lam SK. Functional p53 is required for triptolide-induced apoptosis and AP-1 and nuclear factor-kappaB activation in gastric cancer cells. Oncogene. 2001;20:8009–18. doi: 10.1038/sj.onc.1204981. [DOI] [PubMed] [Google Scholar]
16.Wang X, Matta R, Shen G, Nelin LD, Pei D, Liu Y. Mechanism of triptolide-induced apoptosis: effect on caspase activation and Bid cleavage and essentiality of the hydroxyl group of triptolide. J Mol Med. 2006;84:405–15. doi: 10.1007/s00109-005-0022-4. [DOI] [PubMed] [Google Scholar]
17.Tang ZL. New development in clinical application of Tripierygium wilfordii Hook F [in Chinese] 2004. Papers series of the Fourth National Academic Conference of Tripierygium wilfordii Hook F.
18.Tao XL, Sun Y, Dong Y. A double-blind, controlled trial of Tripterygium wilfordii glycosides in the treatment of rheumatoid arthritis. Arthritis Rheum. 1987;30:59–9. [Google Scholar]
19.Yu DY. Clinical observation of 144 cases of rheumatoid arthritis treated with glycoside of radix Tripterygium wilfordii [in Chinese] J Tradit Chin Med. 1983;3:125–9. [PubMed] [Google Scholar]
20.Huang CF, Wu CB, Shen ZK. Study on the treatment of rheumatoid arthritis with polyglycosides of Tripterygium wilfordii Hook-a randomized, controlled, cross-over clinical trial [in Chinese]. 2003. Third Annual National Meeting of Rheumatology (Chinese)
21.RA Cooperative Group. Clinical trial of Tripterygium wilfordii Hook in the treatment of 31 patients with rheumatoid arthritis [in Chinese] Wuhan Yi Xue Bao. 1977;6:51–3. [Google Scholar]
22.Su DF, Li RL, Sun YJ. Report of 270 patients with rheumatoid arthritis treated with ethyl acetate extract of Tripterygium wilfordii Hook F. [in Chinese] Zhong Yao Yao Li Yu Lin Chuang. 1989;5:40–2. [Google Scholar]
23.Li ZM, Zheng CS. Observation on treatment of systemic lupus erythematosus with extract of Tripterygium wilfordii Hook [in Chinese] J New Chin Med. 1982;12:22–4. [Google Scholar]
24.Liao WQ. Observations on the therapeutic effect of Tripterygium wilfordii Hook F on systemic lupus ethythematosus [in Chinese] Pi Fu Bing Fang Zhi Yan Jiu Tong Xun. 1980;9:14–5. [Google Scholar]
25.Xue ZY. Treating 103 cases of SLE with Tripterygium wilfordii Hook F [in Chinese] Chin J Dermatol. 1982;15:141–3. [Google Scholar]
26.Xue GY, Xue JH, Tang YC. Treatment of 21 patients with SLE with Tripterygium wilfordii Hook [in Chinese] Chin J Dermatol. 1984;17:201–3. [Google Scholar]
27.Su LD, You JC. Comparison of efficacy between Tripterygium wilfordii Hook and cochicine in the treatment of systemic sclerosis [in Chinese] 1988. Third Annual National Meeting of Rheumatology (Chinese)
28.Bei RX, Liu H, Wang XC. Tripterygium wilfordii Hook F in the treatment of rheumatoid arthritis and ankylosing spondylitis [in Chinese] Chin J Orthop. 1988;8:209–13. [Google Scholar]
29.Guo JL, Gao ZG, Zan AC. Treatment of rheumatoid arthritis and ankylosing spondylitis with Tripterygium wilfordii Hook F: 2-5 year follow-up [in Chinese] Chin J Orthop. 1984;4:133–7. [Google Scholar]
30.Fan ZH. Analysis of the therapeutic effect of Tripterygium wilfordii Hook on 52 patients with psoriasis [in Chinese] Acta Acad Med Nanjing. 1984;14:451–3. [Google Scholar]
31.Xu WY, Zheng JR, Lu XY. Tripterygium in dermatologic therapy. Int J Dermatol. 1985;24:152–7. doi: 10.1111/j.1365-4362.1985.tb05746.x. [DOI] [PubMed] [Google Scholar]
32.Xie DF, Shen JS, Fei JF. Experience in the treatment of Behcet's disease with polyglycosides of Tripterygium wilfordii Hook f [in Chinese] Chin J Integr Med. 1983;3:349–50. [Google Scholar]
33.Wan L, Zhao RF, Zhou W, Yuan NM. Clinical analysis of 50 cases of Behcet disease treated by thalidomide combined with Tripterygium glycosides [in Chinese] J Pract Stomatol. 2006;22:659–61. [Google Scholar]
34.Luo HP. Treatment on 10 cases of Behcet's disease using decoction of Tripterygium wilfordii [in Chinese] Jiujiang Med J. 2002;17:41. [Google Scholar]
35.Sun Q, Qiu JF, Cai ZH, Shen MJ. Tripterygium wilfordii treatment of polymyositis and dermatomyositis-preliminary change of creatase [in Chinese] J Chin Physician. 1998;3:54. [Google Scholar]
36.Bai HT, Yang DS, Zheng YJ. Effect of Triptergium glycosides on children with allergic purpura [in Chinese] J Xinxiang Med Coll. 2002;19:282–3. [Google Scholar]
37.Dong Z, Jiao YQ, Lu SG. The use of double-dosed Tripterygium polyglucoside in treating Henoch-Schonlein purpura [in Chinese] Acta Acad Med Xuzhou. 2003;23:334–6. [Google Scholar]
38.Feng B. Observation on the effect of polyglycosides of Tripterygium wilfordii Hook (T2) in 50 cases of leprosy reactive status [in Chinese] Clin J Dermatol. 1985;4:211. [Google Scholar]
39.Lei Gong Teng Cooperative Research Group of Fujian and Jiangsu Provinces. Clinical observation on Chinese herb Lei Gong Teng in treatment of leprosy reaction [in Chinese] Acta Acad Med Sin. 1979;1:72–4. [Google Scholar]
40.Wu YZ. Treatment of neuralgia of lepra reactive status with polyglycosides of Tripterygium wilfordii Hook F (T2) [in Chinese] Chin J Dermatol. 1986;19:217–9. [Google Scholar]
41.Mou LP. The clinical observation of chronic lymphatic thyroiditis with treatment of Tripterygium Witfondii Hooh F. [in Chinese] J Bengbu Med Coll. 2000;25:254–5. [Google Scholar]
42.Jiang X. Clinical observations on the use of the Chinese herb Tripterygium wilfordii Hook for the treatment of nephrotic syndrome. Pediatr Nephrol. 1994;8:343–4. doi: 10.1007/BF00866356. [DOI] [PubMed] [Google Scholar]
43.Xu G, Tu W, Jiang D, Xu C. Tripterygium wilfordii Hook F treatment for idiopathic refractory nephrotic syndrome in adults: a meta-analysis. Nephron Clin Pract. 2009;111:c223–c228. doi: 10.1159/000208990. [DOI] [PubMed] [Google Scholar]
44.Yang FY, Wei CY, Li CY. A controlled study on Tripterygium glycosides for treating IgA nephropathy patients who presented with non-nephrofic syndrome [in Chinese] Chin J Gen Pract. 2008;6:1138–9. [Google Scholar]
45.Xie T, Zhong YX, Mai WM, Huang PP. Clinic research on Tripterygium glycosides for treating IgA nephropathy [in Chinese] Chin J Postgrad Med. 2008;31:35–6. [Google Scholar]
46.Li X, Hao J. Clinical Observation on Urokinase Combined with Tripterygium Wilfordii Polyglycoside For IgA Nephropathy [in chinese] Appl J Gen Pract. 2006;4:410–1. [Google Scholar]
47.Ma WH, Guo XQ, Wei ZH. Effect of Tripterygium Glycosides with Prednisone in Treating Henoch-Schonlein Purpura Nephritis [in chinese] J Appl Clin Pediatr. 2007;22:1344–6. [Google Scholar]
48.Li QH, Hu ZX, Huang MG. Clinical observation on Huang Kui capsule combined with Tripterygium wilfordii polyglycoside for chronic glomerulonephritis [in Chinese] Mod J Integr Tradit Chin West Med. 2005;14:1429–30. [Google Scholar]
49.Zhang CQ, Zhang F, Feng J, Li WB, Yan XN, Hu G. Effects of polyglycoside of Tripterygium wilfordii Hook F on NF-kappa B expression in HaCa Tcells [in Chinese] Shanxi Med J. 2008;37:794–6. [Google Scholar]
50.T2 Study Group of Jiangsu Province. Summary on the clinical trials of T2 in the treatment of 554 patients with various diseases [in Chinese] Ann Chin Acad Med Sin. 1982;3:3–5. [Google Scholar]
51.Yuan XY, Shao KW, Zhang JT. Treatment of diffusive neurodermatitis with Tripterygium wilfordii Hook [in Chinese] Fujian Med J. 1987;9:5. [Google Scholar]
52.Wang YH, Ye H, Yu LX, Yang ZX. The effect of Tripterygium wilfordii combined with corticosteroid in the treatment of pemphigus and pemphigoid [in Chinese] Central China Med J. 2001;25:65–6. [Google Scholar]
53.Tao X, Cush JJ, Garret M, Lipsky PE. A phase I study of ethyl acetate extract of the Chinese antirheumatic herb Tripterygium wilfordii Hook F in rheumatoid arthritis. J Rheumatol. 2001;28:2160–7. [PubMed] [Google Scholar]
54.Cibere J, Deng Z, Lin Y, Ou R, He Y, Wang Z, Thorne A, Lehman AJ, Tsang IK, Esdaile JM. A randomized double blind, placebo controlled trial of topical Tripterygium wilfordii in rheumatoid arthritis: reanalysis using logistic regression analysis. J Rheumatol. 2003;30:465–7. [PubMed] [Google Scholar]
55.Tao X, Younger J, Fan FZ, Wang B, Lipsky PE. Benefit of an extract of Tripterygium wilfordii Hook F in patients with rheumatoid arthritis: a double-blind, placebo-controlled study. Arthritis Rheum. 2002;46:1735–43. doi: 10.1002/art.10411. [DOI] [PubMed] [Google Scholar]
56.He QB. Effects of Tripterygium wilfordii polyglycosidium combined with azithromycin on the treatment of psoriasis vulgaris in 45 cases [in Chinese] J Zhengzhou Univ (Med Sci) 2004;39:896–7. [Google Scholar]
57.Hang SY. Clinic observation of Tripterygium wilfordii combined with Di Yin Pian on the treatment of progressive stage psoriasis vulgaris [in Chinese] South China J Dermatol-Venerol. 2001;8:246–7. [Google Scholar]
58.Ma YB, Cheng SC, Wnag XY. A double-blind research on the therapeutic effect of Tripterygium wilfordii Hook F on progressive stage psoriasis vulgaris [in Chinese] Chin J Convalescent Med. 2000;9:33–5. [Google Scholar]
59.Yang XY, Liu XQ, Li HZ, Lin L, Chen K. Therapeutic effect of Tripterygium wilfordii Hook F combined with erythromycin and glycyrrhizin on 152 cases of psoriasis vulgaris [in Chinese] Chin J Dermatol-Venereol. 2000;14:168–9. [Google Scholar]
60.Chen JZ. Clinic observation of Tripterygium wilfordii combined with Di Yin Pian on the treatment of psoriasis in 87 patients[in chinese] J Henan Med Univ. 2000;35:112–3. [Google Scholar]
61.Zhang FR, Tian RM, Ma SY, Wang XY, Yu ML, Shi ZX. Treatment of active psoriasis vulgaris with Tripterygium wilfordii – double blind controlled triaI [in Chinese] Clin J Dermatol. 1999;28:32–3. [Google Scholar]
62.Feng PH, Zhang Y. Clinic observation of Tripterygium wilfordii combined with Di Yin Pian on the treatment of psoriasis [in Chinese] J Community Med. 2004;2:85. [Google Scholar]
63.Huang YZ, Huang FR, Ma DX. Observation on clinical effect of Tripterygium wilfordii polyglycosidium combined with Di Yin Pian on the treatment of psoriasis vulgaris in 52 cases [in Chinese] Chin J Curr Tradit West Med. 2004;2:238–9. [Google Scholar]
64.Lu GQ, Yin XD, Lu SG. Tripterygium wilfordii combined with Bimolane on the treatment of psoriasis in 98 cases [in Chinese] J Dermatol Venereol. 2003;25:29–30. [Google Scholar]
65.Shen YZ, Wang JQ, Xu XM. Observations on the therapeutic effect of decotion of Tripterygium wilfordii Hook F on psoriasis vulgaris [in Chinese] Mod J Integr Tradit Chin West Med. 2008;17:3597–8. [Google Scholar]
66.Zhan QX, Xu XM. Efficiency of Tripterygiuln wilfordii on treating psoriasis – A systematic review. Chin J Dermatovenereol Integr Tradit West Med. 2007;6:192–6. [Google Scholar]
67.Wong KF, Chan JK, Chan KL, Tam P, Yang D, Fan ST, Luk JM. Immunochemical characterization of the functional constituents of Tripterygium wilfordii contributing to its anti-inflammatory property. Clin Exp Pharmacol Physiol. 2008;35:55–9. doi: 10.1111/j.1440-1681.2007.04740.x. [DOI] [PubMed] [Google Scholar]
68.Lu Y, Fukuda K, Nakamura Y, Kimura K, Kumagai N, Nishida T. Inhibitory effect of triptolide on chemokine expression induced by proinflammatory cytokines in human corneal fibroblasts. Invest Ophthalmol Vis Sci. 2005;46:2346–52. doi: 10.1167/iovs.05-0010. [DOI] [PubMed] [Google Scholar]
69.Lin N, Liu C, Xiao C, Jia H, Imada K, Wu H, Ito A. Triptolide, a diterpenoid triepoxide, suppresses inflammation and cartilage destruction in collagen-induced arthritis mice. Biochem Pharmacol. 2007;73:136–46. doi: 10.1016/j.bcp.2006.08.027. [DOI] [PubMed] [Google Scholar]
70.Gong Y, Xue B, Jiao J, Jing L, Wang X. Triptolide inhibits COX-2 expression and PGE2 release by suppressing the activity of NF-kappaB and JNK in LPS-treated microglia. J Neurochem. 2008;107:779–88. doi: 10.1111/j.1471-4159.2008.05653.x. [DOI] [PubMed] [Google Scholar]
71.Kim YH, Lee SH, Lee JY, Choi SW, Park JW, Kwon TK. Triptolide inhibits murine-inducible nitric oxide synthase expression by down-regulating lipopolysaccharide-induced activity of nuclear factor-kappa B and c-Jun NH2-terminal kinase. Eur J Pharmacol. 2004;494:1–9. doi: 10.1016/j.ejphar.2004.04.040. [DOI] [PubMed] [Google Scholar]
72.Liou JT, Chen ZY, Ho LJ, Yang SP, Chang DM, Liang CC, Lai JH. Differential effects of triptolide and tetrandrine on activation of COX-2, NF-kappaB, and AP-1 and virus production in dengue virus-infected human lung cells. Eur J Pharmacol. 2008;589:288–98. doi: 10.1016/j.ejphar.2008.04.056. [DOI] [PMC free article] [PubMed] [Google Scholar]
73.Krakauer T, Chen X, Howard OM, Young HA. Triptolide attenuates endotoxin- and staphylococcal exotoxin-induced T-cell proliferation and production of cytokines and chemokines. Immunopharmacol Immunotoxicol. 2005;27:53–66. doi: 10.1081/iph-51294. [DOI] [PubMed] [Google Scholar]
74.Qiu D, Zhao G, Aoki Y, Shi L, Uyei A, Nazarian S, Ng JC, Kao PN. Immunosuppressant PG490 (triptolide) inhibits T-cell interleukin-2 expression at the level of purine-box/nuclear factor of activated T-cells and NF-kappaB transcriptional activation. J Biol Chem. 1999;274:13443–50. doi: 10.1074/jbc.274.19.13443. [DOI] [PubMed] [Google Scholar]
75.Wang Y, Jia L, Wu CY. Triptolide inhibits the differentiation of Th17 cells and suppresses collagen-induced arthritis. Scand J Immunol. 2008;68:383–90. doi: 10.1111/j.1365-3083.2008.02147.x. [DOI] [PubMed] [Google Scholar]
76.Tao X, Davis LS, Lipsky PE. Effect of an extract of the Chinese herbal remedy Tripterygium wilfordii Hook F on human immune responsiveness. Arthritis Rheum. 1991;34:1274–81. doi: 10.1002/art.1780341011. [DOI] [PubMed] [Google Scholar]
77.Zhu KJ, Shen QY, Cheng H, Mao XH, Lao LM, Hao GL. Triptolide affects the differentiation, maturation and function of human dendritic cells. Int Immunopharmacol. 2005;5:1415–26. doi: 10.1016/j.intimp.2005.03.020. [DOI] [PubMed] [Google Scholar]
78.Chen X, Murakami T, Oppenheim JJ, Howard OM. Triptolide, a constituent of immunosuppressive Chinese herbal medicine, is a potent suppressor of dendritic-cell maturation and trafficking. Blood. 2005;106:2409–16. doi: 10.1182/blood-2005-03-0854. [DOI] [PMC free article] [PubMed] [Google Scholar]
79.Liu HK, Perrier S, Lipina C, Finlay D, McLauchlan H, Hastie CJ, Hundal HS, Sutherland C. Functional characterisation of the regulation of CAAT enhancer binding protein alpha by GSK-3 phosphorylation of threonines 222/226. BMC Mol Biol. 2006;7:14. doi: 10.1186/1471-2199-7-14. [DOI] [PMC free article] [PubMed] [Google Scholar]
80.Kappos L, Gold R, Miller DH, Macmanus DG, Havrdova E, Limmroth V, Polman CH, Schmierer K, Yousry TA, Yang M, Eraksoy M, Meluzinova E, Rektor I, Dawson KT, Sandrock AW, O'Neill GN. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet. 2008;372:1463–72. doi: 10.1016/S0140-6736(08)61619-0. [DOI] [PubMed] [Google Scholar]
81.Mrowietz U, Asadullah K. Dimethylfumarate for psoriasis: more than a dietary curiosity. Trends Mol Med. 2005;11:43–8. doi: 10.1016/j.molmed.2004.11.003. [DOI] [PubMed] [Google Scholar]
82.Shear NH, Prinz J, Papp K, Langley RG, Gulliver WP. Targeting the interleukin-12/23 cytokine family in the treatment of psoriatic disease. J Cutan Med Surg. 2008;12(Suppl. 1):S1–10. doi: 10.2310/7750.2008/08070. [DOI] [PubMed] [Google Scholar]
83.Liu J, Wu QL, Feng YH, Wang YF, Li XY, Zuo JP. Triptolide suppresses CD80 and CD86 expressions and IL-12 production in THP-1 cells. Acta Pharmacol Sin. 2005;26:223–7. doi: 10.1111/j.1745-7254.2005.00035.x. [DOI] [PubMed] [Google Scholar]
84.Liu Y, Chen Y, Liu FQ, Lamb JR, Tam PK. Combined treatment with triptolide and rapamycin prolongs graft survival in a mouse model of cardiac transplantation. Transpl Int. 2008;21:483–94. doi: 10.1111/j.1432-2277.2007.00630.x. [DOI] [PubMed] [Google Scholar]
85.Zhang Y, Ma X. Triptolide inhibits IL-12/IL-23 expression in APCs via CCAAT/enhancer-binding protein alpha. J Immunol. 2010;184:3866–77. doi: 10.4049/jimmunol.0903417. [DOI] [PMC free article] [PubMed] [Google Scholar]
86.Premkumar V, Dey M, Dorn R, Raskin I. MyD88-dependent and independent pathways of toll-like receptors are engaged in biological activity of triptolide in ligand-stimulated macrophages. BMC Chem Biol. 2010;10:3. doi: 10.1186/1472-6769-10-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
87.Liu YJ, Yang ZB, Lv N, Li JY. Effects of Triperygium wiIfordii ointment on expression of Intercelluar adhesion molecule-1 and matrix metallo-proteinase-9 in psoriatic lesion.[in Chinese] Chin J Dermatovenereol Integr Tradit West Med. 2007;6:213–5. [Google Scholar]
88.Xiao T, Guo YJ, Wu J, Wu J, Wang YK, He CD, Chen HD. Effect of immunosuppressants on secretion of CXCL11/I-TAC by HaCaT cells. J China Med Univ. 2008;37:16–8. [Google Scholar]
89.Vispe S, DeVries L, Creancier L, Besse J, Breand S, Hobson DJ, Svejstrup JQ, Annereau JP, Cussac D, Dumontet C, Guilbaud N, Barret JM, Bailly C. Triptolide is an inhibitor of RNA polymerase I and II-dependent transcription leading predominantly to down-regulation of short-lived mRNA. Mol Cancer Ther. 2009;8:2780–90. doi: 10.1158/1535-7163.MCT-09-0549. [DOI] [PubMed] [Google Scholar]
90.Pan J. RNA polymerase – an important molecular target of triptolide in cancer cells. Cancer Lett. 2010;292:149–52. doi: 10.1016/j.canlet.2009.11.018. [DOI] [PubMed] [Google Scholar]
91.Wei YS, Adachi I. Inhibitory effect of triptolide on colony formation of breast and stomach cancer cell lines. Zhongguo Yao Li Xue Bao. 1991;12:406–10. [PubMed] [Google Scholar]
92.Shao F, Wang G, Xie H, Zhu X, Sun J, A J. Pharmacokinetic study of triptolide, a constituent of immunosuppressive Chinese herb medicine, in rats. Biol Pharm Bull. 2007;30:702–7. doi: 10.1248/bpb.30.702. [DOI] [PubMed] [Google Scholar]
93.Zheng JR, Xu LF, Ma L, Wang DH, Gao JW. Studies on pharmacological actions of total glycosides in Tripterygium wilfordii [in Chinese] Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 1983;5:1–8. [PubMed] [Google Scholar]
94.Wang ZF, Zhang YH, Huang GZ. An experimental, pathological study of subchronic intoxication of ethyl acetate extract of Tripterygium wilfordii Hook [in Chinese] J TongJi Med Coll. 1991;20:247–50. [Google Scholar]
95.Cheng YL, Ye JR, Lin DJ. [Some toxicities of triptolide in mice and dogs (author's translation)] Zhongguo Yao Li Xue Bao. 1981;2:70–2. [PubMed] [Google Scholar]
96.Li H, Cheng QR, Dong DC. Observation on clinical effect on treatment of IgA nephropathy with Tripterygium wilfordii Hook [in Chinese] Shanghai Yi Xue. 2010;16:223–4. [Google Scholar]
97.Liu WZ, Chen RX. Studies on the efficacy of polyglycosides of Tripterygium wilfordii Hook in the treatment of nephritis [in Chinese] Shanghai Zhong Yi Za Zhi. 1990;2:5. [Google Scholar]
98.Pan YR. Treatment of purpura nephritis with Tripterygium wilfordii Hook F [in Chinese] Acta Acad Med Sin. 1987;9:2–4. [Google Scholar]
99.Wang QW, Li LS, Zhang JH. Clinical studies of treatment of idiopathic IgA nephropathy with Tripterygium wilfordii Hook F [in Chinese] Jiangsu Med. 1991;1:7–9. [Google Scholar]
100.Su DF, Li RL, Sun YJ. Report of 270 patients with rheumatoid arthritis treated with ethyl acetate extract of Tripterygium wilfordii Hook F [in Chinese] Pharmacol Clin Tradit Chin Med. 1989;5:40–2. [Google Scholar]
101.Chan MA, Kohlmeier JE, Branden M, Jung M, Benedict SH. Triptolide is more effective in preventing T cell proliferation and interferon-gamma production than is FK506. Phytother Res. 1999;13:464–7. doi: 10.1002/(sici)1099-1573(199909)13:6<464::aid-ptr483>3.0.co;2-4. [DOI] [PubMed] [Google Scholar]
102.Qiu D, Kao PN. Immunosuppressive and anti-inflammatory mechanisms of triptolide, the principal active diterpenoid from the Chinese medicinal herb Tripterygium wilfordii Hook. F. Drugs R D. 2003;4:1–18. doi: 10.2165/00126839-200304010-00001. [DOI] [PubMed] [Google Scholar]
103.Jiang L, Zhao N, Ni L. Retrospective study of adverse events in patients with rheumatoid arthritis treated with second-line drugs [in Chinese] Zhonghua Liu Xing Bing Xue Za Zhi. 2002;23:213–7. [PubMed] [Google Scholar]
104.Zhou J, Zhu Q, Yang X. Clinical observation of side effects of Tripterygium preparation [in Chinese] Zhongguo Zhong Xi Yi Jie He Za Zhi. 1999;19:77–9. [PubMed] [Google Scholar]
105.Gu CX. Cause of amenorrhea after treatment with Tripterygium wilfordii F [in Chinese] Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 1989;11:151–3. [PubMed] [Google Scholar]
106.Qian SZ. Tripterygium wilfordii, a Chinese herb effective in male fertility regulation. Contraception. 1987;36:335–45. doi: 10.1016/0010-7824(87)90104-1. [DOI] [PubMed] [Google Scholar]
107.Zhen QS, Ye X, Wei ZJ. Recent progress in research on Tripterygium: a male antifertility plant. Contraception. 1995;51:121–9. doi: 10.1016/0010-7824(94)00018-r. [DOI] [PubMed] [Google Scholar]
108.Meikle AW. Endocrine Replacement Therapy in Clinical Practice (Contemporary Endocrinology) New York, NY: Humana Press; 2003. [Google Scholar]
109.Chou WC, Wu CC, Yang PC, Lee YT. Hypovolemic shock and mortality after ingestion of Tripterygium wilfordii hook F.: a case report. Int J Cardiol. 1995;49:173–7. doi: 10.1016/0167-5273(95)02282-2. [DOI] [PubMed] [Google Scholar]
110.Pyatt DW, Yang Y, Mehos B, Le A, Stillman W, Irons RD. Hematotoxicity of the chinese herbal medicine Tripterygium wilfordii Hook F in CD34-positive human bone marrow cells. Mol Pharmacol. 2000;57:512–8. doi: 10.1124/mol.57.3.512. [DOI] [PubMed] [Google Scholar]
111.Chan WY, Ng TB. Adverse effect of Tripterygium wilfordii extract on mouse embryonic development. Contraception. 1995;51:65–71. doi: 10.1016/0010-7824(94)00001-d. [DOI] [PubMed] [Google Scholar]
112.Takei A, Nagashima G, Suzuki R, Hokaku H, Takahashi M, Miyo T, Asai J, Sanada Y, Fujimoto T. Meningoencephalocele associated with Tripterygium wilfordii treatment. Pediatr Neurosurg. 1997;27:45–8. doi: 10.1159/000121224. [DOI] [PubMed] [Google Scholar]
113.Guo JL, Yuan SX, Wang XC, Xu SX, LI DD. Tripterygium wilfordii Hook F in rheumatoid arthritis and ankylosing spondylitis. Preliminary report. Chin Med J (Engl) 1981;94:405–12. [PubMed] [Google Scholar]
114.Zhu TZ. Explore the causes of death in 90 cases with intoxication of Tripterygium wilfordii Hook [in Chinese] Beijing Zhong Yi. 1995;2:35–7. [Google Scholar]
115.Su D, Song Y, Li R. Comparative clinical study of rheumatoid arthritis treated by triptolide and an ethyl acetate extract of Tripterygium wilfordii [in Chinese] Zhong Xi Yi Jie He Za Zhi. 1990;10:144–6. 131. [PubMed] [Google Scholar]
116.Zhang F, Li YC. Progress in structure modification of triptolide[in chinese] Yao Xue Xue Bao. 2004;39:857–64. [PubMed] [Google Scholar]
117.Krishna G, Liu K, Shigemitsu H, Gao M, Raffin TA, Rosen GD. PG490-88, a derivative of triptolide, blocks bleomycin-induced lung fibrosis. Am J Pathol. 2001;158:997–1004. doi: 10.1016/S0002-9440(10)64046-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
118.Pan F, Fisniku O, Wynn C, Erickson LM, Crews G, Jang MS, Sudo Y, Tamura K, Kobayashi M, Benediktsson H, Jiang H. PG490-88, a new immunosuppressant, effectively prevents acute and chronic rejection in rat renal allografts. Transplant Proc. 2005;37:134–6. doi: 10.1016/j.transproceed.2004.12.054. [DOI] [PubMed] [Google Scholar]
119.Kiviharju TM, Lecane PS, Sellers RG, Peehl DM. Antiproliferative and proapoptotic activities of triptolide (PG490), a natural product entering clinical trials, on primary cultures of human prostatic epithelial cells. Clin Cancer Res. 2002;8:2666–74. [PubMed] [Google Scholar]
120.Harousseau JL, Dombret H, Pigneux A, Michallet M, Brandely M. 2008. p. 2008. Phase I study of F60008, a triptolide derivative, in patients with refractory or relapsing acute leukemias. 13th Congress of the European Hematology Association (EHA)
121.Kitzen JJ, de Jonge MJ, Lamers CH, Eskens FA, van der BD, van Doorn L, Ter Steeg J, Brandely M, Puozzo CH, Verweij J. Phase I dose-escalation study of F60008, a novel apoptosis inducer, in patients with advanced solid tumours. Eur J Cancer. 2009;45:1764–72. doi: 10.1016/j.ejca.2009.01.026. [DOI] [PubMed] [Google Scholar]
122.Ren YX, Zhou R, Tang W, Wang WH, Li YC, Yang YF, Zuo JP. (5R)-5-hydroxytriptolide (LLDT-8) protects against bleomycin-induced lung fibrosis in mice. Acta Pharmacol Sin. 2007;28:518–25. doi: 10.1111/j.1745-7254.2007.00524.x. [DOI] [PubMed] [Google Scholar]
123.Zhou R, Wang JX, Tang W, He PL, Yang YF, Li YC, Li XY, Zuo JP. (5R)-5-hydroxytriptolide inhibits IFN-gamma-related signaling. Acta Pharmacol Sin. 2006;27:1616–21. doi: 10.1111/j.1745-7254.2006.00457.x. [DOI] [PubMed] [Google Scholar]
124.Zhou R, Tang W, He PL, Yang YF, Li YC, Zuo JP. (5R)-5-hydroxytriptolide inhibits the immune response of human peripheral blood mononuclear cells. Int Immunopharmacol. 2009;9:63–9. doi: 10.1016/j.intimp.2008.09.014. [DOI] [PubMed] [Google Scholar]
125.Shao F, Wang GJ, Sun JG, Xie HT, Zhang R, Zhu XY. Pharmacokinetics of triptolide in Beagle dogs [in Chinese] Yao Xue Xue Bao. 2007;42:61–5. [PubMed] [Google Scholar]

[b1] 1.Raychaudhuri SP, Farber EM. The prevalence of psoriasis in the world. J Eur Acad Dermatol Venereol. 2001;15:16–7. doi: 10.1046/j.1468-3083.2001.00192.x. [DOI] [PubMed] [Google Scholar]

[b2] 2.Yip SY. The prevalence of psoriasis in the Mongoloid race. J Am Acad Dermatol. 1984;10:965–8. doi: 10.1016/s0190-9622(84)80314-x. [DOI] [PubMed] [Google Scholar]

[b3] 3.Tao X, Lipsky PE. The Chinese anti-inflammatory and immunosuppressive herbal remedy Tripterygium wilfordii Hook F. Complementary and alternative therapies for rheumatic diseases II. Rheum Dis Clin North Am. 2000;26:29–50. doi: 10.1016/s0889-857x(05)70118-6. [DOI] [PubMed] [Google Scholar]

[b4] 4.Gutian Hospital and Beisha Hospital FP. Report on the therapeutic effect of the herbal medicine Tripterygium wilfordii Hook F on reactive status of leprosy [in Chinese] Pi Fu Bing Fang Zhi Tong Xun. 1972;2:29–30. [Google Scholar]

[b5] 5.Chen BJ. Triptolide, a novel immunosuppressive and anti-inflammatory agent purified from a Chinese herb Tripterygium wilfordii Hook F. Leuk Lymphoma. 2001;42:253–65. doi: 10.3109/10428190109064582. [DOI] [PubMed] [Google Scholar]

[b6] 6.Asano K, Matsuishi J, Yu Y, Kasahara T, Hisamitsu T. Suppressive effects of Tripterygium wilfordii Hook F, a traditional Chinese medicine, on collagen arthritis in mice. Immunopharmacol. 1998;39:117–26. doi: 10.1016/s0162-3109(98)00006-x. [DOI] [PubMed] [Google Scholar]

[b7] 7.Chang ML, Yang LL, Chang DM, Kuo SY, Chu SJ. The influence of Chinese traditional medicine on the production and activity of interleukin 1 (IL-1) [in Chinese] Zhonghua Min Guo Wei Sheng Wu Ji Mian Yi Xue Za Zhi. 1993;26:15–24. [PubMed] [Google Scholar]

[b8] 8.Chang DM, Chang WY, Kuo SY, Chang ML. The effects of traditional antirheumatic herbal medicines on immune response cells. J Rheumatol. 1997;24:436–41. [PubMed] [Google Scholar]

[b9] 9.Tao X, Schulze-Koops H, Ma L, Cai J, Mao Y, Lipsky PE. Effects of Tripterygium wilfordii Hook F extracts on induction of cyclooxygenase 2 activity and prostaglandin E2 production. Arthritis Rheum. 1998;41:130–8. doi: 10.1002/1529-0131(199801)41:1<130::AID-ART16>3.0.CO;2-4. [DOI] [PubMed] [Google Scholar]

[b10] 10.Ho LJ, Chang DM, Chang ML, Kuo SY, Lai JH. Mechanism of immunosuppression of the antirheumatic herb TWHf in human T cells. J Rheumatol. 1999;26:14–24. [PubMed] [Google Scholar]

[b11] 11.Wu Y, Wang Y, Zhong C, Li Y, Li X, Sun B. The suppressive effect of triptolide on experimental autoimmune uveoretinitis by down-regulating Th1-type response. Int Immunopharmacol. 2003;3:1457–65. doi: 10.1016/S1567-5769(03)00144-9. [DOI] [PubMed] [Google Scholar]

[b12] 12.Kupchan SM, Court WA, Dailey RG, Jr, Gilmore CJ, Bryan RF. Triptolide and tripdiolide, novel antileukemic diterpenoid triepoxides from Tripterygium wilfordii. J Am Chem Soc. 1972;94:7194–5. doi: 10.1021/ja00775a078. [DOI] [PubMed] [Google Scholar]

[b13] 13.Chen BJ, Chen Y, Cui X, Fidler JM, Chao NJ. Mechanisms of tolerance induced by PG490-88 in a bone marrow transplantation model. Transplantation. 2002;73:115–21. doi: 10.1097/00007890-200201150-00022. [DOI] [PubMed] [Google Scholar]

[b14] 14.Liu Q, Chen T, Chen H, Zhang M, Li N, Lu Z, Ma P, Cao X. Triptolide (PG-490) induces apoptosis of dendritic cells through sequential p38 MAP kinase phosphorylation and caspase 3 activation. Biochem Biophys Res Commun. 2004;319:980–6. doi: 10.1016/j.bbrc.2004.04.201. [DOI] [PubMed] [Google Scholar]

[b15] 15.Jiang XH, Wong BC, Lin MC, Zhu GH, Kung HF, Jiang SH, Yang D, Lam SK. Functional p53 is required for triptolide-induced apoptosis and AP-1 and nuclear factor-kappaB activation in gastric cancer cells. Oncogene. 2001;20:8009–18. doi: 10.1038/sj.onc.1204981. [DOI] [PubMed] [Google Scholar]

[b16] 16.Wang X, Matta R, Shen G, Nelin LD, Pei D, Liu Y. Mechanism of triptolide-induced apoptosis: effect on caspase activation and Bid cleavage and essentiality of the hydroxyl group of triptolide. J Mol Med. 2006;84:405–15. doi: 10.1007/s00109-005-0022-4. [DOI] [PubMed] [Google Scholar]

[b17] 17.Tang ZL. New development in clinical application of Tripierygium wilfordii Hook F [in Chinese] 2004. Papers series of the Fourth National Academic Conference of Tripierygium wilfordii Hook F.

[b18] 18.Tao XL, Sun Y, Dong Y. A double-blind, controlled trial of Tripterygium wilfordii glycosides in the treatment of rheumatoid arthritis. Arthritis Rheum. 1987;30:59–9. [Google Scholar]

[b19] 19.Yu DY. Clinical observation of 144 cases of rheumatoid arthritis treated with glycoside of radix Tripterygium wilfordii [in Chinese] J Tradit Chin Med. 1983;3:125–9. [PubMed] [Google Scholar]

[b20] 20.Huang CF, Wu CB, Shen ZK. Study on the treatment of rheumatoid arthritis with polyglycosides of Tripterygium wilfordii Hook-a randomized, controlled, cross-over clinical trial [in Chinese]. 2003. Third Annual National Meeting of Rheumatology (Chinese)

[b21] 21.RA Cooperative Group. Clinical trial of Tripterygium wilfordii Hook in the treatment of 31 patients with rheumatoid arthritis [in Chinese] Wuhan Yi Xue Bao. 1977;6:51–3. [Google Scholar]

[b22] 22.Su DF, Li RL, Sun YJ. Report of 270 patients with rheumatoid arthritis treated with ethyl acetate extract of Tripterygium wilfordii Hook F. [in Chinese] Zhong Yao Yao Li Yu Lin Chuang. 1989;5:40–2. [Google Scholar]

[b23] 23.Li ZM, Zheng CS. Observation on treatment of systemic lupus erythematosus with extract of Tripterygium wilfordii Hook [in Chinese] J New Chin Med. 1982;12:22–4. [Google Scholar]

[b24] 24.Liao WQ. Observations on the therapeutic effect of Tripterygium wilfordii Hook F on systemic lupus ethythematosus [in Chinese] Pi Fu Bing Fang Zhi Yan Jiu Tong Xun. 1980;9:14–5. [Google Scholar]

[b25] 25.Xue ZY. Treating 103 cases of SLE with Tripterygium wilfordii Hook F [in Chinese] Chin J Dermatol. 1982;15:141–3. [Google Scholar]

[b26] 26.Xue GY, Xue JH, Tang YC. Treatment of 21 patients with SLE with Tripterygium wilfordii Hook [in Chinese] Chin J Dermatol. 1984;17:201–3. [Google Scholar]

[b27] 27.Su LD, You JC. Comparison of efficacy between Tripterygium wilfordii Hook and cochicine in the treatment of systemic sclerosis [in Chinese] 1988. Third Annual National Meeting of Rheumatology (Chinese)

[b28] 28.Bei RX, Liu H, Wang XC. Tripterygium wilfordii Hook F in the treatment of rheumatoid arthritis and ankylosing spondylitis [in Chinese] Chin J Orthop. 1988;8:209–13. [Google Scholar]

[b29] 29.Guo JL, Gao ZG, Zan AC. Treatment of rheumatoid arthritis and ankylosing spondylitis with Tripterygium wilfordii Hook F: 2-5 year follow-up [in Chinese] Chin J Orthop. 1984;4:133–7. [Google Scholar]

[b30] 30.Fan ZH. Analysis of the therapeutic effect of Tripterygium wilfordii Hook on 52 patients with psoriasis [in Chinese] Acta Acad Med Nanjing. 1984;14:451–3. [Google Scholar]

[b31] 31.Xu WY, Zheng JR, Lu XY. Tripterygium in dermatologic therapy. Int J Dermatol. 1985;24:152–7. doi: 10.1111/j.1365-4362.1985.tb05746.x. [DOI] [PubMed] [Google Scholar]

[b32] 32.Xie DF, Shen JS, Fei JF. Experience in the treatment of Behcet's disease with polyglycosides of Tripterygium wilfordii Hook f [in Chinese] Chin J Integr Med. 1983;3:349–50. [Google Scholar]

[b33] 33.Wan L, Zhao RF, Zhou W, Yuan NM. Clinical analysis of 50 cases of Behcet disease treated by thalidomide combined with Tripterygium glycosides [in Chinese] J Pract Stomatol. 2006;22:659–61. [Google Scholar]

[b34] 34.Luo HP. Treatment on 10 cases of Behcet's disease using decoction of Tripterygium wilfordii [in Chinese] Jiujiang Med J. 2002;17:41. [Google Scholar]

[b35] 35.Sun Q, Qiu JF, Cai ZH, Shen MJ. Tripterygium wilfordii treatment of polymyositis and dermatomyositis-preliminary change of creatase [in Chinese] J Chin Physician. 1998;3:54. [Google Scholar]

[b36] 36.Bai HT, Yang DS, Zheng YJ. Effect of Triptergium glycosides on children with allergic purpura [in Chinese] J Xinxiang Med Coll. 2002;19:282–3. [Google Scholar]

[b37] 37.Dong Z, Jiao YQ, Lu SG. The use of double-dosed Tripterygium polyglucoside in treating Henoch-Schonlein purpura [in Chinese] Acta Acad Med Xuzhou. 2003;23:334–6. [Google Scholar]

[b38] 38.Feng B. Observation on the effect of polyglycosides of Tripterygium wilfordii Hook (T2) in 50 cases of leprosy reactive status [in Chinese] Clin J Dermatol. 1985;4:211. [Google Scholar]

[b39] 39.Lei Gong Teng Cooperative Research Group of Fujian and Jiangsu Provinces. Clinical observation on Chinese herb Lei Gong Teng in treatment of leprosy reaction [in Chinese] Acta Acad Med Sin. 1979;1:72–4. [Google Scholar]

[b40] 40.Wu YZ. Treatment of neuralgia of lepra reactive status with polyglycosides of Tripterygium wilfordii Hook F (T2) [in Chinese] Chin J Dermatol. 1986;19:217–9. [Google Scholar]

[b41] 41.Mou LP. The clinical observation of chronic lymphatic thyroiditis with treatment of Tripterygium Witfondii Hooh F. [in Chinese] J Bengbu Med Coll. 2000;25:254–5. [Google Scholar]

[b42] 42.Jiang X. Clinical observations on the use of the Chinese herb Tripterygium wilfordii Hook for the treatment of nephrotic syndrome. Pediatr Nephrol. 1994;8:343–4. doi: 10.1007/BF00866356. [DOI] [PubMed] [Google Scholar]

[b43] 43.Xu G, Tu W, Jiang D, Xu C. Tripterygium wilfordii Hook F treatment for idiopathic refractory nephrotic syndrome in adults: a meta-analysis. Nephron Clin Pract. 2009;111:c223–c228. doi: 10.1159/000208990. [DOI] [PubMed] [Google Scholar]

[b44] 44.Yang FY, Wei CY, Li CY. A controlled study on Tripterygium glycosides for treating IgA nephropathy patients who presented with non-nephrofic syndrome [in Chinese] Chin J Gen Pract. 2008;6:1138–9. [Google Scholar]

[b45] 45.Xie T, Zhong YX, Mai WM, Huang PP. Clinic research on Tripterygium glycosides for treating IgA nephropathy [in Chinese] Chin J Postgrad Med. 2008;31:35–6. [Google Scholar]

[b46] 46.Li X, Hao J. Clinical Observation on Urokinase Combined with Tripterygium Wilfordii Polyglycoside For IgA Nephropathy [in chinese] Appl J Gen Pract. 2006;4:410–1. [Google Scholar]

[b47] 47.Ma WH, Guo XQ, Wei ZH. Effect of Tripterygium Glycosides with Prednisone in Treating Henoch-Schonlein Purpura Nephritis [in chinese] J Appl Clin Pediatr. 2007;22:1344–6. [Google Scholar]

[b48] 48.Li QH, Hu ZX, Huang MG. Clinical observation on Huang Kui capsule combined with Tripterygium wilfordii polyglycoside for chronic glomerulonephritis [in Chinese] Mod J Integr Tradit Chin West Med. 2005;14:1429–30. [Google Scholar]

[b49] 49.Zhang CQ, Zhang F, Feng J, Li WB, Yan XN, Hu G. Effects of polyglycoside of Tripterygium wilfordii Hook F on NF-kappa B expression in HaCa Tcells [in Chinese] Shanxi Med J. 2008;37:794–6. [Google Scholar]

[b50] 50.T2 Study Group of Jiangsu Province. Summary on the clinical trials of T2 in the treatment of 554 patients with various diseases [in Chinese] Ann Chin Acad Med Sin. 1982;3:3–5. [Google Scholar]

[b51] 51.Yuan XY, Shao KW, Zhang JT. Treatment of diffusive neurodermatitis with Tripterygium wilfordii Hook [in Chinese] Fujian Med J. 1987;9:5. [Google Scholar]

[b52] 52.Wang YH, Ye H, Yu LX, Yang ZX. The effect of Tripterygium wilfordii combined with corticosteroid in the treatment of pemphigus and pemphigoid [in Chinese] Central China Med J. 2001;25:65–6. [Google Scholar]

[b53] 53.Tao X, Cush JJ, Garret M, Lipsky PE. A phase I study of ethyl acetate extract of the Chinese antirheumatic herb Tripterygium wilfordii Hook F in rheumatoid arthritis. J Rheumatol. 2001;28:2160–7. [PubMed] [Google Scholar]

[b54] 54.Cibere J, Deng Z, Lin Y, Ou R, He Y, Wang Z, Thorne A, Lehman AJ, Tsang IK, Esdaile JM. A randomized double blind, placebo controlled trial of topical Tripterygium wilfordii in rheumatoid arthritis: reanalysis using logistic regression analysis. J Rheumatol. 2003;30:465–7. [PubMed] [Google Scholar]

[b55] 55.Tao X, Younger J, Fan FZ, Wang B, Lipsky PE. Benefit of an extract of Tripterygium wilfordii Hook F in patients with rheumatoid arthritis: a double-blind, placebo-controlled study. Arthritis Rheum. 2002;46:1735–43. doi: 10.1002/art.10411. [DOI] [PubMed] [Google Scholar]

[b56] 56.He QB. Effects of Tripterygium wilfordii polyglycosidium combined with azithromycin on the treatment of psoriasis vulgaris in 45 cases [in Chinese] J Zhengzhou Univ (Med Sci) 2004;39:896–7. [Google Scholar]

[b57] 57.Hang SY. Clinic observation of Tripterygium wilfordii combined with Di Yin Pian on the treatment of progressive stage psoriasis vulgaris [in Chinese] South China J Dermatol-Venerol. 2001;8:246–7. [Google Scholar]

[b58] 58.Ma YB, Cheng SC, Wnag XY. A double-blind research on the therapeutic effect of Tripterygium wilfordii Hook F on progressive stage psoriasis vulgaris [in Chinese] Chin J Convalescent Med. 2000;9:33–5. [Google Scholar]

[b59] 59.Yang XY, Liu XQ, Li HZ, Lin L, Chen K. Therapeutic effect of Tripterygium wilfordii Hook F combined with erythromycin and glycyrrhizin on 152 cases of psoriasis vulgaris [in Chinese] Chin J Dermatol-Venereol. 2000;14:168–9. [Google Scholar]

[b60] 60.Chen JZ. Clinic observation of Tripterygium wilfordii combined with Di Yin Pian on the treatment of psoriasis in 87 patients[in chinese] J Henan Med Univ. 2000;35:112–3. [Google Scholar]

[b61] 61.Zhang FR, Tian RM, Ma SY, Wang XY, Yu ML, Shi ZX. Treatment of active psoriasis vulgaris with Tripterygium wilfordii – double blind controlled triaI [in Chinese] Clin J Dermatol. 1999;28:32–3. [Google Scholar]

[b62] 62.Feng PH, Zhang Y. Clinic observation of Tripterygium wilfordii combined with Di Yin Pian on the treatment of psoriasis [in Chinese] J Community Med. 2004;2:85. [Google Scholar]

[b63] 63.Huang YZ, Huang FR, Ma DX. Observation on clinical effect of Tripterygium wilfordii polyglycosidium combined with Di Yin Pian on the treatment of psoriasis vulgaris in 52 cases [in Chinese] Chin J Curr Tradit West Med. 2004;2:238–9. [Google Scholar]

[b64] 64.Lu GQ, Yin XD, Lu SG. Tripterygium wilfordii combined with Bimolane on the treatment of psoriasis in 98 cases [in Chinese] J Dermatol Venereol. 2003;25:29–30. [Google Scholar]

[b65] 65.Shen YZ, Wang JQ, Xu XM. Observations on the therapeutic effect of decotion of Tripterygium wilfordii Hook F on psoriasis vulgaris [in Chinese] Mod J Integr Tradit Chin West Med. 2008;17:3597–8. [Google Scholar]

[b66] 66.Zhan QX, Xu XM. Efficiency of Tripterygiuln wilfordii on treating psoriasis – A systematic review. Chin J Dermatovenereol Integr Tradit West Med. 2007;6:192–6. [Google Scholar]

[b67] 67.Wong KF, Chan JK, Chan KL, Tam P, Yang D, Fan ST, Luk JM. Immunochemical characterization of the functional constituents of Tripterygium wilfordii contributing to its anti-inflammatory property. Clin Exp Pharmacol Physiol. 2008;35:55–9. doi: 10.1111/j.1440-1681.2007.04740.x. [DOI] [PubMed] [Google Scholar]

[b68] 68.Lu Y, Fukuda K, Nakamura Y, Kimura K, Kumagai N, Nishida T. Inhibitory effect of triptolide on chemokine expression induced by proinflammatory cytokines in human corneal fibroblasts. Invest Ophthalmol Vis Sci. 2005;46:2346–52. doi: 10.1167/iovs.05-0010. [DOI] [PubMed] [Google Scholar]

[b69] 69.Lin N, Liu C, Xiao C, Jia H, Imada K, Wu H, Ito A. Triptolide, a diterpenoid triepoxide, suppresses inflammation and cartilage destruction in collagen-induced arthritis mice. Biochem Pharmacol. 2007;73:136–46. doi: 10.1016/j.bcp.2006.08.027. [DOI] [PubMed] [Google Scholar]

[b70] 70.Gong Y, Xue B, Jiao J, Jing L, Wang X. Triptolide inhibits COX-2 expression and PGE2 release by suppressing the activity of NF-kappaB and JNK in LPS-treated microglia. J Neurochem. 2008;107:779–88. doi: 10.1111/j.1471-4159.2008.05653.x. [DOI] [PubMed] [Google Scholar]

[b71] 71.Kim YH, Lee SH, Lee JY, Choi SW, Park JW, Kwon TK. Triptolide inhibits murine-inducible nitric oxide synthase expression by down-regulating lipopolysaccharide-induced activity of nuclear factor-kappa B and c-Jun NH2-terminal kinase. Eur J Pharmacol. 2004;494:1–9. doi: 10.1016/j.ejphar.2004.04.040. [DOI] [PubMed] [Google Scholar]

[b72] 72.Liou JT, Chen ZY, Ho LJ, Yang SP, Chang DM, Liang CC, Lai JH. Differential effects of triptolide and tetrandrine on activation of COX-2, NF-kappaB, and AP-1 and virus production in dengue virus-infected human lung cells. Eur J Pharmacol. 2008;589:288–98. doi: 10.1016/j.ejphar.2008.04.056. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b73] 73.Krakauer T, Chen X, Howard OM, Young HA. Triptolide attenuates endotoxin- and staphylococcal exotoxin-induced T-cell proliferation and production of cytokines and chemokines. Immunopharmacol Immunotoxicol. 2005;27:53–66. doi: 10.1081/iph-51294. [DOI] [PubMed] [Google Scholar]

[b74] 74.Qiu D, Zhao G, Aoki Y, Shi L, Uyei A, Nazarian S, Ng JC, Kao PN. Immunosuppressant PG490 (triptolide) inhibits T-cell interleukin-2 expression at the level of purine-box/nuclear factor of activated T-cells and NF-kappaB transcriptional activation. J Biol Chem. 1999;274:13443–50. doi: 10.1074/jbc.274.19.13443. [DOI] [PubMed] [Google Scholar]

[b75] 75.Wang Y, Jia L, Wu CY. Triptolide inhibits the differentiation of Th17 cells and suppresses collagen-induced arthritis. Scand J Immunol. 2008;68:383–90. doi: 10.1111/j.1365-3083.2008.02147.x. [DOI] [PubMed] [Google Scholar]

[b76] 76.Tao X, Davis LS, Lipsky PE. Effect of an extract of the Chinese herbal remedy Tripterygium wilfordii Hook F on human immune responsiveness. Arthritis Rheum. 1991;34:1274–81. doi: 10.1002/art.1780341011. [DOI] [PubMed] [Google Scholar]

[b77] 77.Zhu KJ, Shen QY, Cheng H, Mao XH, Lao LM, Hao GL. Triptolide affects the differentiation, maturation and function of human dendritic cells. Int Immunopharmacol. 2005;5:1415–26. doi: 10.1016/j.intimp.2005.03.020. [DOI] [PubMed] [Google Scholar]

[b78] 78.Chen X, Murakami T, Oppenheim JJ, Howard OM. Triptolide, a constituent of immunosuppressive Chinese herbal medicine, is a potent suppressor of dendritic-cell maturation and trafficking. Blood. 2005;106:2409–16. doi: 10.1182/blood-2005-03-0854. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b79] 79.Liu HK, Perrier S, Lipina C, Finlay D, McLauchlan H, Hastie CJ, Hundal HS, Sutherland C. Functional characterisation of the regulation of CAAT enhancer binding protein alpha by GSK-3 phosphorylation of threonines 222/226. BMC Mol Biol. 2006;7:14. doi: 10.1186/1471-2199-7-14. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b80] 80.Kappos L, Gold R, Miller DH, Macmanus DG, Havrdova E, Limmroth V, Polman CH, Schmierer K, Yousry TA, Yang M, Eraksoy M, Meluzinova E, Rektor I, Dawson KT, Sandrock AW, O'Neill GN. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet. 2008;372:1463–72. doi: 10.1016/S0140-6736(08)61619-0. [DOI] [PubMed] [Google Scholar]

[b81] 81.Mrowietz U, Asadullah K. Dimethylfumarate for psoriasis: more than a dietary curiosity. Trends Mol Med. 2005;11:43–8. doi: 10.1016/j.molmed.2004.11.003. [DOI] [PubMed] [Google Scholar]

[b82] 82.Shear NH, Prinz J, Papp K, Langley RG, Gulliver WP. Targeting the interleukin-12/23 cytokine family in the treatment of psoriatic disease. J Cutan Med Surg. 2008;12(Suppl. 1):S1–10. doi: 10.2310/7750.2008/08070. [DOI] [PubMed] [Google Scholar]

[b83] 83.Liu J, Wu QL, Feng YH, Wang YF, Li XY, Zuo JP. Triptolide suppresses CD80 and CD86 expressions and IL-12 production in THP-1 cells. Acta Pharmacol Sin. 2005;26:223–7. doi: 10.1111/j.1745-7254.2005.00035.x. [DOI] [PubMed] [Google Scholar]

[b84] 84.Liu Y, Chen Y, Liu FQ, Lamb JR, Tam PK. Combined treatment with triptolide and rapamycin prolongs graft survival in a mouse model of cardiac transplantation. Transpl Int. 2008;21:483–94. doi: 10.1111/j.1432-2277.2007.00630.x. [DOI] [PubMed] [Google Scholar]

[b85] 85.Zhang Y, Ma X. Triptolide inhibits IL-12/IL-23 expression in APCs via CCAAT/enhancer-binding protein alpha. J Immunol. 2010;184:3866–77. doi: 10.4049/jimmunol.0903417. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b86] 86.Premkumar V, Dey M, Dorn R, Raskin I. MyD88-dependent and independent pathways of toll-like receptors are engaged in biological activity of triptolide in ligand-stimulated macrophages. BMC Chem Biol. 2010;10:3. doi: 10.1186/1472-6769-10-3. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b87] 87.Liu YJ, Yang ZB, Lv N, Li JY. Effects of Triperygium wiIfordii ointment on expression of Intercelluar adhesion molecule-1 and matrix metallo-proteinase-9 in psoriatic lesion.[in Chinese] Chin J Dermatovenereol Integr Tradit West Med. 2007;6:213–5. [Google Scholar]

[b88] 88.Xiao T, Guo YJ, Wu J, Wu J, Wang YK, He CD, Chen HD. Effect of immunosuppressants on secretion of CXCL11/I-TAC by HaCaT cells. J China Med Univ. 2008;37:16–8. [Google Scholar]

[b89] 89.Vispe S, DeVries L, Creancier L, Besse J, Breand S, Hobson DJ, Svejstrup JQ, Annereau JP, Cussac D, Dumontet C, Guilbaud N, Barret JM, Bailly C. Triptolide is an inhibitor of RNA polymerase I and II-dependent transcription leading predominantly to down-regulation of short-lived mRNA. Mol Cancer Ther. 2009;8:2780–90. doi: 10.1158/1535-7163.MCT-09-0549. [DOI] [PubMed] [Google Scholar]

[b90] 90.Pan J. RNA polymerase – an important molecular target of triptolide in cancer cells. Cancer Lett. 2010;292:149–52. doi: 10.1016/j.canlet.2009.11.018. [DOI] [PubMed] [Google Scholar]

[b91] 91.Wei YS, Adachi I. Inhibitory effect of triptolide on colony formation of breast and stomach cancer cell lines. Zhongguo Yao Li Xue Bao. 1991;12:406–10. [PubMed] [Google Scholar]

[b92] 92.Shao F, Wang G, Xie H, Zhu X, Sun J, A J. Pharmacokinetic study of triptolide, a constituent of immunosuppressive Chinese herb medicine, in rats. Biol Pharm Bull. 2007;30:702–7. doi: 10.1248/bpb.30.702. [DOI] [PubMed] [Google Scholar]

[b93] 93.Zheng JR, Xu LF, Ma L, Wang DH, Gao JW. Studies on pharmacological actions of total glycosides in Tripterygium wilfordii [in Chinese] Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 1983;5:1–8. [PubMed] [Google Scholar]

[b94] 94.Wang ZF, Zhang YH, Huang GZ. An experimental, pathological study of subchronic intoxication of ethyl acetate extract of Tripterygium wilfordii Hook [in Chinese] J TongJi Med Coll. 1991;20:247–50. [Google Scholar]

[b95] 95.Cheng YL, Ye JR, Lin DJ. [Some toxicities of triptolide in mice and dogs (author's translation)] Zhongguo Yao Li Xue Bao. 1981;2:70–2. [PubMed] [Google Scholar]

[b96] 96.Li H, Cheng QR, Dong DC. Observation on clinical effect on treatment of IgA nephropathy with Tripterygium wilfordii Hook [in Chinese] Shanghai Yi Xue. 2010;16:223–4. [Google Scholar]

[b97] 97.Liu WZ, Chen RX. Studies on the efficacy of polyglycosides of Tripterygium wilfordii Hook in the treatment of nephritis [in Chinese] Shanghai Zhong Yi Za Zhi. 1990;2:5. [Google Scholar]

[b98] 98.Pan YR. Treatment of purpura nephritis with Tripterygium wilfordii Hook F [in Chinese] Acta Acad Med Sin. 1987;9:2–4. [Google Scholar]

[b99] 99.Wang QW, Li LS, Zhang JH. Clinical studies of treatment of idiopathic IgA nephropathy with Tripterygium wilfordii Hook F [in Chinese] Jiangsu Med. 1991;1:7–9. [Google Scholar]

[b100] 100.Su DF, Li RL, Sun YJ. Report of 270 patients with rheumatoid arthritis treated with ethyl acetate extract of Tripterygium wilfordii Hook F [in Chinese] Pharmacol Clin Tradit Chin Med. 1989;5:40–2. [Google Scholar]

[b101] 101.Chan MA, Kohlmeier JE, Branden M, Jung M, Benedict SH. Triptolide is more effective in preventing T cell proliferation and interferon-gamma production than is FK506. Phytother Res. 1999;13:464–7. doi: 10.1002/(sici)1099-1573(199909)13:6<464::aid-ptr483>3.0.co;2-4. [DOI] [PubMed] [Google Scholar]

[b102] 102.Qiu D, Kao PN. Immunosuppressive and anti-inflammatory mechanisms of triptolide, the principal active diterpenoid from the Chinese medicinal herb Tripterygium wilfordii Hook. F. Drugs R D. 2003;4:1–18. doi: 10.2165/00126839-200304010-00001. [DOI] [PubMed] [Google Scholar]

[b103] 103.Jiang L, Zhao N, Ni L. Retrospective study of adverse events in patients with rheumatoid arthritis treated with second-line drugs [in Chinese] Zhonghua Liu Xing Bing Xue Za Zhi. 2002;23:213–7. [PubMed] [Google Scholar]

[b104] 104.Zhou J, Zhu Q, Yang X. Clinical observation of side effects of Tripterygium preparation [in Chinese] Zhongguo Zhong Xi Yi Jie He Za Zhi. 1999;19:77–9. [PubMed] [Google Scholar]

[b105] 105.Gu CX. Cause of amenorrhea after treatment with Tripterygium wilfordii F [in Chinese] Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 1989;11:151–3. [PubMed] [Google Scholar]

[b106] 106.Qian SZ. Tripterygium wilfordii, a Chinese herb effective in male fertility regulation. Contraception. 1987;36:335–45. doi: 10.1016/0010-7824(87)90104-1. [DOI] [PubMed] [Google Scholar]

[b107] 107.Zhen QS, Ye X, Wei ZJ. Recent progress in research on Tripterygium: a male antifertility plant. Contraception. 1995;51:121–9. doi: 10.1016/0010-7824(94)00018-r. [DOI] [PubMed] [Google Scholar]

[b108] 108.Meikle AW. Endocrine Replacement Therapy in Clinical Practice (Contemporary Endocrinology) New York, NY: Humana Press; 2003. [Google Scholar]

[b109] 109.Chou WC, Wu CC, Yang PC, Lee YT. Hypovolemic shock and mortality after ingestion of Tripterygium wilfordii hook F.: a case report. Int J Cardiol. 1995;49:173–7. doi: 10.1016/0167-5273(95)02282-2. [DOI] [PubMed] [Google Scholar]

[b110] 110.Pyatt DW, Yang Y, Mehos B, Le A, Stillman W, Irons RD. Hematotoxicity of the chinese herbal medicine Tripterygium wilfordii Hook F in CD34-positive human bone marrow cells. Mol Pharmacol. 2000;57:512–8. doi: 10.1124/mol.57.3.512. [DOI] [PubMed] [Google Scholar]

[b111] 111.Chan WY, Ng TB. Adverse effect of Tripterygium wilfordii extract on mouse embryonic development. Contraception. 1995;51:65–71. doi: 10.1016/0010-7824(94)00001-d. [DOI] [PubMed] [Google Scholar]

[b112] 112.Takei A, Nagashima G, Suzuki R, Hokaku H, Takahashi M, Miyo T, Asai J, Sanada Y, Fujimoto T. Meningoencephalocele associated with Tripterygium wilfordii treatment. Pediatr Neurosurg. 1997;27:45–8. doi: 10.1159/000121224. [DOI] [PubMed] [Google Scholar]

[b113] 113.Guo JL, Yuan SX, Wang XC, Xu SX, LI DD. Tripterygium wilfordii Hook F in rheumatoid arthritis and ankylosing spondylitis. Preliminary report. Chin Med J (Engl) 1981;94:405–12. [PubMed] [Google Scholar]

[b114] 114.Zhu TZ. Explore the causes of death in 90 cases with intoxication of Tripterygium wilfordii Hook [in Chinese] Beijing Zhong Yi. 1995;2:35–7. [Google Scholar]

[b115] 115.Su D, Song Y, Li R. Comparative clinical study of rheumatoid arthritis treated by triptolide and an ethyl acetate extract of Tripterygium wilfordii [in Chinese] Zhong Xi Yi Jie He Za Zhi. 1990;10:144–6. 131. [PubMed] [Google Scholar]

[b116] 116.Zhang F, Li YC. Progress in structure modification of triptolide[in chinese] Yao Xue Xue Bao. 2004;39:857–64. [PubMed] [Google Scholar]

[b117] 117.Krishna G, Liu K, Shigemitsu H, Gao M, Raffin TA, Rosen GD. PG490-88, a derivative of triptolide, blocks bleomycin-induced lung fibrosis. Am J Pathol. 2001;158:997–1004. doi: 10.1016/S0002-9440(10)64046-1. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b118] 118.Pan F, Fisniku O, Wynn C, Erickson LM, Crews G, Jang MS, Sudo Y, Tamura K, Kobayashi M, Benediktsson H, Jiang H. PG490-88, a new immunosuppressant, effectively prevents acute and chronic rejection in rat renal allografts. Transplant Proc. 2005;37:134–6. doi: 10.1016/j.transproceed.2004.12.054. [DOI] [PubMed] [Google Scholar]

[b119] 119.Kiviharju TM, Lecane PS, Sellers RG, Peehl DM. Antiproliferative and proapoptotic activities of triptolide (PG490), a natural product entering clinical trials, on primary cultures of human prostatic epithelial cells. Clin Cancer Res. 2002;8:2666–74. [PubMed] [Google Scholar]

[b120] 120.Harousseau JL, Dombret H, Pigneux A, Michallet M, Brandely M. 2008. p. 2008. Phase I study of F60008, a triptolide derivative, in patients with refractory or relapsing acute leukemias. 13th Congress of the European Hematology Association (EHA)

[b121] 121.Kitzen JJ, de Jonge MJ, Lamers CH, Eskens FA, van der BD, van Doorn L, Ter Steeg J, Brandely M, Puozzo CH, Verweij J. Phase I dose-escalation study of F60008, a novel apoptosis inducer, in patients with advanced solid tumours. Eur J Cancer. 2009;45:1764–72. doi: 10.1016/j.ejca.2009.01.026. [DOI] [PubMed] [Google Scholar]

[b122] 122.Ren YX, Zhou R, Tang W, Wang WH, Li YC, Yang YF, Zuo JP. (5R)-5-hydroxytriptolide (LLDT-8) protects against bleomycin-induced lung fibrosis in mice. Acta Pharmacol Sin. 2007;28:518–25. doi: 10.1111/j.1745-7254.2007.00524.x. [DOI] [PubMed] [Google Scholar]

[b123] 123.Zhou R, Wang JX, Tang W, He PL, Yang YF, Li YC, Li XY, Zuo JP. (5R)-5-hydroxytriptolide inhibits IFN-gamma-related signaling. Acta Pharmacol Sin. 2006;27:1616–21. doi: 10.1111/j.1745-7254.2006.00457.x. [DOI] [PubMed] [Google Scholar]

[b124] 124.Zhou R, Tang W, He PL, Yang YF, Li YC, Zuo JP. (5R)-5-hydroxytriptolide inhibits the immune response of human peripheral blood mononuclear cells. Int Immunopharmacol. 2009;9:63–9. doi: 10.1016/j.intimp.2008.09.014. [DOI] [PubMed] [Google Scholar]

[b125] 125.Shao F, Wang GJ, Sun JG, Xie HT, Zhang R, Zhu XY. Pharmacokinetics of triptolide in Beagle dogs [in Chinese] Yao Xue Xue Bao. 2007;42:61–5. [PubMed] [Google Scholar]

PERMALINK

Triptolide in the treatment of psoriasis and other immune-mediated inflammatory diseases

Rui Han

Martin Rostami-Yazdi

Sascha Gerdes

Ulrich Mrowietz

Abstract

Introduction

Figure 1.

Application of triptolide

Clinical use of triptolide

Clinical studies using triptolide

Clinical studies with triptolide in psoriasis

Table 1.

Mode of action of triptolide

Pharmacokinetics

Table 2.

Adverse effects

Outlook

Figure 2.

Figure 3.

Conclusions

Competing Interests

REFERENCES

ACTIONS

PERMALINK

RESOURCES

Cite

Add to Collections

PERMALINK

Triptolide in the treatment of psoriasis and other immune-mediated inflammatory diseases

Rui Han

Martin Rostami-Yazdi

Sascha Gerdes

Ulrich Mrowietz

Abstract

Introduction

Figure 1.

Application of triptolide

Clinical use of triptolide

Clinical studies using triptolide

Clinical studies with triptolide in psoriasis

Table 1.

Mode of action of triptolide

Pharmacokinetics

Table 2.

Adverse effects

Outlook

Figure 2.

Figure 3.

Conclusions

Competing Interests

REFERENCES

ACTIONS

PERMALINK

RESOURCES

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