Clematis

Scientific Name(s): Clematis virginiana L. Family: Ranunculaceae

Common Name(s): Clematis , devil's-darning-needle , old-man's beard , traveler's-joy , vine bower , virgin's bower , woodbine , Umdlonzo (Zulu)

Uses

Clematis has been evaluated for its anti-inflammatory, cytotoxic, and antimicrobial effects.

Dosing

No clinical evidence supports dosage recommendations for clematis.

Contraindications

Contraindications have not been identified.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

Skin irritation, hypo- or hyperpigmentation of the skin, profuse salivation, blistering, inflamed eyes, abdominal cramping, vomiting of blood, weakness, bloody diarrhea, and painful, excessive or bloody urine.

Toxicology

Poisoning symptoms may include dizziness, confusion, possible fainting, and convulsions.

Botany

Clematis is a genus of mostly climbing perennial shrubs in the buttercup family with approximately 355 species worldwide, mainly in North America and Asia. Over 70 species are used in Chinese traditional medicine, 1 and several species are cultivated in North America for their beautiful flowers. The common species include woodbine ( C. virginiana ), virgin's bower ( Clematis cirrhosa ), old-man's beard ( Clematis vitalba ), and vine bower ( Clematis viticella ).

C. virginiana is a trailing vine that can grow up to 15 m higher than other botanicals, often resulting in a bower or shaded shelter. The long, feathery, beard-like tail on the fruit led to the common name “old-man's beard.” This species is a North American native plant that was once included in a continental pharmacopeia as a medicine.

Clematis grows in thickets, roadsides, woods, and stream banks. It can be found in Manitoba and Quebec, as far south as Alabama and Louisiana, and west to Kansas. The vine has leaves divided into 3 oval and toothed leaflets, each on long, tendril-like stalks that aid in its climbing habit. From July to September, it displays creamy white flowers that bloom into large clusters that become fruit heads with long plume-like tails. 2 , 3

Other related species in the genus include: Clematis dioica from tropical areas of Central and South America, 4 Clematis recta ( Clematis erecta ) of Southern Europe, C. vitalba of Eurasian and North African origin, 5 Clematis chinensis Osbeck (Wei Ling Xian) of Chinese origin, 6 and Clematis thunbergii from Senegal. 4

History

The popular use of C. virginiana for skin disorders (sores, cuts), itching, and venereal eruptions in North American pioneer medicine was probably learned from American Indians. 2 Throughout history, the leaf of the plant was used in folk remedies for treating cancers and tumors, as well as for itching, fever, renosis, nephrosis, ulcers, and scrofula. 3 Past uses also indicate diuretic, poisonous, rubefacient, sudorific, purgative, and vesicant properties. The Chinese have traditionally used the roots and rhizomes of C. chinensis , Clematis mandschurica Rupr., and Clematis hexapetala Pall., referred to as “weilingxian” in Chinese, for their analgesic, abirritative, antibacterial, antiphlogistic, anticancer, and diuretic effects. 1 Clematis armandii and Clematis montana , referred to as “mu tong,” have been used in China to decrease fever in order to induce urination, stimulate menstrual discharge, and promote lactation. 7 In Anatolia, Turkey, ground leaves or aerial parts are applied to inflamed joint(s) for 15 to 30 minutes to provide pain relief. The irritation causes a gap to open on the skin, which causes drainage of edema. Sometimes, the wound is plugged by a grape dreg to promote continuous drainage. To cure the open wound, Plantago major is applied. Additionally, C. vitalba branches have been used to alleviate tooth pain by smoking the branch like a cigarette. 8 Clematis has long been cultivated as a woody climbing or trailing vine for growing over a fence or wherever dense foliage is desired. Other reports have mentioned using the fuzzy seed mass for smoking and utilizing the young shoots of the Eurasian variety ( Clematis taurica ) in cooking.

Chemistry

Early literature reports extraction of alkaloid, glycoside, and saponin fractions from certain species. 9 Members of Ranunculaceae contain protoanemonin, an irritant compound found mostly in the fresh leaves and sap that is derived from a precursor glycoside known as ranunculin. 10 The same principles for C. vitalba and anemonin, caulosaponin, caulosapogenin, stigmasterol glycoside, ceryl alcohol, myricylalcohol, beta-siterosterol, trimethylamine, n-triacontane, n-nonacosane, ginnone, ginnol, and campesterol, as well as beheinc-, caffeic-, chlorogenic-, and melissic-acid have also been reported. 3 The dried seeds contain approximately 15% protein and 14% fat.

More recent reports identify anemonin (the dilactone of cyclobutane-1,2-diol-1,2 diacrylic acid derived from the cyclodimerization of protoanemonin) in Clematis hirsutissima , 11 a new oleanic saponin named clemontanoside B from C. montana leaves, 12 2 saponins named hushangoside and hederagenin glycoside from the stems of C. montana , 13 other saponins from Clematis species, 14 clemontanoside F from the roots of C. montana , 15 and 2 triterpenoid saponins named clematichineno-side A and B from the roots of C. chinensis . 16 The major components of the essential oil of C. hexapetala are palmitic acid and 3-hydroxy-4-methoxyl benzaldehyde. 17

Uses and Pharmacology

Anti-inflammatory effects

Clematis species have been traditionally used in several cultures for their anti-inflammatory effects. Although not fully understood, these effects may be due to inhibition of proinflammatory cytokines and inhibition of cyclooxygenase (COX) enzymes. Specifically, the ethanolic extracts of 3 Clematis species (ie, Clematis pickeringii , Clematis microphyllia , Clematis glycinoides ) were found, albeit at differing degrees, to inhibit COX-1, COX-2, and 5-lipoxygenase, with the exception that stem and leaf extracts of C. microphyllia did not inhibit COX-2. The highest inhibition was noted with C. pickeringii . 18

Animal data

In a murine model, the compound vitalboside was isolated from C. vitalba and studied for its anti-inflammatory effects. Vitalboside exerted a potent and dose-dependent, anti-inflammatory effect on carrageenan-induced paw edema. Additionally, antipyretic and antinociceptive effects were noted with vitalboside. 8

Similarly, Clematis brachiata exerted anti-inflammatory effects at doses of 100, 200, and 400 mg/kg on carrageenan-induced paw edema in rats. The 400 mg/kg dose was the most potent. Antipyretic and antinociceptive effects were also noted with treatment. Specifically, at a dose of 400 mg/kg, C. brachiata was found to lower body temperature in rats more so than indomethacin. 19

The triterpene saponin, AR-6, has been isolated from C. chinensis and evaluated for its anti-inflammatory effects. In rats with adjuvant-induced arthritis, the oral administration of AR-6 was associated with a reduction in the severity of clinical symptoms, absence of hyperplasia in the synovial membranes, and decreases in prostaglandin E 2 (PGE 2 ), tumor necrosis factor (TNF)-alpha, and nitric oxide levels. 20

In an osteoarthritis model in rats and in rabbit chondrocytes, the saponin fraction of C. chinensis was evaluated for its effects on cartilage and proteoglycan injury. Cartilage erosion and proteoglycan degradation were decreased in a dose-dependent manner with C. chinensis at doses of 50, 100, and 200 mg/kg. It was also shown to prevent chondrocyte impairment. Thus, the authors concluded that C. chinensis were beneficial in an osteoarthritis model by ameliorating joint destruction and protecting cartilage through inhibition of extracellular matrix degradation and chondrocyte injury. 21

In a model of rat chondrocytes, C. mandshurica inhibited staurosporin-induced apoptosis, which was mediated by the premitochondrial antiapoptotic factor, 14-3-3. 22

In mouse peritoneal macrophages, C. mandshurica inhibited lipopolysaccharide (LPS)-interferon (IFN)-gamma-induced nitric oxide and PGE 2 production in peritoneal macrophages in a dose-dependent manner. Additionally, the compound blocked cell proliferation and cytokine production (interleukin [IL]-2, and IFN-gamma) in murine splenocytes that were stimulated with concanavalin A. 23

A study was conducted to assess the anti-inflammatory effects of C. mandshurica on adjuvant arthritis in rats. Subcutaneous administration of C. mandshurica reduced swelling similarly as with rats receiving dexamethasone as a control. Specifically, when clematis was given on the same day or 5 days prior to the inflammatory insult, a reduction in inflammation was noted compared with the control rats. Clematis administration was also associated with a reduction in TNF-alpha and IL-1 production, with an increase in the production of IL-10, a cytokine that suppresses TNF-alpha production. 24

The compound SKI 306X has been used in Asian countries for the treatment of inflammatory diseases such as arthritis. It contains the compounds C. mandshurica , Trichosanthes kirilowii , and Prunella vulgaris in a ratio of 1:2:1. 25 Specifically, the active ingredients exerting anti-inflammatory effects have been identified as oleanolic acid and rosmarinic acid. 26 In a study, bovine cartilage explants were cultured for 7 days with or without IL-1beta in the presence or absence of SKI 306X components. A concentration-dependent inhibition of proteoglycan degradation mediated by IL-1beta occurred with SKI 306X and its components. Specifically, at 100 mcg/mL, SKI 306X, Clematis , Prunella , and Trichosanthes inhibited the release of glycosaminoglycan to 50%, 65%, 34%, and 73%, respectively. Additionally, at 100 mcg/mL, the release of nitric oxide was inhibited to 22%, 47%, 21%, and 52%, respectively, suggesting cartilage-protective activity. Lastly, Clematis and Trichosanthes blocked the production of PGE 2 in a concentration-dependently manner, demonstrating anti-inflammatory activity. 25

Clinical data

In the same study, SKI 306X, C. mandshurica , and P. vulgaris were found to inhibit IL-1beta dose-dependently in human peripheral blood mononuclear cells. The inhibition of TNF-alpha occurred in a concentration-dependent manner for SKI 306X, C. mandshurica , T. kirilowii , and P. vulgaris . 25

A 4-week, randomized, double-blind, double-dummy clinical trial assessed the safety and efficacy of SKI306X in comparison with diclofenac for the treatment of knee osteoarthritis. Two-hundred forty-nine South Korean patients between 35 and 75 years of age with knee osteoarthritis diagnosed according to the American College of Rheumatology (ACR) criteria experiencing at least moderate pain were randomized to receive SKI306X 200 mg 3 times daily or diclofenac sustained release 100 mg once daily. The visual analog scale scores declined between baseline and the fourth week of treatment by −14.18 mm in the SKI306X group compared with −15.49 in the diclofenac group. This difference of −1.31 mm between groups was not statistically significant ( P = 0.53). Both treatments were well tolerated; however, more patients in the diclofenac group reported heartburn compared with those receiving SKI306X. Elevations in liver function tests were more frequently noted in the diclofenac group compared with SKI306X ( P = 0.01) for both AST and ALT levels). 27

In a multicenter, randomized, double-blind, double-dummy, phase 3, noninferiority clinical study, Korean patients 8 to 80 years of age with rheumatoid arthritis (RA) for at least 3 months' duration and classified with functional ACR I, II, or III at enrollment were assessed for pain relief and tolerability. Patients were allowed to continue on stable dose of disease-modifying antirheumatic drugs (DMARDs) and oral corticosteroid doses of prednisone 10 mg or less. A 14-day washout period occurred in which nonsteroidal anti-inflammatory drugs (NSAIDs) were discontinued. Following the washout period, patients were required to have an increase in pain and exhibit active disease. They were then randomized to receive either SKI306X orally 3 times daily or celecoxib 200 mg orally twice daily for 6 weeks. Both treatment groups received placebo in addition to their active treatment to maintain blinding. One hundred eighty-three patients were randomized to the treatment groups. Both treatment groups had a statistically significant reduction in pain from baseline at weeks 3 and 6; however, no differences were found between groups. According to predefined criteria, it was determined that SKI306X was considered noninferior to celecoxib. Additionally, the number of patients achieving ACR20 response rates or using rescue medication (ie, acetaminophen 650 mg) did not differ between the 2 treatment groups. Therefore, SKI306X may be a potential anti-inflammatory option for patients suffering from inflammatory diseases such as RA. 26

In another study involving C. chinensis , 7 new triterpene saponins were isolated and, together with 17 known saponins, were assayed for their potential anti-inflammatory activity. Of the 24 saponins tested, 11 were determined to exhibit inhibition against COX-1 and COX-2. However, none of the compounds exhibited selective inhibition against COX-2. 28

Cytotoxic effects
In vitro data

Four triterpene glycosides were isolated from the aboveground part of Clematis ganpiniana . Three of these compounds demonstrated cytotoxic activities against estrogen-independent human breast cancer cells (MDA-MB-231) and estrogen-dependent human breast cancer cells (MCF-7). The compound alpha-hederin showed the strongest anticancer activity and highest apoptosis rates. 1

Animal data

In an in vitro model, C. chinensis exerted cytotoxic effects on EAC cells (concentration that inhibits 50% [IC 50 ] 242 mcg/mL), S180A cells (IC 50 193 mcg/mL), and HepA cells (IC 50 130 mcg/mL). As part of this same study, clematis was also found to inhibit the growth of mouse tumors in an in vivo model with inhibitory rates of 40.3% (0.25 g/kg), 55.1% (0.5 g/kg), and 53% (1 g/kg). However, mouse survival time was not affected by clematis. 29

Antimicrobial effects
Animal data

Research reveals no animal data regarding the antimicrobial effects of clematis.

Clinical data

Four triterpene glycosides were isolated from the aboveground part of C. ganpiniana . The compound alpha-hederin demonstrated antibacterial effects against micrococcus luteus, Escherichia coli , Bacillus subtilis , Candida albicans , Staphylococcus aureus , and Bacillus pumilus . The other compounds did not show activity. 1

A mannose-binding lectin isolated from C. montana exerted antiviral effects against HIV. Anti-HIV activity occurred at medium effective concentration values of 11 ± 3.9 mcg/mL and 71 ± 41 mcg/mL for HIV-1 and HIV-2, respectively. Antiviral activity was also noted against influenza A H1N1 subtype, H3N2 subtype, influenza B, parainfluenza-3, and virus reovirus-1. 7

The antimycotic activity of C. vitalba was assessed using the agar diffusion well bioassay method. The compound exerted antimycotic activity against a broad range of pathogenic yeast and yeast-like microorganisms, with minimal inhibitory concentrations ranging from 1.4 to 12.3 mcg/mL. This activity was determined to occur only in methanol fractions of the compound. 30

Two compounds, beta-magnoflorine and alpha-magnoflorine, were isolated from Clematis parviolba and assessed for their antifungal effects. Both compounds exerted anti-inflammatory effects against Penicillium avellaneum UC-4376. 31

C. dioica has demonstrated activity against Neisseria gonorrhea in an in vitro model. 32

Other uses

The diuretic effects of Clematis montevidensis were investigated in rats administered isotonic saline solution. Infusions of the root and aerial part of the plant demonstrated moderate diuretic activity believed to be due to oleanolic acid isolated from the plant. 33

Dosage

No clinical evidence supports dosage recommendations for clematis.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

When the plants are handled or eaten, protoanemonin irritates and blisters the skin. A case report describes a man 34 years of age who developed hypo- and hyperpigmented areas on his skin following application of fresh C. chinensis to his wrist for pain relief. He used the product for 13 months and reported pruritic erythema with each twice weekly application. Subsequent examination by a physician confirmed the finding, and he tested positive on a patch test with both alcoholic and aqueous extracts of C. chinensis . Other adverse effects that may occur after contact with fresh C. chinensis include erythema, bullae, palpitations, and dyspnea. 34 Intense inflammation and burning of the digestive tract and around the mouth. Other adverse effects associated with oral intake include profuse salivation, blistering, inflamed eyes, abdominal cramping, vomiting of blood, weakness, and bloody diarrhea. 10 Kidneys may also be irritated, resulting in painful and excessive urination and bloody urine, ultimately leading to diminished urinary output.

Toxicology

A poisonous-plant reference focused on those buttercup species that contained protoanemonin in the fresh leaves and sap, including clematis. Poisoning symptoms may include dizziness, confusion, possible fainting, and convulsions.

Fatalities are not common, probably due to the rapid and intense acrid taste and irritation resulting from oral contact. If a large amount has been accidentally ingested, gastric lavage is recommended, followed by demulcents to soothe irritated membranes. Because protoanemonin is present mainly in fresh plant material, cooking or drying results in its decomposition.

Bibliography

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