Cat's Claw (Vincaria)

OVERVIEW

Cat’s claw, also known by its Spanish name, uña de gato, is an herb that has gained recent popularity in the U.S. herb market. Uña de gato is the common name for at least 20 plants (from 12 different families) with sharp, curved thorns (Obregon, 1995; Cabieses, 1994). Among them are two climbing, woody vines: Uncaria tomentosa and U. guianensis, the two species of Uncaria (there are approximately 60 species) native to the South and Central American tropical rain forests that are the subject of this monograph. According to U.S. herb industry policy, the standardized common name “cat’s claw” refers to only U. tomentosa (McGuffin et al., 2000), presumably because products containing U. guianensis were not generally available in the U.S. market during most of the 1990s, having been introduced in the past several years. [Editors’ note: For the purposes of this monograph, U. tomentosa will be abbreviated as “UT” and U. guianensis will be abbreviated as “UG”. Because the information on each species and chemotype may be specific to that particular species or chemotype, it may have been preferable to write two or three separate monographs instead of one. However, the editors chose to include all the relevant information on “cat’s claw” in this single monograph, with subheadings designating species and chemotypes, where applicable. In doing so, the editors acknowledge that actions and uses based on one species or chemotype may not be transferable to another.]
Both UT and UG are said to have a long history of use by the indigenous people to treat a diverse set of health problems, particularly rheumatism, arthritis, and other chronic inflammatory disorders, gastric ulcers and gastrointestinal disorders, tumors, and as a contraceptive (Cabieses, 1994; Jones, 1995; Obregon, 1995; Anon.,1996; Miller, 2001). Although no written records are available describing their traditional use (Cabieses, 1994), a study of the medicinal system of the Ashaninca (also spelled Asháninka) tribe in Peru has been published [TK: ref]. To the priests of this tribe, cat’s claw (UT) is a sacred plant used to eliminate disturbance in the communication between body and spirit (Keplinger et al., 1999). One account of the Asháninka Indians states that the priests differentiate between the two UT chemotypes and use only the pentacyclic oxindole alkaloid (POA) chemotype (Keplinger, 1999), but how the priests can distinguish between chemotypes without the scientific tools of chemical analysis is not described. Despite some recent interest in this herb’s potential immunomodulating activity, ethnomedical evidence of such use is lacking.
Several types of cat’s claw preparations have grown in popularity in the U.S. with the market defined by the following four types of products offered mainly by three manufacturers, each with their own distinct focus: (1) a hydroalcoholic UT extract standardized to pentacyclic oxindole alkaloids (POAs), (2) an aqueous UT extract standardized to carboxy alkyl esters (CAEs), (3) and an aqueous UG extract. A fourth type of relatively generic cat’s claw product (usually labeled as UT) is made from the raw root bark, either powdered in capsules and tablets, or finely cut for tea products (decoction, the traditional form of use). Little scientific research has been performed on this fourth class of crude products. Occasionally, products labeled as “cat’s claw” in ethnic markets have been shown to be mislabeled due to the vast number of plants going by the common name cat’s claw and the lack of adequate quality control in some small importers and distributors. in 199?TK a case of poisoning was reported in South Texas involving a product labeled “cat’s claw” containing…. [TK-MB: in HG database, MB searching.]

Fourteen clinical trials on various preparations are summarized herein. One controlled clinical trial with UG suggests efficacy in the treatment of osteoarthritis of the knee (Piscoya et al., 2001). While cat’s claw’s popularity is partly due to European reports of its clinical effectiveness in combination with AZT (zidovudine) for AIDS treatment, these findings need to be confirmed by well-controlled clinical studies. Other current studies report on cat’s claw’s anti-inflammatory and antioxidant properties, and its ability to affect gene expression and thereby modulate the immune system.
Cat’s claw is not yet popular in mainstream retail markets, being sold primarily in health food stores where it ranked 25th in total herb sales in 2000 (Richman and Witkowski, 2001), mail order, and in the ethnic Hispanic market.

DESCRIPTION

Cat’s claw preparations are made from extracts of the dried stalk or root bark of U. tomentosa (Willd.) DC. or U. guianensis (Aubl.) Gmel. [Fam. Rubiaceae]. Given that a considerable proportion of the cat’s claw is still wild harvested, it would be prudent not to utilize the root, as the vine can regenerate when the stalk is cut above ground level. Uncaria tomentosa and U. guianensis are distinguished by flower color, thorn shape, and leaf characteristics (Jones, 1995; Cabrieses, 1994). The U. tomentosa plants occur naturally as two chemotypes that appear identical botanically, but are chemically different in their alkaloid content (Laus et al., 1997). One chemotype contains predominantly pentacyclic oxindole alkaloids (POAs) with little or no tetracyclic oxindole alkaloids, and the other contains tetracyclic oxindole alkaloids (TOAs) with either no POAs or up to a considerable amount. TOAs are believed to act antagonistically to some POA activity (Wurm et al., 1998). Studies demonstrating that purified POA or TOA share the same bioactivity as cat’s claw preparations but enhanced for the relative concentrations in these extracts are lacking, and it may well be that these chemical constituents are more useful as marker compounds rather than mediating the bioactivity of the botanical While early studies focused on POAs as the active components, more recent studies report that activity is well spread over a range of polar materials. Several commercial preparations of U. tomentosa are available: one hydroalcoholic extract standardized to POAs (containing no TOAs); a nonstandardized mixture of both chemotypes; and an aqueous extract, ultrafiltrated, containing a negligible level of oxindole alkaloids, and standardized to carboxy alkyl esters (CAEs). One U. guianensis preparation is available that is composed of a freeze-dried aqueous extract. No monographs on any cat’s claw preparation have been published to date in any official pharmacopeias.

PRIMARY USES

Anti-Inflammatory
** Osteoarthritis (of the knee)
• UG: reduces pain (Piscoya et al., 2001)

** Rheumatoid Arthritis, adjunct therapy to conventional treatment
• UT-POAs: reduces number of painful and swollen joints (Mur et al., 2002; Immodal, 1995, 2002)

OTHER POTENTIAL USES

[Editors’ note: the following other potential uses are based on clinical trials unless otherwise noted.]
** Anti-inflammatory, Gastrointestinal
• UG: protects gastric epithelial cells against NSAID-induced gastritis and apoptosis in in vitro tests (Sandoval et al., 2002; Miller et al., 1999)
• UT-unspecified: protects gastric epithelial cells against NSAID-induced gastritis and apoptosis in animal and in vitro tests (Sandoval et al., 2002; Sandoval-Chacon et al., 1998)
• UT-POAs: ulcers and gastritis (Immodal 1995, 1999a)

** Antioxidant
• UG: effectively scavenges DPPH (a, a-diphenyl-ß-picrylhydrazyl), protects against deoxyribose degradation, and inhibits ABTS (2,2’-azinobis[3-ethyl-benzthiazoline-6-sulfonic acid]) radicals in in vitro tests (Sandoval et al., 2002); limits gastric epithelial cell death in response to oxidative stress in vitro (Miller et al., 2001)
• UT-unspecified: effectively scavenges DPPH, protects against deoxyribose degradation, and inhibits ABTS radicals in in vitro tests (Sandoval et al., 2002); cytoprotective against oxidative stress in vitro(Sandoval-Chacon et al., 1998)

** Cancer, adjunctive to chemotherapy & radiation
• UT-POAs: increases vitality and reduces side effects (Immodal, 1995, 1999a, 2002)

** DNA-Repair / Antimutagenic
• UT-unspecified: decreased mutagenicity of one smoker’s urine (Rizzi et al., 1993)
• UT-CAEs: enhanced DNA repair (Sheng et al., 2001)

** External Use
• UT-POAs: Herpes simplex and Varicella-zoster (Immodal 1995, 1999a, 2002)

** HIV, adjunctive to antiretroviral therapy
• UT-POAs: stabilizes and/or reduces CD4-cell count, increases vitality and mobility, reduced HIV-related symptoms (Immodal, 1995, 1999a, 2002)

** Immune System Support
• UT-CAEs: extends immunity from pheumonia vaccine (Lamm et al., 2001); increases white blood cells (Sheng et al., 2001, 2000a) in animal study (Sheng et al, 2000b)

** Protection against UV radiation
• UT-unspecified: cytoprotective against UV radiation in vitro (Sandoval et al., 2000; Rizzi et al., 1993).

DOSAGES

Crude Preparations
Note: There is little scientific or clinical documentation supporting the use of crude cat’s claw products. Most clinical research has been conducted on special standardized preparations of various types.

** Uncaria guianensis
• Capsules: aqueous extract of bark powder, freeze-dried: 100 mg 1–3 times daily (Piscoya et al., 2001; Miller, 2001a).

** Uncaria tomentosa, chemotype and active component unspecified
• Capsules: 350–500mg, 1–2 times daily (CAMR, 1999).
• Decoction: 1 g root bark boiled for 15 minutes in 250 ml water, 1–3 times daily (Access, 2000; CAMR, 1999).
• Tincture: 1–2 ml, 2–3 times daily (CAMR, 1999).

Standardized Preparations
** Uncaria tomentosa, standardized to CAEs
• Tablets: 350 mg daily (Lamm et al., 2001; Sheng et al., 2001, 2000a).

** Uncaria tomentosa standardized to POAs
• Capsules: 20 mg (0.26 mg POAs), 3 times daily for the first 10 days, and one capsule daily thereafter (Enzymatic Therapy, 2002).
• Capsules: 1–3 caps/day (in acute cases, triple dose for 1st wk) (Immodal, 1995).
• Drops: Adults: 3x20 d/day; 3–6 yrs: 3x7 d/day; 7–9 yrs: 3x10 d/day; 10–12 yrs: 3x15 d/day; 12+yrs: 3x20 d/day (Immodal, 1995).
• Tea: 20 g ground root bark in 1 L water, boil 45 min, cool 10min, filter, add water to make 1 L. Adults: 60 ml decoction in 60 ml hot water before breakfast; Children: decoction in hot water before breakfast according to the following amounts: 3–6yrs: 20 ml in 20 ml; 7–9 yrs: 30 ml in 30 ml; 10–12 yrs: 50 ml in 50 ml; 12+yrs: same as adult (Immodal, 1995).
• Ointment: apply externally several times daily (Immodal, 1995).
• Spray: apply externally several times daily (Immodal, 1995).

DURATION OF ADMINISTRATION

At this time, there is little scientific information other than ethnobotanical observations and 14 clinical trials (including case reports and treatment observations on how long cat’s claw can be consumed. Published clinical trials have been conducted from as short as 4 weeks to 1 year of continuous internal use, while unpublished treatment observations using Krallendorn® (Immodal Pharmaka GmbH) products report on continuous (uncontrolled) use for up to 10 years. There are no known reports of adverse effects associated with the use of cat’s claw preparations for extended periods.

CHEMISTRY

Although chemical research on cat’s claw began with UG in 1952 (Cabieses, 1994), most of the chemical research since then has focussed on UT and its alkaloids, particularly the oxindole alkaloids. However, these alkaloids are a small component of cat’s claw accounting for 9mg/g in Uncaria tomentosa and 0.3mg/g in Uncaria guianensis (Sandoval et al. 2002),[what’s the general range in %? TK], which is rich in flavanoids, quinovic glycosides, polyhodroxylated triterpines, and tannins. While earlier studies reported alkaloids as the active components of cat’s claw (Aguilar et al., 2000; Laus et al., 1998; Stuppner et al., 1993; Kreutzkamp, 1984; Wagner et al., 1985a, 1985b), more recent studies report that bioactivity is spread over a wide range of components (Aguilar et al., 2002; Sandoval et al., 2002; Kitajima et al., 2000; Lee et al., 1999; Sheng et al., 1998; Wirth and Wagner, 1997; Aquino et al., 1991, 1989; Cerri et al., 1988), and one study suggests that the anti-inflammatory and antioxidant activities of cat’s claw are not affected by the presence or relative level of alkaloids (Sandoval et al., 2002). As in an determination of the source of bioactivity in an unknown natural product any proposed active constituent must mimic the actions of the extract from which it was derived, and exert these actions at a concentration that reflects its relative amount within that botanical or botanical extract.

Uncaria guianensis
The little chemical research performed on UG has been limited to its alkaloid, quinovic acid glycoside, and flavanol content. UG contains very low levels of alkaloids — 35 times less than UT (Sandoval et al., 2002; Miller et al., 2001) — including speciophylline, mitraphylline, isomitraphylline, uncarine E, and uncarine C (Sandoval et al., 2002; Miller et al., 2001; Lee et al., 1999). UG also contains quinovic acid glycosides (Yépez et al., 1991), flavanols (catechin, epigallocatechin, epicatechin and epigallocatechin) (Sandoval et al., 2002; Miller et al., 2001), and polyphenols (Miller et al., 2001). UG has lower concentrations of the flavanols (except for epigallocatechin) than does UT (Sandoval et al., 2002).

Uncaria tomentosa
UT has two chemotypes: the pentacyclic alkaloid type and tetracyclic alkaloid type. The first contains pentacyclic oxindole alkaloids (POAs), which some consider to be the main active component of cat’s claw (Immodal 1995, 1999a, 1999b), with little or no tetracyclic oxindole alkaloids (TOAs). The second chemotype contains predominantly TOAs with either no POAs or up to a considerable amount of POAs (Laus et al., 1997). TOAs are considered antagonistic to the purported beneficial effects of the POAs (Wurm et al., 1998) and thus the significance in distinguishing the differences between the two chemotypes.

POAs in UT include pteropodine, isopteropodine, speciophylline, uncarine F, mitraphylline, isomitraphylline, uncarine E, and uncarine C (Muhammad et al., 2001a; Laus et al., 1997; Stuppner et al., 1992; Wagner et al., 1985b). The TOAs present in UT include rhynchophylline, isorhynchophylline, corynoxeine, isocorynoxeine (Keplinger et al., 1999; Laus et al., 1997; Wagner et al., 1985b). Other alkaloids in UT include pentacyclic indol alkaloids (akuammigine, tetrahydroalstonine, isoajmalicin) (Laus et al., 1997), tetracyclic indol alkaloids (hirsutine, dihydrocorynantheine, hirsuteine, corynantheine) (Keplinger et al., 1999; Laus et al., 1997) and precursor alkaloids (5a-carboxystrictosidine, lyaloside) (Aquino et al., 1991).

In addition to alkaloids, UT contains triterpenes (ursolic acid derivatives, quinovic acid glycosides, oleanolic acid derivatives) (Laus et al., 1997; Aquino et al., 1991, 1990, 1989; Cerri et al.¸1988), polyhydroxylated triterpenes (Aquino et al., 1991, 1990, 1989; Cerri et al.¸1988), procyanidins ([-]-epicatechin, cinchonain 1a, cinchonain 1b) (Wirth and Wagner, 1997), sterols (ß-sitosterol, stigmasterol, campesterol) (Senatore et al., 1989), flavanols (catechin, epigallocatechin, epicatechin and epigallocatechin) (Sandoval et al., 2002), tannins (Laus et al., 1997; Aquino et al., 1990, 1989) and carboxy alkyl esters (CAEs) (Sheng et al., 2001).

PHARMACOLOGICAL ACTIONS

Human
** Uncaria guianensis
• Anti-inflammatory: significantly reduced pain associated with activity in patients with osteoarthritis of the knee (Piscoya et al., 2001).

** Uncaria tomentosa—unspecified preparations
• Antimutagenic: ingestion for 15 days decreased mutagenicity of one smoker’s urine (Rizzi et al., 1993).

** Uncaria tomentosa—Standardized to CAEs
• Immunomodulation/immune support: enhanced response to pneumoccoccal vaccine by reducing decay of antibody titers and elevating lymphocyte/neutrophil) (Lamm et al., 2001); decreased DNA damage (measured as single strand breaks in DNA) from single dose of hydrogen peroxide and increased DNA repair. (Sheng et al., 2001); increased white blood cell levels in healthy males (Sheng et al., 2000a)
• Antimutagenic: decreased DNA damage (measured as single strand breaks in DNA) from single dose of hydrogen peroxide and increased DNA repair. (Sheng et al., 2001); enhances DNA repair (Sheng et al., 2000a)

** Uncaria tomentosa—POA chemotype
• Anti-inflammatory: reduced number of painful and tender joints and decreased duration of morning stiffness in rheumatoid arthritis patients (Mur et al., 2002; Immodal, 1995, 2002); eliminated symptoms and need for antacids in ulcer and gastritis patients (Immodal 1995, 1999a).
• Immunomodulation/immune support: increased vitality and reduced side effects in cancer patients undergoing chemotherapy, radiation or surgery (Immodal 1995, 1999a, 2002); reduced HIV-related symptoms and increased vitality of HIV patients receiving antiretroviral treatment, increased lymphocyte numbers in HIV patients although total leukocyte numbers remained unchanged, stabilized or increased CD4 cell count in HIV patients (Immodal 1995, 1999a, 2002).

Animal
** Uncaria tomentosa—unspecified preparations
• Anti-inflammatory: significantly reduced paw volume in carrageen-induced rat paw edema (Aguilar et al., 2002, 2000; Aquino et al., 1991); protected against NSAID-induced gastritis by reducing lesions and apoptosis of the mucosal epithelial cells (Sandoval et al., 2002); prevention of NSAID-induced enteropathy in rats (Sandoval-Chacon et al, 1998)

** Uncaria tomentosa—Standardized to CAEs
• Immunomodulation/immune support: increased DNA repair of single and double strand breaks from whole body irradiation in rats (Sheng et al., 2000a); increased white blood cell count sooner, and all fractions proportionally, compared with control in rat model of chemotherapy-induced leukopenia (Sheng et al, 2000b)

** Uncaria tomentosa–POA chemotype
• Anti-inflammatory: significantly reduced paw volume in carrageen-induced rat paw edema (Aguilar et al., 2002, 2000)

** Isolated Components of Uncaria species
[Editors’ note: The studies referenced in this subsection were performed with compounds isolated from U. rhynchophylla or U. sinensis. While these compounds are also found in U. guianensis and/or U. tomentosa, no studies have been performed on extracts or fractions derived from UG or UT to verify that these actions apply to them as well; thus their clinical significance is undetermined. These studies have been included because some proponents of the UT product standardized to POAs cite them in support of the POA-antagonistic effects of TOAs.]
• Isorhynchophylline reduced blood pressure and heart rate in rats and dogs (Shi et al., 1989); rhynchophylline and isorhynchophylline reduced blood pressure and heart rate in dogs, with isorhychophylline demonstrating a stronger effect (Shi et al., 1992).

In vitro
** Uncaria guianensis
• Anti-inflammatory: reduces excessive production of cytokines and inflammatory mediators at the genetic level (Sandoval et al., 2002; Piscoya et al., 2001; Sandoval et al. 2000) with UG being more potent than UT (Sandoval et al., 2002), and at extract concentrations far lower than required for antioxidant activity (Piscoya et al., 2001); prevents and eliminates gastrointestinal injury and inflammation in NSAID-induced gastritis (Sandoval et al 2002).
• Antioxidant: scavenges DPPH (UG more potent than UT despite lower concentrations of alkaloids and favanols), protects against deoxyribose degradation in a dose-dependent manner, and inhibits ABTS-radicals (Sandoval et al., 2002); effectively scavenges free radicals and inhibits lipid peroxidation (Piscoya et al., 2001); protects human gastric epithelial cells from apoptosis induced by DPPH, peroxynitrite and H2O2 (Miller et al., 2001).

** Uncaria tomentosa–unspecified preparations
• Anti-inflammatory: reduces excessive production of cytokines and inflammatory mediators at the genetic level with UG being more potent than UT, and at extract concentrations far lower than required for antioxidant activity (Sandoval et al., 2002; Piscoya et al., 2001); suppressed tumor necrosis factor alpha (TNFa) production by 65–85% (Sandoval et al., 2000); prevents and eliminates gastrointestinal injury and inflammation in NSAID-induced gastritis (Piscoya et al., 2001; Sandoval et al., 2000; Sandoval-Chacon et al., 1998). Reduces COX2 expression (Piscoya et al, 2001)
• Antioxidant: scavenges DPPH (UG more potent than UT reflected as lower IC50 value despite lower concentrations of alkaloids and favanols), protects against deoxyribose degradation in a dose-dependent manner, and inhibits ABTS-radicals (Sandoval et al., 2002, 2000); effectively scavenges free radicals and inhibits lipid peroxidation (Piscoya et al., 2001); protects human gastric epithelial cells from apoptosis induced by DPPH, peroxynitrite and hydrogen peroxide (Miller et al., 2001); reduces peroxynitrite-induced apoptosis in human gastric epithelial cells and in macrophages (Sandoval-Chacon et al., 1998); protective against UV irradiation-induced cytotoxicity (Sandoval et al., 2000).
• Immunomodulation/immune support: Increased cytokine (IL-1 and IL-6) production in alveolar macrophages (Lemaire et al., 1999) although high concentrations were used that might reflect a toxicologic response and may be incompatible with in vivo efficacy (Sandoval et al., 2002).
• Antimutagenic: protective against photomutagenesis, (Rizzi et al., 1993).

** Uncaria tomentosa–Standardized to CAEs
• Immunomodulation/immune support: CAEs: significantly increased PHA (phytohemagglutinin)-stimulated lymphocyte proliferation in splenocytes and significantly elevated WBC count (Sheng et al., 2000a).
• Antimutagenic: inhibited proliferation and induced apoptosis in some tumor cell lines (Sheng et al., 1998) at high concentrations that might not be achievable with standard dosing and are likely to reflect a toxicologic response (Sandoval et al., 2000).

** Uncaria tomentosa–POA chemotype
• Anti-inflammatory: moderate to weak activity against cyclo-oxygenase-1 and -2 (COX-1 and COX-2) (Aguilar et al., 2002);
• Antimutagenic: Inhibited proliferation in some human tumor cell lines (Immodal, 1999b).

** Isolated Chemical Components from Cat’s Claw
• Immunomodulation/Immune Support: Phagocytosis was enhanced in vitro by pteropodine, isomitraphylline & isorhynchophylline (three POAs isolated from UT), but phagocytosis was enhanced in vivo only after addition of catechin to POAs (Wagner et al., 1985a, 1985b; Kreutzkamp, 1984); POAs isolated from UT induced endothelial cells to release a factor that inhibited proliferation of normal human lymphoblasts and stimulated proliferation of normal human resting lymphocytes, while TOAs dose-dependently reduced these effects (Wurm et al., 1998); POAs isolated from UT inhibited growth of HL60 and U-937 leukemic cells, with uncarine F demonstrating the strongest effect; (Stuppner et al., 1993 cited in Keplinger et al., 1999); isopteropodine (POA isolated from UT) increases the phagocytosis of granulocytes and RES (reticuloendothelial system) cells (Kreutzkamp, 1984; Wagner et al., 1985a, 1985b).
• Anti-inflammatory: 17 non-alkaloid HPLC fractions from UT reduced TNFa and nitrite production induced by lipopolysaccharide (LPS) in RAW 264.7 cells (Sandoval et al., 2002); one quinovic acid glycoside isolated from UT demonstrated anti-inflammatory effects, but it appears that the strong anti-inflammatory effects of cat’s claw extracts and fractions may be the result of the synergistic activity of a combination of compounds (Aquino et al., 1991); moderate anti-inflammatory activity has been demonstrated for ß-sitosterol, stigmasterol and campesterol isolated from UT (Senatore et al., 1989); one procyanidine (cinchonain Ib) isolated from UT inhibited 5-lipoxygenase, demonstrating anti-inflammatory activity (Wirth and Wagner, 1997).
• Antiviral: 9 quinovic acid glycosides isolated from UT showed moderate antiviral activity against vesicular stomatitis virus, but at concentrations approaching cellular toxicity (Aquino et al., 1989); two quinovic acid glycocides isolated from UT (those with free carboxyl groups) reduced by 50% the viral cytopathic effect of rhinovirus type 1b infection (Aquino et al., 1989)
• Antimutagenic: Uncarine D showed weak cytocoxic activity against SK-MEL, KB, BT-549 and SK-OV-3 cell lines with IC50 values between 30 and 40 ug/ml, while uncarine C exhibited weak cytocoxicity only against ovarian carcinoma (IC50 at 37 ug/ml).(Muhammad et al., 2001b). However, given the concentration of Uncarine C in cat’s claw, the amount of cat’s claw that would have to be consumed to achieve these concentrations in vivo is unrealistic. In addition to the antimutagenic activity, UT extracts and factions exert a direct antiproliferative activity on the MCF7 human breast cancer cell line. The bioassay-directed fraction from barks and leaves resulted in the isolation of 2 active fractions, displaying an IC50 of 10 mg/ml and 20 mg/ml, respectively and an antiproliferative effect, with about 90% of inhibition at a concentration of 100 mg/ml (Riva et al., 2001). As noted above for the alkaloids Uncarine D and C, these fractions would require an unrealistic consumption of kilogram quantities of cat’ claw to achieve these actions.

** Isolated Chemical Components from other Uncaria species
[Editors’ note: The studies referenced in this subsection were performed with compounds isolated from U. rhynchophylla or U. sinensis. While these compounds are also found in U. guianensis and/or U. tomentosa, no studies have been performed on extracts or fractions derived from UG or UT to verify that these actions apply to them as well; thus their clinical significance is undetermined. These studies have been included because some proponents of the UT product standardized to POAs cite them in support of the POA-antagonistic effects of TOAs.]
• Rhynchophylline and isorhynchophylline produced negative chronotropic and inotropic effects (Zhu and Guozing, 1993); rhynchophylline inhibits platelet aggregation (Chen et al., 1992; Jin et al., 1991); rhynchophylline may be a calcium antagonist (Sun et al., 1988; Zhang et al., 1987); rhynchophylline, corynoxeine, isorhynchophylline, isocorynoxeine, and indole alkaloids such as hirsuteine and hirsutine inhibit Ca2+ influx which protects against glutamate-induced neuronal death (Shimada et al, 1999; Yano et al., 1991); corynantheine and dihydrocorynantheine have sedative action which in toxic dosages may lead to respiratory paralysis and ataxia (Kanatani, 1985); corynantheine and dihydrocorynantheine reduced specific [3H]5-HT binding and were found to be partial agonists for 5-HT receptors (Kanatani, 1985)

MECHANISMS OF ACTION

Uncaria guianensis
** Anti-inflammatory
• Modifies gene expression by inhibiting redox-sensitive transcription factors (Piscoya et al., 2001, Sandoval et al, 2002).
• Inhibits transcription factor NF-kB thereby modifying expression of genes involved in the inflammatory process including TNFalpha, inducible nitric oxide synthase (iNOS), and COX-2 (Sandoval et al., 2002; Piscoya et al., 2001).
• Inhibits production of TNFalpha (Sandoval et al., 2002; Piscoya et al., 2001, Sandoval et al, 2000) with UG being more potent than UT (Sandoval et al., 2002).
• Decreases production of lipopolysaccharide-induced prostaglandin E-2 (Piscoya et al., 2001).

** Antioxidant
• Scavenges DPPH (UG more potent than UT despite lower concentrations of alkaloids and flavanols), protects against deoxyribose degradation in a dose-dependent manner, and inhibits ABTS-radicals (Sandoval et al., 2002).
• Effectively scavenges free radicals and inhibits lipid peroxidation (Piscoya et al., 2001; Miller et al., 2001).
• Protects human gastric epithelial cells from apoptosis induced by DPPH, peroxynitrite and hydrogen peroxide (Miller et al., 2001).
• Protects against UV radiation-induced cell death (Sandoval et al, 2000)
• More effective in limiting the cellular response to oxidants than degrading the oxidant itself (Miller et al., 2001; Piscoya et al., 2001).

Uncaria tomentosa–unspecified
** Anti-inflammatory
• Modifies gene expression by inhibiting redox-sensitive transcription factors (Piscoya et al., 2001; Sandoval et al., 2000; Sandoval-Chacon et al., 1998).
• Inhibits transcription factor NF-kB thereby modifying expression of more than 28 genes involved in the inflammatory process including TNFa, iNOS, and COX-2 (Aguilar et al., 2002; Sandoval et al., 2002; Piscoya et al., 2001; Sandoval-Chacon et al., 1998).
• Inhibits lipopolysaccharide-induced iNOS gene expression, nitrite formation, and cell death (Sandoval-Chacon et al., 1998).
• Inhibits production of TNFa, iNOS, and COX-2 (Sandoval et al., 2002; Piscoya et al., 2001; Sandoval-Chacon et al., 1998).
• Moderate to weak activity against COX-1 and COX-2 (Aguilar et al., 2002).
• Decreased production of lipopolysaccharide-induced prostaglandin E-2 (Piscoya et al., 2001).
• Suppressed TNFa production (Sandoval et al., 2002; Piscoya et al., 2001; Sandoval-Chacon et al., 1998) by 65–85% (Sandoval et al., 2000).

** Antioxidant
• Scavenges DPPH (UG more potent than UT despite lower concentrations of alkaloids and flavanols), protects against deoxyribose degradation in a dose-dependent manner, and inhibits ABTS-radicals (Sandoval et al., 2002; 2000).
• Effectively scavenges free radicals and inhibits lipid peroxidation (Piscoya et al., 2001).
• Protects human gastric epithelial cells from apoptosis induced by DPPH, peroxynitrite and H2O2 (Miller et al., 2001).
• Reduces peroxynitrite-induced apoptosis in human gastric epithelial cells and in macrophages (Sandoval-Chacon et al., 1998).
• Cytoprotective against UV irradiation (Sandoval et al., 2000).

** Immunomodulation/immune support
• Increased cytokine (IL-1 and IL-6) production in alveolar macrophages (Lemaire et al., 1999) although high concentrations were used suggesting that this action could only be observed in vivo with ingestion of kilogram quantities; a dosing regimen that might reflect a toxicologic response (Sandoval et al., 2002).
• Stimulates interleukin-1 (IL-1) and interleukin-6 (IL-6) production at a rate of 10.0 x and 7.5x control levels, respectively. The effect is dose-dependent and diminishes when the dose exceeds the range of 0.025-0.1 mg/mL (Lemaire et al., 1999-in vitro).

Uncaria tomentosa–Standardized to CAEs
** Anti-mutagenic
• Stimulation of DNA repair mechanisms (Sheng et al., 2000a, 2001)
• Immunomodulation/immune support.
• Stimulates lymphocyte proliferation and elevates white blood cells (Sheng et al., 2000a, 2000b; Lamm et al., 2000).

** Anti-tumor
• Suppresses tumor growth through selective induction of apoptosis in two human leukemic cell lines (K562 and HL60) and one human EBV-transformed B lymphoma cell line (Raji) (Sheng et al., 1998); however, some authors have reported apoptosis in these same cell lines due to inhibition of NF-kB (Sandoval et al., 2002; Mannick et al., 1997; Beg and Baltimore, 1996).

Uncaria tomentosa–POA chemotype
** Anti-inflammatory
• Moderate to weak activity against COX-1 and COX-2 (Aguilar et al., 2002).
• Inhibits synthesis of NF-kB (Aguilar et al., 2002; 2000).

** Immunomodulation/Immune Support
• POAs Induce the release of a lymphocyte-growth factor from endothelial cells that regulates lymphocyte proliferation (Wurm et al., 1998), but does not change total leukocyte numbers (Keplinger et al., 1999). TOAs act antagonistically to this effect of POAs (Wurm et al., 1998; Keplinger et al., 1999).

CONTRAINDICATIONS

Cat’s claw has been contraindicated for leukemia patients awaiting bone marrow transplant, any patient awaiting organ transplant, persons with iatrically-induced immunosuppression (e.g., organ transplants), autoimmune disease, multiple sclerosis, or tuberculosis (CAMR, 1999). These contraindications are based on the belief that cat’s claw is an immunostimulant. However, some researchers disagree with this view (Miller, 2001b; Miller et al., 1999; Sandoval-Chacon et al., 1998; Sandoval et al., 2000, 2002) and suggest that cat’s claw may be helpful for transplant patients (Miller, 2001a). The suppression of TNFalpha is a hallmark of numerous autoimmune disorders, including those in which cat’s claw offers benefits (arthritis, gut inflammation) and lowering TNFalpha levels, as with cat’s claw, may indeed be desirable rather than contraindicated for these patients. HIV/AIDS patients should proceed with caution when introducing any new therapeutic agent (Miller, 2001b). Cat’s claw is not for use in children under 3 years due to lack of data regarding its effects on the immature immune system (Immodal, 1995).
Pregnancy and Lactation: Not recommended (Jones, 1995) due to lack of data regarding the effects of cat’s claw on the immature immune system (Immodal, 1995).

ADVERSE EFFECTS

Recent human trials have concluded that the various cat’s claw preparations tested are safe, with no adverse effects reported in liver, renal, central nervous system, or hematological function (Piscoya et al., 2001; Sheng et al., 2001, 2000a; Lamm et al., 2000). Cat claw teas or crude extracts may cause mild nausea, due to the bitter taste (Williams, 2001); however, this appears speculative as nausea is not a frequently reported effect. In one case report, a patient with systemic lupus erythematosus experienced acute renal failure, which the authors attributed to an idiosyncratic adverse reaction to the purported cat’s claw preparation which was not adequately documented (Hilepo et al., 1997).

Uncaria guianensis
In one study infrequent reports of headache, dizziness, and vomiting were reported but the incidence and frequency were the same as with placebo (Piscoya et al., 2001).

Uncaria tomentosa-CAEs
None reported.

Uncaria tomentosa – POA chemotype
In AIDS patients and patients receiving large doses of chemotherapy, individual cases of a mild erythrocytosis have been reported. During the first 1–2 weeks of ingesting cat’s claw tea (Krallendorn®) temporary constipation or mild diarrhea was sometimes observed. Increased occurrence of acne symptoms has been reported in HIV patients with prior symptoms. In rare cases, elevated uric acid values were observed in HIV and cancer patients; extensive die off in tumor patients may cause lytic fever lasting 1–2 weeks (Immodal, 1999a, 1995).

Components from Other Species of Uncaria
CC products containing larger amounts of TOAs could possibly result in sedative effects and circulatory complaints (e.g., reduced blood pressure, coronary blood flow, and heart rate; inhibited platelet aggregation) (Reinhard, 1999), due to the reported effects of TOAs in Uncaria species other than UT or UG (Shi et al., 1992, 1989; Jin et al., 1991). However, no such effects have been reported in studies using products made with UT or UG.

DRUG INTERACTIONS

Uncaria guianensis
None reported.

Uncaria tomentosa – unspecified preparations
UT may potentially reduce the rate of metabolism and thus increase serum levels of drugs taken orally as observed in an in vitro assay on an unspecified UT tincture where the CYP3A4 isozyme production was inhibited (Budzinski et al., 2000).

Some authors warn that some unspecified forms of cat’s claw may increase the effects of anticoagulants and antihypertensives (Fetrow and Avila, 2000; CAMR, 1999; Spaulding-Albright , 1997; INPR, 1999). However, this is based on research on TOA components isolated from Uncaria species other than UG or UT. While it is possible that cat’s claw products rich in TOAs may interact with these classes of drugs, there are no reliable data to support this conclusion. Further, there is little evidence to support this interaction with cat’s claw products that contain little or no TOAs such as UG products or the UT product Krallendorn®, or C-Med-100® (AF Nutraceutical Group).

Uncaria tomentosa – Standardized to CAEs
None reported.

Uncaria tomentosa – POA chemotype
According to a communication to physicians and pharmacists from the leading Austrian research and manufacturing company on cat’s claw, the following advice should be given to patients, based on the products proposed immunomodulatory effects:
Take between chemotherapy treatments and after completion, but not with chemotherapy treatments; Do not take in conjunction with passive animal vaccines, intravenous hyperimmunoglobulin therapy; intravenous thymic extracts, drugs using animal protein or peptide hormones (e.g., bovine or porcine insulin), cryoprecipitates, or fresh blood plasma (Immodal, 1995).

AMERICAN HERBAL PRODUCTS ASSOCIATION (AHPA) SAFETY RATING

Class 4: Insufficient data available for classification (McGuffin et al., 1997).
[Editors’ Note: Cat’s claw was not widely marketed during the time that the literature upon which this is based, mainly 1980s and early to mid-1990s. Of potential relevance is the fact that numerous studies show cat’s claw to be safe. Human, animal, and in vitro studies demonstrate the antimutagenic activity of cat’s claw (Sheng et al., 2001, 2000a, 1998; Immodal, 1999b; Leon et al., 1996; Rizzi et al., 1993), One human trial found no toxic effects at a dose of 350 mg/day of C-Med-100® for 6 consecutive weeks (Sheng et al., 2000a). One animal study reports an LD50 of greater than 16 g/kg of body weight using a freeze-dried aqueous extract of POA type UT (Kynoch and Lloyd, 1975), while a second reports an LD50 of greater than 8 g/kg for C-Med-100. Another study found daily oral administration of an aqueous-acid extract of UT at 1000 mg/kg body weight for 28 days to be atoxic in rats (Swendson and Skydsgaard, 1986). In an additional test, an aqueous extract of UT was atoxic up to the maximum dosage of 5g/kg body weight administered orally, and up to a concentration of 2g/kg body weight administered intraperitoneally (Kreutzkamp, 1984). The alkaloid fraction of UT was found to be atoxic up to the maximum dosage of 2 g/kg body weight orally and 1 g/kg body weight intraperitoneally (Kreutzkamp, 1984).]

REGULATORY STATUS

Austria: Prescription drug Krallendorn® (pentacyclic chemotype).
Canada: Status undetermined. No products containing cat’s claw are listed in the Health Canada Drugs Product Database (Health Canada, 2001).
Germany: No German Commission E monograph (Blumenthal et al., 1998). No monograph in the German Pharmacopoeia (DAB, 1999).
Sweden: No products containing cat’s claw are listed in the Medical Products Agency (MPA) “Authorised Natural Remedies” (MPA, 2001).
Switzerland: No products containing cat’s claw are listed in the Swiss Drug Compendium (Morant and Ruppanner, 2001). No monograph in the Swiss Pharmacopoeia.
U.K.: Not listed in the General Sale List (GSL, 1994). No monograph in the British Pharmacopoeia.
U.S.: Dietary supplement (USC, 1994). No monograph in the USP-NF.

CLINICAL REVIEW

There are 14 clinical trials on various preparations made from the two species of Uncaria summarized in the clinical studies Tables in this monograph. In general, the studies are relatively small, most are uncontrolled, and some have not been published. One prospective (P), randomized (R ), double-blind (DB), placebo-controlled (PC), parallel group (PG), multi-center (MC) trial was conducted on 45 men who consumed 100 mg of a freeze-dried aqueous extract of UG for 4 weeks for osteoarthritis of the knee (Piscoya et al., 2001). The study reports a significant improvement in pain associated with activity, and medical and patient assessment scores, but no significant improvement in pain at rest or at night, or knee circumference. There were no significant side effects in the UG and placebo groups.

Three trials tested the UT-CAE preparation (C-Med-100®) on immunomodulatory parameters. One small R, PC trial (n=23) resulted in no loss of immunity after 5 months in patients given a pneumonia vaccine after 2 months of treatment with 700 mg per day of the UT-CAE extract when compared to loss in the placebo group (Lamm et al., 2001). Another small trial (n=12) reported an increase in DNA repair with no adverse effects (Sheng et al., 2001). An uncontrolled trial on healthy volunteers resulted in an increase in white blood cells (Sheng et al., 2000a).

Three trials tested a proprietary extract of UT standardized to POAs (Krallendorn®) for anti-inflammatory effects. One 52-week trial on 40 people with rheumatoid arthritis (RA) used 60 mg. per day of the extract in tablets (Mur et al., 2002). The first phase (24 weeks) was R, DB, PC; the second phase (28 weeks) was not blinded—all patients received the treatment. There was a significant decrease in pain and a shorter period of morning stiffness for the treatment group compared to placebo after the first phase and a further reduction after the second phase. The placebo-cat’s claw treatment group experienced some reduction of symptoms in the second phase. Two small uncontrolled, unpublished trials test the UT-POA extract on patients with RA (Immodal, 1995, 2002) and on ulcers and gastritis (Immodal, 1995, 1999a).

Five trials tested the UT-POA extract for its effects on immune function. All five trials are uncontrolled and unpublished, thereby raising questions as to the significance of the results. Two trials tested the UT-POA extract as an adjuvant therapy for chemotherapy, radiation and brain tumor or surgery (Immodal 1995, 1999a, 2002) with generally favorable results, including patients’ reports of a greater sense of vitality and fewer side effects; three additional trials tested UT-POA extract as an adjuvant therapy for HIV-positive patients (Immodal 1995, 1999a, 2002), with stabilized or increased CD-4 cell counts, increased vitality and no adverse effects.

Two uncontrolled, unpublished trials were performed on the UT-POA extract in topical preparations for use on lesions caused by Herpes simplex (Immodal, 1995, 1999a, 2002) and Varicella zoster (Immodal, 1995, 1999a, 2002), showing improvement and no adverse effects.

BRANDED PRODUCTS

C-MED-100®: AF Nutraceutical Group, Inc. / 31 Edgecliff Road / Upper Montclair, NJ 07043 / U.S. / Tel.: (973) 267-6691/ Fax: (973) 267-6693 / Email: info@afnutra.com / www.afnutra.com. Patented extract of Uncaria tomentosa, standardized to 8% by Carboxy alkyl esters. Ultrafiltrated, 100% water soluble extract spray-dried and compressed into 350 mg tablets.

Krallendorn® Capsules: Immodal Pharmaka GmbH / Bundesstrasse 44 / 6111 Volders / Austria / Tel.: +43-05-22-45-7678 / Fax: +43-05-22-45-7646. Cat’s claw root bark (pentacyclic chemotype) hydroalcoholic extract standardized to contain 1.3% POAs, and undetectable TOAs.

Krallendorn® Drops: Immodal Pharmaka GmbH. Cat’s claw root bark (pentacyclic chemotype) hydroalcoholic extract standardized to contain 1.3% POAs, and undetectable TOAs; each 100 g of drop solution contains 600 mg cat’s claw extract, water, ethanol (95% by volume).

Krallendorn® Ointment: Immodal Pharmaka GmbH. Cat’s claw root bark (pentacyclic chemotype) hydroalcoholic extract standardized to contain 1.3% POAs, and undetectable TOAs; each 75 g of ointment contains 300 mg cat’s claw extract.

Krallendorn® Spray: Immodal Pharmaka GmbH. Cat’s claw root bark (pentacyclic chemotype) hydroalcoholic extract standardized to contain 1.3% POAs, and undetectable TOAs; each 100 g of spray solution contains 600 mg cat’s claw extract.

Krallendorn® Tea: Immodal Pharmaka GmbH. Cat’s claw root bark (pentacyclic chemotype), ground.

Vincaria™: Rainforest Nutritionals, Inc, Carson City, NV/ www.rainforest-inc.com/ a freeze dried extract of Uncaria guianensis, 100mg capsules

*American equivalents, if any, are found in the Product Table on page XXX.

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New Glossary Words and Abbreviations
TNF?: tumor necrosis factor alpha
COX-2:
NF-kB:
iNOS:
IL-1
IL-6
TOA
POA
CAE
UT
UG
DPPH
ABTS