Thunder God Vine
Tripterygium wilfordii Hook. Family: Celastraceae
Huang-t'eng ken ( yellow vine root ), lei-kung t'eng , lei gong teng (Chinese), thunder god vine , thunder of god vine , tsao-ho-hua ( early rice flower )
 
Clinical Overview
Uses
Thunder god vine has been evaluated for use primarily in rheumatoid arthritis (RA); however, its adverse event profile and limited quality trials restrict any recommendations for clinical use. Antifertility properties in men have been described, while amenorrhea was observed in women.

Dosing
In RA trials, 60 mg/day of T2 (a chloroform-methanol extract of Tripterygium wilfordii ) for 12 weeks has been evaluated, as well as ethanol/ethyl alcohol root extract 180 to 360 mg/day. Several long-term studies have evaluated the use of 1 mg/kg/day of T2 for up to 5 years; however, adequate safety data during the same time period are limited.

Contraindications
Contraindications have not been determined. Due to immune suppression, thunder god vine preparations should not be used in immune-compromised patients.

Pregnancy/Lactation
Avoid use. Embryotoxicity has been demonstrated in mice.

Interactions
None well documented.

Adverse Reactions
Clinically important adverse events have been reported in clinical trials. GI upset, male and female infertility, and immune suppression are common side effects of thunder god vine.

Toxicology
Information is limited. Embryotoxicity was demonstrated in mice, including neural effects, absence of limb buds, and ophthalmic-related effects.

 
Botany
Tripterygium is a woody perennial twining vine native to parts of China, Korea, Japan, and Taiwan, and is usually found growing close to water sources. It has reddish-brown branches with oval leaves. In the summer, small white terminal flowers bloom. Some disagreements about the taxonomy of related species exist. 1 , 2
 
History
The thunder god vine has been used for centuries in traditional Chinese medicine to treat fever, boils, abscesses, and inflammation. Preparations of Tripterygium have been used since the 1960s in China to treat RA and inflammation; however, toxicity concerns limited its use to a hot water decoction. Attempts have been made to limit the toxicity through different extraction methods and by using only the less toxic portion of the plant root. It has also been used as an insecticide and as rat and bird poison. 1
 
Chemistry
The major constituent isolated from thunder god vine roots has been identified as the diterpenoid triptolide. Other constituents, some of which may be pharmacologically as important as triptolide, include sesquiterpenes (eg, dihydroagarofurans, alkaloids), diterpenes (eg, tripdiolide, tripchlorolide), and triterpenes. Methods of extraction include aqueous and ethanol processes. 1 , 2
 
Uses and Pharmacology
Antifertility   An antifertility effect was observed in men participating in a study to evaluate the effect of T. wilfordii in RA. Mean sperm density and motility were lower in the treatment arm (20 to 30 mg of extract per day) versus control. Follicle-stimulating hormone was higher in the treatment group; however, testosterone levels and libido appeared unaffected. Similar observations have been reported for a related species. These observations led to the extraction and further evaluation of the chemical constituent triptolide and other compounds as potential male contraceptive agents. These compounds appear to act primarily on sperm development (eg, sperm head-tail separation) rather than affecting testosterone levels, with sperm returning to normal after 6 weeks; however, high quality clinical trials are lacking to confirm efficacy or safety. 3 , 4 , 5 , 6 , 7
Renal effects   Limited clinical trials have demonstrated positive effects of extracts in renal-associated conditions, such as renal transplant and idiopathic refractory nephrotic syndrome, although the effects may be largely due to immune-modulation rather than direct activity on the kidney. One trial evaluated the effect of T. wilfordii in renal transplant recipients over 5 years; however, there did not appear to be any randomization or blinding in the study. 8 In a study lasting longer than 1 year, the same group of researchers evaluated the effect on sirolimus-induced proteinuria in similar patients. 9 Three trials included in a meta-analysis on idiopathic refractory nephrotic syndrome showed beneficial effects on laboratory indices such as proteinuria, hypoalbuminemia, edema, and hypercholesterolemia. 10
Rheumatoid arthritis   Animal and human studies, as well as in vitro models, have shown thunder god vine to exert effects in autoimmune diseases. Interference in cytokine transcription, response of mononuclear cells, generation of cytotoxic T-cells, prostaglandin secretion, IL-2 production, and inhibition of T-cell and B-cell proliferation are among the suggested mechanisms. 11 , 12 , 13 , 14 , 15 The major immunosuppressive activity is due to the diterpenoids triptolide and tripdiolide. 2 , 16 Other chemical compounds may also be involved. 17 , 18
Few clinical trials have been conducted that are methodologically sound. In some, there is no randomization, in others, no control group or comparator, and in some, the preparation is used in combination with other agents. However, in those few that do meet quality criteria, T. wilfordii possessed beneficial effects on RA symptoms and clinically important adverse events. 2 , 19 , 20
Improvements in both patient- and physician-rated tenderness, swelling, and morning stiffness have been demonstrated. Laboratory indices of the disease, including erythrocyte sedimentation rate, immunoglobulin G, immunoglobulin M, immunoglobulin A, and C-reactive protein also improved. 2 , 20 , 21 , 22 A trial conducted among US participants in 2005 found a greater effect for a T. wilfordii extract than sulfasalazine in treating RA over 24 weeks, with similar adverse event rates. 23
Other effects
Antiviral   Neotripterifordin showed potent anti-HIV replication activity in vitro. 24 , 25 Triptofordin C-2 and other sesquiterpene components of thunder god vine have been evaluated for their antiviral activity, including activity against human cytomegalovirus. 26
Antitumor   Low doses of the diterpene triptolide showed antileukemic and antitumor activity in rodents; while demethylzeylasteral demonstrated antiangiogenic properties. 27 , 28 , 29 Effects of thunder god vine on tumor necrosis factor have been reported. 30
CNS   Animal models have been used to demonstrate anti-inflammatory protective action on dopamine neurons by triptolide and trichlorolide. Clinical studies are lacking. 1 , 31 , 32
 
Administration & Dosage
In RA trials, 60 mg/day of T2 (a chloroform-methanol extract of T. wilfordii ) for 12 weeks has been evaluated, as well as ethanol/ethyl alcohol root extract 180 to 360 mg/day. 2 , 21 , 22
Few long-term studies have evaluated the use of 1 mg/kg/day of T2 for up to 5 years; however, adequate safety data during the same time period are limited. 8 , 9
The effective antifertility dose has been suggested at one-third the recommended dose for treatment of arthritis; however, quality clinical trials are lacking to confirm efficacy and safety. 3
 
Pregnancy/Lactation
Avoid use. Embryotoxicity was demonstrated in mice fed an aqueous extract of T. wilfordii and included neural effects, absence of limb buds, and ophthalmic-related effects. 33 Amenorrhea is reported among women participating in clinical trials. 2 , 9
 
Interactions
None well documented.
 
Adverse Reactions
Clinically important adverse events have been reported in clinical trials.
GI upset (including nausea, abdominal pain, indigestion, flatulence, constipation, and diarrhea), male and female infertility, and immune suppression are common adverse effects of thunder god vine. Hair loss, skin rash, and blisters have also been reported. 2 , 3 , 8 , 19
 
Toxicology
Information is limited; however, one case report describes an incidence of death in a seemingly young and healthy male 3 days postingestion of the drug. Later investigation found some incidence of coexisting cardiac damage. 34 Treatments of 50 mcg per mouse 3 times weekly in one preparation were lethal. 27
Embryotoxicity was demonstrated in mice fed an aqueous extract of T. wilfordii for 10 days, and included neural effects, absence of limb buds, and ophthalmic-related effects. 33
 
References
 

1. Brinker AM, Ma J, Lipsky PE, Raskin I. Medicinal chemistry and pharmacology of genus Tripterygium ( Celastraceae ) [published correction appears in Phytochemistry . 2007;68(13):1819]. Phytochemistry . 2007;68(6):732-766.  PubMed

 

2. Canter PH, Lee HS, Ernst E. A systematic review of randomised clinical trials of Tripterygium wilfordii for rheumatoid arthritis. Phytomedicine . 2006;13(5):371-377.  PubMed

 

3. Lopez LM, Grimes DA, Schulz KF. Nonhormonal drugs for contraception in men: a systematic review. Obstet Gynecol Surv . 2005;60(11):746-752.  PubMed

 

4. Lue Y, Sinha Hikim AP, Wang C, et al. Triptolide: a potential male contraceptive. J Androl . 1998;19(4):479-486.  PubMed

 

5. Zhen Q, Ye X, Wei ZJ. Recent progress in research on Tripterygium : a male antifertility plant. Contraception . 1995;51(2):121-129.  PubMed

 

6. Matlin SA, Belenguer A, Stacey VE, et al. Male antifertility compounds from Tripterygium wilfordii Hook f. Contraception . 1993;47(4):387-400.  PubMed

 

7. Qian SZ. Tripterygium wilfordii , a Chinese herb effective in male fertility regulation. Contraception . 1987;36(3):335-345.  PubMed

 

8. Ji SM, Wang QW, Chen JS, Sha GZ, Liu ZH, Li LS. Clinical trial of Tripterygium wilfordii Hook F. in human kidney transplantation in China. Transplant Proc . 2006;38(5):1274-1279.  PubMed

 

9. Ji SM, Li LS, Wen JQ, et al. Therapeutic effect of Tripterygium wilfordii on proteinuria associated with sirolimus in renal transplant recipients. Transplant Proc . 2008;40(10):3474-3478.  PubMed

 

10. 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(4):c223-c228.  PubMed

 

11. Li XW, Weir MR. Radix Tripterygium wilfordii —a Chinese herbal medicine with potent immunosuppressive properties. Transplantation . 1990;50(1):82-86.  PubMed

 

12. Chang DM, Chang WY, Kuo SY, Chang ML. The effects of traditional antirheumatic herbal medicines on immune response cells. J Rheumatol . 1997;24(3):436-441.  PubMed

 

13. 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(10):1274-1281.  PubMed

 

14. Ye WH. Mechanism of treating rheumatoid arthritis with polyglycosides of Tripterygium wilfordii Hook (T II). III. Study on inhibitory effect of T II on in vitro Ig secreted by peripheral blood mononuclear cells from normal controls and RA patients [in Chinese]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao . 1990;12(3):217-222.  PubMed

 

15. Sylvester J, Liacini A, Li WQ, Dehnade F, Zafarullah M. Tripterygium wilfordii Hook F extract suppresses proinflammatory cytokine-induced expression of matrix metalloproteinase genes in articular chondrocytes by inhibiting activating protein-1 and nuclear factor-kappaB activities. Mol Pharmacol . 2001;59(5):1196-1205.  PubMed

 

16. Tao X, Cai JJ, Lipsky PE. The identity of immunosuppressive components of the ethyl acetate extract and chloroform methanol extract (T2) of Tripterygium wilfordii Hook. F. J Pharmacol Exp Ther . 1995;272(3):1305-1312.  PubMed

 

17. Tamaki T, Kawamura A, Komatsu Y, Kawamura H, Maruyama H, Morota T. Phenolic nortriterpene demethylzeylasteral: a new immunosuppressive component of Tripterygium wilfordii Hook f. Transplant Proc . 1996;28(3):1379-1380.  PubMed

 

18. Yu DQ, Zhang DM, Wang HB, Liang XT. Structure modification of triptolide, a diterpenoid from Tripterygium wilfordii [in Chinese]. Yao Xue Xue Bao . 1992;27(11):830-836.  PubMed

 

19. Little CV, Parsons T. Herbal therapy for treating osteoarthritis. Cochrane Database Syst Rev . 2001;(1):CD002947.

10.1002/14651858.CD002948
PubMed

 

20. Cameron M, Gagnier JJ, Little CV, Parsons TJ, Blümle A, Chrubasik S. Evidence of effectiveness of herbal medicinal products in the treatment of arthritis. Part 2: rheumatoid arthritis. Phytother Res . 2009;23(12):1647-1662.  PubMed

 

21. Tao XL, Sun Y, Dong Y, et al. A prospective, controlled, double-blind, cross-over study of Tripterygium wilfordii hook F in treatment of rheumatoid arthritis. Chin Med J (Engl) . 1989;102(5):327-332.  PubMed

 

22. 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(7):1735-1743.  PubMed

 

23. Goldbach-Mansky R, Wilson M, Fleischmann R, et al. Comparison of Tripterygium wilfordii Hook F versus sulfasalazine in the treatment of rheumatoid arthritis: a randomized trial. Ann Intern Med . 2009;151(4):229-240, W49-W51.  PubMed

 

24. Chen K, Shi Q, Fujioka T, et al. Anti-AIDS agents—XIX. Neotripterifordin, a novel anti-HIV principle from Tripterygium wilfordii : isolation and structural elucidation. Bioorg Med Chem . 1995;3(10):1345-1348.  PubMed

 

25. Chen K, Shi Q, Fujioka T, et al. Anti-AIDS agents, 4. Tripterifordin, a novel anti-HIV principle from Tripterygium wilfordii : isolation and structural elucidation. J Nat Prod . 1992;55(1):88-92.  PubMed

 

26. Hayashi K, Hayashi T, Ujita K, Takaishi Y. Characterization of antiviral activity of a sesquiterpene, triptofordin C-2. J Antimicrob Chemother . 1996;37(4):759-768.  PubMed

 

27. Shamon LA, Pezzuto JM, Graves JM, et al. Evaluation of the mutagenic, cytotoxic, and antitumor potential of triptolide, a highly oxygenated diterpene isolated from Tripterygium wilfordii . Cancer Lett . 1997;112(1):113-117.  PubMed

 

28. Xu JY, Yang J, Li LZ. Antitumor effect of Tripterygium wilfordii [in Chinese]. Zhongguo Zhong Xi Yi Jie He Za Zhi . 1992;12(3):161-164, 134.  PubMed

 

29. Ushiro S, Ono M, Nakayama J, et al. New nortriterpenoid isolated from anti-rheumatoid arthritic plant, Tripterygium wilfordii , modulates tumor growth and neovascularization. Int J Cancer . 1997;72(4):657-663.  PubMed

 

30. Zeng X, Zhang N. The effects of a single active ingredient (T4) of Tripterygium wilfordii Hook on the production of tumor necrosis factor by the peripheral blood mononuclear cells and synovium cells of rheumatoid arthritis patients [in Chinese]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao . 1996;18(2):138-142.  PubMed

 

31. Chen LW, Wang YQ, Wei LC, Shi M, Chan YS. Chinese herbs and herbal extracts for neuroprotection of dopaminergic neurons and potential therapeutic treatment of Parkinson's disease. CNS Neurol Disord Drug Targets . 2007;6(4):273-281.  PubMed

 

32. Li FQ, Lu XZ, Liang XB, et al. Triptolide, a Chinese herbal extract, protects dopaminergic neurons from inflammation-mediated damage through inhibition of microglial activation. J Neuroimmunol . 2004;148(1-2):24-31.  PubMed

 

33. Chan WY, Ng TB. Adverse effect of Tripterygium wilfordii extract on mouse embryonic development. Contraception . 1995;51(1):65-71.  PubMed

 

34. 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(2):173-177.  PubMed