Posted 17 August 2014 - 05:16 PM
Baical skullcap
HISTORICAL NOTE
Baical skullcap is a TCM herb used to clear ‘heat and dry dampness’. Diseases with heat are associated with symptoms such as fever, irritability, thirst, cough and expectoration of thick, yellow sputum. Damp diseases may be associated with diarrhoea, a feeling of heaviness of the chest and painful urination (Bensky & Gamble 1986). From a modern perspective this suggests that baical may be useful for infection and inflammation of the respiratory, digestive and urinary systems. Scientific investigations have indeed shown that baical skullcap and its constituents have antibacterial, antiviral, anti-inflammatory, hepatoprotective and diuretic actions (Zhang et al 2001).
OTHER NAMES
Baical skullcap, Chinese skullcap, huang qin (Mandarin), ogon (Japanese), scute
BOTANICAL NAME/FAMILY
Scutellaria baicalensis Georgi (family Lamiaceae)
PLANT PART USED
Root
CHEMICAL COMPONENTS
Baical skullcap contains numerous flavonoids and their glycosides. The main flavonoids are baicalin and its aglycone, baicalein, and wogonin. Resin and tannins are also present.
Baical also contains melatonin. It has been shown that dietary melatonin directly contributes to the circulating level of the hormone. The clinical effects of plant-derived melatonin remains to be investigated (Hardeland & Poeggeler 2003). Baicalin itself is poorly absorbed from the gut, but is hydrolysed to its aglycone, baicalein, by intestinal bacteria and then restored to its original form from the absorbed baicalein in the body (Akao et al 2000).
MAIN ACTIONS
The actions of baical skullcap, some of its individual constituents, and combination formulations have been studied in various models.
Anti-inflammatory
The anti-inflammatory activity of baical skullcap has been well documented by in vitro and in vivo studies. The main constituents responsible are baicalein and wogonin (Chang et al 2001, Chi et al 2001, Chung et al 1995, Huang et al 2006, Krakauer et al 2001, Li et al 2000a, Park et al 2001, Wakabayashi 1999).
In a study using mice, baicalein 50 mg/kg has been shown to ameliorate the inflammatory symptoms of induced colitis, including body weight loss, blood haemoglobin content, rectal bleeding and other histological and biochemical parameters (Hong et al 2002). Pretreatment with wogonin also significantly reduced ethanol-induced gastric damage in vivo (Park et al 2004) and reduced immunoglobulin E, IL-4, IL-5 and IL-10 secretion in a colitis-induced mouse model (Lim 2004). The methanolic extract of the baical skullcap root and its flavonoids wogonin, baicalein and baicalin have been shown to inhibit lipopolysaccharide-induced inflammation of the gingivae (gums) in vivo. The three flavonoids exerted an anti-inflammatory effect similar to prednisolone. In addition, the flavonoids exerted a moderate inhibition (33–36%) of collagenolytic activity, comparable to the 40% inhibition by tetracycline. Meanwhile, the cellular activity of fibroblasts was augmented remarkably (40%) by baicalein and slightly by baicalin and wogonin. Consistent with the cellular activation, the flavonoids enhanced the synthesis of both collagen and total protein in fibroblasts in vitro (Chung et al 1995).
The anti-inflammatory mechanisms are varied and summarised below.
Chemokine binding
It has been proposed that the anti-inflammatory activity is partly caused by limiting the biological function of chemokines.
Excessive release of pro-inflammatory cytokines mediates the toxic effect of superantigenic staphylococcal exotoxins. In vitro data suggest that baicalin may be therapeutically useful for mitigating the pathogenic effects of staphylococcal exotoxins by inhibiting the signalling pathways activated by superantigens (Krakauer et al 2001).
Baicalin inhibited the binding of a number of chemokines to human leukocytes or cells expressing specific chemokine receptors, with an associated reduced capacity of the chemokines to induce cell migration. Based on these results, it is possible that the anti-inflammatory mechanism of baicalin is to bind a variety of chemokines and limit their biological function (Bao et al 2000, Li et al 2000a).
Four major flavonoids from baical have been shown in vitro to suppress eotaxin. Eotaxin is an eosinophil-specific chemokine associated with the recruitment of eosinophils to sites of allergic inflammation. Eotaxin is produced by IL-4 plus TNF-alpha-stimulated human fibroblasts. This may explain why it has been used traditionally in the treatment of bronchial asthma (Nakajima et al 2001). Various flavonoids, including wogonin and baicalein, have been shown to inhibit chemically induced histamine release from rat mast cells in vitro (Kubo et al 1984).
COX-2 inhibition
Wogonin is a direct COX-2 inhibitor. Wogonin inhibits both inducible nitric oxide synthase and cyclo-oxygenase 2 induction (Chen et al 2001 & 2008, Chi et al 2001, Wakabayashi & Yasui 2000). Wogonin has been shown to inhibit inducible PGE2 production in macrophages by inhibiting COX-2 (Wakabayashi & Yasui 2000). Additionally baicalein, but not baicalin, has been shown to inhibit COX-2 expression in lipopolysaccharide induced RAW 264.7 cells (a murine leukaemic macrophage-like cell line) (Woo et al 2006). Both compounds also suppressed inducible NO synthase (iNOS) protein expression, iNOS mRNA expression, and NO production in a dose-dependent manner.
Wogonin may be beneficial for COX-2-related skin disorders. When applied topically to the dorsal skin of mice, it inhibited COX-2 expression and PGE2 production (Byoung et al 2001, Chi et al 2003, Park et al 2001).
Lipoxygenase inhibition
The inhibition of the 5-lipoxygenase pathway of arachidonic acid metabolism may be one of the mechanisms of baicalein’s anti-inflammatory activity according to an in vivo study (Butenko et al 1993).
Nitric oxide synthase inhibition
Baicalein and wogonin attenuate lipopolysaccharide-stimulated nitric oxide synthase induction in macrophages, which helps to explain the anti-inflammatory action of these flavonoid compounds (Cheng et al 2007, Wakabayashi 1999).
Antioxidant activity
The anti-inflammatory activity of baicalein may be associated with inhibition of leukocyte adhesion by the scavenging of reactive oxygen intermediates (Shen et al 2003).
Nuclear factor kappa B inhibition
Baicalin has been shown to inhibit nuclear factor kappa B (NFkB) in vitro (Cheng et al 2007, Hsieh et al 2007, Kim et al 2006, Wang et al 2006).
Antifibrotic
A methanolic extract of baical skullcap has been shown to inhibit fibrosis and lipid peroxidation induced by bile duct ligation or carbon tetrachloride in rat liver. Bile duct ligation in rodents is an experimental model for extrahepatic cholestasis caused by, for example, cholelithiasis (gall stones). Liver fibrosis was assessed by histological observation and by measuring levels of liver hydroxyproline, lipid peroxidation based on malondialdehyde production, and serum enzyme activities. Treatment with baical skullcap significantly reduced the levels of liver hydroxyproline and malondialdehyde, with improved histological findings (Nan et al 2002).
Hepatoprotective
Baicalein, baicalin and wogonin have been shown to have hepatoprotective effects in vivo. The flavonoids decrease the toxicity produced by a variety of chemicals. Significant protective effects were seen by comparing the serum levels of AST and ALT and by histopathologic examination (Lin & Shieh 1996). Two different dried root preparations of baical skullcap (1% of total feed) were added to the diet of animals that were subsequently exposed to aflatoxin-B1 (de Boer et al 2005). Mix A contained 3.13 microgram/g baicalin, 1.5 microgram/g baicalein, 0.021 microgram/g wogonin and 65.3 nmol/g melatonin compared to 0.94 microgram/g baicalin, 0.41 microgram/g baicalein, and 0.003 microgram/g wogonin and 1176 nmol/g melatonin in mix B. The addition of mix A and B reduced hepatic damage by approximately 60 and 77%, respectively. The feed mixtures also increased the expression of the gene for glutathione S-transferase A5 by 2.5 to 3.0-fold. Interestingly the mix with the lower concentration of flavonoids was the more protective. The authors explain this by stating that it was probably due to the much higher (18-fold) amount of melatonin which has been shown to enhance aflatoxin detoxification pathways in animals.
Baicalein, baicalin and wogonin have also been shown to inhibit hemin-nitrite-H2O2 induced liver injury in a dose-dependent manner by inhibiting oxidation and nitration (Zhao et al 2006). In other in vitro and in vivo studies baicalin reduced tert-butyl hydroperoxide hepatic damage, attenuated glutathione depletion, ALT and AST levels and reduced oxidative stress (Hwang et al 2005). Additionally, further histopathological examination showed a significant reduction in the incidence of hepatic lesions and swelling.
In combination
The combination Sho-saiko-to (a Japanese herbal supplement containing baical skullcap, also known as Minor Bupleurum Combination and Xiao Chai Hu Tang in Mandarin) has been shown to inhibit chemical hepatocarcinogenesis in animals, act as a biological response modifier and suppress the proliferation of hepatoma cells by inducing apoptosis and arresting the cell cycle. These effects may be due to baicalin, baicalein and saikosaponins (from Bupleurum falcatum), which have the ability to inhibit cell proliferation (Shimizu 2000). Further testing is required to determine the role of baical skullcap in achieving these effects.
Antioxidant
Several studies have shown baical skullcap constituents to be antioxidant in vitro and in vivo. Flavones produced a concentration-dependent protection of liposome membrane against UV-induced oxidation. The ability to scavenge free radicals and protect against the effects of lipid peroxidation (in this case caused by sunlight irradiation) may in part account for the herb’s underlying mechanism of action (Gabrielska et al 1997).
Fourteen flavonoids and flavone glycosides have been demonstrated to possess good free radical scavenging properties in vitro (Gao et al 1999, Lin & Shieh 1996). Baicalin has been found to have the most potent antioxidant effect (Bochorakova et al 2003).
Baicalin’s antioxidant effect is based on scavenging superoxide radicals, whereas baicalein is a good xanthine oxidase inhibitor. Xanthine oxidase inhibitors are known to be therapeutically useful for the treatment of hepatitis and brain tumours (Gao et al 2001).
Oxidative stress plays an important role in the pathological process of neurodegenerative diseases including Alzheimer’s disease. The protective effects of baical flavonoids on the oxidative injury of neuronal cells have been demonstrated in vitro (Choi et al 2002, Gao et al 2001).
Anti-allergic
Flavonoids have anti-allergic activities and are known to inhibit histamine release from basophils and mast cells. Luteolin and baicalein have been shown to inhibit IgE antibody-mediated immediate and late phase allergic reactions in mice. In an in-vitro study, luteolin and baicalein inhibited IgE-mediated histamine release from mast cells. The compounds also inhibited IgE-mediated TNF-alpha and IL-6 production from mast cells. However, the compounds did not affect the histamine, serotonin or platelet-activating factor-induced cutaneous reactions in rats (Kimata et al 2000). Wogonin, wogonoside and 3,5,7,2′,6′-pentahydroxyl flavanone isolated from baical skullcap decrease histamine, leukotriene B4 and IgE in vitro (Lim 2004).
Baicalein is 5–10-fold more potent than the anti-allergic drug azelastine. Baicalein significantly suppressed leukotriene C4 release by polymorphonuclear leukocytes obtained from asthmatic patients compared with healthy subjects (Niitsuma et al 2001).
Neuroprotective
Many in vitro and in vivo trials have demonstrated the neuroprotective effects of flavonoids derived from baical skullcap (Cho & Lee 2004, Heo et al 2004, Piao et al 2004, Shang et al 2006a, Son et al 2004).
Cerebral ischaemia can cause a significant elevation in the concentrations of amino acid neurotransmitters in the cerebral cortex. Baicalin administration can attenuate the elevations of glutamic acid and aspartic acid induced by cerebral ischaemia. This research demonstrates that baicalin may act as a neuroprotectant during cerebral ischaemia. Wogonin has been shown to exert a neuroprotective effect by inhibiting microglial activation, which is a critical component of pathogenic inflammatory responses in neurodegenerative diseases. Wogonin inhibited inflammatory activation of cultured brain microglia by diminishing lipopolysaccharide-induced TNF-alpha, IL-1-beta and NO production. Wogonin inhibited NO production by suppressing iNOS induction and NF-kappa-B activation in microglia. The neuroprotective effect of wogonin has also been shown in vivo using two experimental brain injury models (Lee et al 2003).
An in vivo study in rats induced with permanent global ischaemia demonstrated that daily oral doses of baical skullcap flavonoids (35 mg/kg) for 19–20 days statistically increased learning and memory ability and attenuated neural injury (Shang et al 2005). A follow-up in vivo study demonstrated that the flavonoid fraction also reduced neural damage and memory deficits after permanent cerebral ischaemia (Shang et al 2006b).
Another in vivo study investigated the neuroprotective effects of baicalein in a Parkinsonian experimental model and demonstrated improved motor coordination and a reduction in spontaneous motor activity (Cheng et al 2008). This was thought to be the result of increased dopamine and serotonin levels in the striatum, leading to increased dopaminergic neurons and an inhibition of oxidative stress. Baical skullcap is used in TCM for the treatment of stroke. Methanol extracts from the dried roots (0.1–10 mg/kg IP) significantly protected neurons against 10 min transient forebrain ischaemia. The extract inhibited microglial TNF-alpha and NO production, and protected cells from hydrogen peroxide-induced toxicity in vitro (Kim et al 2001).
Hypotensive
Treatment with baicalein lowered blood pressure in hypertensive but not in normotensive rats according to one study (Takizawa et al 1998). Baical extract and baicalein have also been shown to lower blood pressure in rats and cats (Kaye et al 1997, Takizawa et al 1998). The exact mechanisms underlying the hypotensive action are unclear. One in vivo study has shown that Scutellaria baicalensis extract produces peripheral vasodilatation (Lin et al 1980). A 2005 review concluded that baical skullcap is effective for renin-dependent hypertension and that in vivo effects may be due to the inhibition of lipoxygenase, reducing the production and release of arachidonic-acid derived vasoconstrictor substances (Huang et al 2005).
Vascular activity
Monocyte chemotactic protein-1 (MCP-1), a potent chemoattractant for monocytes, plays a crucial role in cases of early inflammatory responses, including atherosclerosis. Wogonin has been shown to inhibit MCP-1 induction by endothelial cells in a dose-dependent manner. Wogonin and baical skullcap may be potentially beneficial in inflammatory and vascular disorders (Chang et al 2001). Baicalein significantly suppressed intimal hyperplasia and cell proliferation in a vascular injury study in vivo (Peng et al 2008).
Antiplatelet
Baical flavonoids have been shown to inhibit platelet aggregation in vitro (Kubo et al 1985). Baicalein inhibited the elevation of calcium induced by thrombin and thrombin receptor agonist peptide. These findings suggest a potential benefit of baicalein in the treatment of arteriosclerosis and thrombosis (Kimura et al 1997).
Cholesterol reduction
Flavonoids are known to reduce cholesterol. A 30-day study of induced hyperlipidaemia in rats found that baicalein, quercetin, rutin and naringin reduced cholesterol, with baicalein the most potent. Baicalein was also the most effective flavonoid in reducing triglyceride levels (De Oliveira et al 2002). In another in vivo study, rats were fed a cholesterol-laden diet and half were also given S. baicalensis radix extract (Regulska-Ilow et al 2004). The treatment rats displayed a significant reduction in plasma triglycerides and total cholesterol compared with control animals. The mechanism may be due to the increased activity of lecithin cholesterol acyltransferase (You et al 2008).
Anxiolytic
Wogonin, baicalein, scutellarein and baicalin (in reducing order of potency), which all contain a certain flavonoid phenylbenzopyrone nucleus, have been shown in vitro to bind with the benzodiazepine site of the GABA-A receptor (Hui et al 2000).
Oral administration of wogonin (7.5–30 mg/kg) has been shown to interact with GABA-A receptors and produce an anxiolytic response that was similar to diazepam in the elevated plus-maze. Unlike benzodiazepines, wogonin was able to reduce anxiety without causing sedation or myorelaxation (Hui et al 2002, Kwok et al 2002).
Baicalin (10 mg/kg IP) and baicalin (20 mg/kg IP) have also been shown in vivo to produce an anxiolytic effect, mediated through activation of the benzodiazepine binding sites of GABA-A receptors (Liao et al 2003).
Two other flavones, 5,7-dihydroxy-6-methoxyflavone (oroxylin A) and 5,7,2’-trihydroxy-6, 8-dimethoxyflavone (K36), also act as antagonists at the GABA-A recognition site and have demonstrated anxiolytic activity in vivo (Huen et al 2003a, b).
A water-extract of baical skullcap demonstrated anticonvulsant activity against electroshock-induced tonic seizures in vivo. Interestingly, the authors suggest that the effect might not be via the activation of the benzodiazepine binding site of GABA-A receptors, but probably via the prevention of seizure spread (Liao et al 2003, Wang et al 2000). A more recent study has shown that wogonin has anticonvulsive effects mediated by GABA (Park et al 2007).
Antimicrobial
Numerous studies have found that baical extract and flavonoids exert antibacterial, antiviral and antifungal actions. The antimicrobial effect of baical extract is mild and the clinical efficacy of baical in infectious diseases may be more associated with its anti-inflammatory rather than its antimicrobial activities.
Antibacterial
Baical skullcap decoction was investigated for bacteriostatic and bactericidal activity against a selection of oral bacteria, including suspected periodontopathogens. At a concentration of 2%, the decoction was bacteriostatic for 8 of 11 bacteria tested, but a concentration of 3.13% or greater was required for bactericidal effect (Tsao et al 1982).
Baical aqueous-extract, but not its flavonoids, baicalin and baicalein, demonstrated antibacterial effects against the enteric pathogen Salmonella typhimurium. The effect was compatible with commercial antibiotics including ampicillin, chloramphenicol, and streptomycin. In contrast, the growth of a non-pathogenic Escherichia coli strain was unaffected by baical (Hahm et al 2001). One study demonstrated that the addition of baical skullcap in vitro improved the responsiveness of antibiotics for the treatment of MRSA (Yang et al 2005).
Baicalin has been shown to reduce the pathogenic effects of superantigenic staphylococcal exotoxins by inhibiting the signalling pathways activated by superantigens (Krakauer et al 2001).
Antiviral
Antiviral effects have been demonstrated for baical in numerous in vitro and in vivo tests. Baical extract significantly inhibits hepatitis C RNA replication in vivo (Tang et al 2003) and in vitro studies have found that:
Intraperitoneal and intranasal administration of baical flavonoids significantly inhibits influenza virus in vivo and in vitro (Nagai et al 1989, 1992a, 1992b, 1995a, 1995b).
Baicalein inhibits HIV-1 infection at the level of viral entry (a process known to involve interaction between HIV-1 envelope proteins and the cellular CD4 and chemokine receptors) (Li et al 2000b).
Baicalin inhibits human T-cell leukaemia virus type I (HTLV-I) (Baylor et al 1992).
Aqueous extract inhibits HIV type-1 protease (Lam et al 2000).
Baicalin inhibits HIV-1 infection and replication (Li et al 1993).
Baical flavonoids inhibit Epstein-Barr virus early antigen activation (Konoshima et al 1992).
Wogonin suppresses hepatitis B virus surface antigen production without evidence of cytotoxicity (Huang et al 2000).
5,7,4′-trihydroxy-8-methoxyflavone inhibits the fusion of influenza virus with endosome/lysosome membrane (Nagai et al 1995a).
Virus replication is suppressed, partly by inhibiting the fusion of viral envelopes with the endosome/lysosome membrane which occurs at the early stage of the virus infection cycle (Nagai et al 1995b).
The flavones in baical have potent influenza virus sialidase inhibitory activity and anti-influenza virus activity in vivo (Nagai et al 1992b).
Baicalin may selectively induce apoptosis of HIV-infected human T-leukaemia (CEM-HIV) cells, which have a high virus-releasing capacity, and stimulate proliferation of CEM-HIV cells, which have a relatively lower capacity of HIV-production (Wu et al 1995).
Antifungal
Antifungal activity has been demonstrated by several studies (Blaszczyk et al 2000, Yang et al 1995). Baical extract showed clear fungistatic activities in vitro against some cutaneous and unusual pathogenic fungi, and particularly against strains of Candida albicans, Cryptococcus neoformans and Pityrosporum ovale. The antifungal substance was isolated and found to be baicalein (Yang et al 1995). Of 56 Chinese antimicrobial plants, baical root extract had the highest activity against C. albicans (Blaszczyk et al 2000).
Anti-ulcerogenic
Extracts prepared from grass and roots of S. baicalensis showed high anti-ulcerogenic activity in vivo (Amosova et al 1998).
Antidiabetic
5-alpha-aldose inhibition
Diabetic patients may accumulate intracellular quantities of the sugars sorbitol and dulcitol, because of an increase in the polyol pathway involving the enzyme 5-alpha-aldose. Oral baicalin and liquid extract of licorice (also rich in flavonoids) reduced the sorbitol levels in the red blood cells of diabetic rats (Lin et al 1980, Zhou & Zhang 1989).
Alpha-glucosidase inhibition
Alpha-glucosidase inhibitors (e.g. acarbose) are a class of oral medicine for type 2 diabetes, which blocks the enzymes that digest starches in food. The result is a slower and lower rise in blood glucose throughout the day, especially immediately after meals. Methanol extracts of S. baicalensis, Rheum officinale and Paeonia suffruticosa showed potent inhibitory activity against rat intestinal sucrase. The active principles were identified as baicalein and methyl gallate (from the latter two plants). In addition to its activity against the rat enzyme, baicalein also inhibited human intestinal sucrase in vitro (Nishioka et al 1998).
Anti-emetic
Pretreatment with baical root extract has been shown to decrease cisplatin-induced pica in rats (animal models use the level of kaolin [type of clay] intake as a measure of the intensity of nausea). This suggests that baical may help to reduce cisplatin-induced nausea and emesis during cancer therapy (Aung et al 2003, Mehendale et al 2004, Wu et al 1995), although clinical testing is required to confirm significance.
Two in vivo trials found that S. baicalensis significantly attenuated ritonavir-induced pica, and demonstrated possible efficacy for the management of ritonavir-induced nausea in HIV treatment (Aung et al 2005, Mehendale et al 2007).
Renal–urinary tract activity
Baicalein inhibited angiotensin II-induced increases in the cellular protein content of aortic smooth muscle cells in vitro (Natarajan et al 1994). In another in vitro study, baicalein prevented the angiotensin II-induced increase in renal vascular resistance by 50% and promoted glomerular filtration rate (Bell-Quilley et al 1993). Pretreatment with baicalein significantly inhibited a decrease in nephrotoxin-induced glomerular filtration rate and renal blood flow in vivo (Wu et al 1993). Oral intake of baical flavonoids and extract has been shown to produce a diuretic effect.
Anticancer
Immunostimulation (in combination)
Sho-saiko-to has been shown to stimulate granulocyte colony-stimulating factor (G-CSF), which may explain its use in infectious diseases and cancer (Yamashiki et al 1992). Like growth hormone, IL-2 and -4 and interferon, G-CSF is a signalling ligand that stimulates immune function. G-CSF, a glycoprotein produced mainly by macrophages, induces proliferation of neutrophil colonies and differentiation of precursor cells to neutrophils. It also stimulates the activity of mature neutrophils (Hill et al 1993).
Sho-saiko-to is known to significantly suppress cancer development in the liver. Moderate regulation of the cytokine production system in patients with hepatitis C by using Sho-saiko-to may be useful in the prevention of disease progression (Yamashiki et al 1997). One possible mechanism for the beneficial effects of this formula in patients with liver cirrhosis may be the improvement in production of IL-12, which is an important cytokine for maintenance of normal systemic defence and bioregulation. This effect of Sho-saiko-to is attributed to two of its seven herb components, baical and licorice root (Yamashiki et al 1999).
Patients who were given baical skullcap showed a tendency towards an increase in the relative number of T-lymphocytes and their theophylline-resistant population during antitumour chemotherapy. The immunoregulation index in this case was approximately twice the background value during the period of investigation. The inclusion of baical skullcap in the therapeutic complex promoted an increase in the number of immunoglobulins A at a stable level of IgG (Smolianinov et al 1997).
Apoptosis induction
Baicalein, baicalin and wogonin have been shown to induce apoptosis, disrupt the mitochondria and inhibit proliferation in various human hepatoma cell lines (Chang et al 2002, Chen et al 2000). The platelet-type 12-lipoxygenase (12-LOX) pathway is a critical regulator of prostate cancer progression and apoptosis by affecting various proteins regulating these processes. Baicalein inhibits 12-LOX and may be a potential therapeutic agent in the treatment of prostate cancer (Pidgeon et al 2002) as well as breast cancer (Tong et al 2002) and lung cancer (Leung et al 2007).
Antiproliferative
Baicalein, baicalin and wogonin have been shown to induce apoptosis and inhibit proliferation in various human hepatoma cell lines (Chang et al 2002).
Baicalin has been shown to inhibit the proliferation of prostate cancer cells in vitro. However, the response to baicalin differed among different cell lines (Chan et al 2000).
COX-2, which converts arachidonic acid to PGE2, is highly expressed in head and neck squamous cell carcinoma (HNSCC). S. baicalensis, but not baicalein, suppressed proliferation, cell nuclear antigen expression and PGE2 synthesis. A 66% reduction in tumour mass was observed in the mice with HNSCC. Baical selectively and effectively inhibits cancer cell growth in vitro and in vivo and can be an effective chemotherapeutic agent for HNSCC (Zhang et al 2003).
In a study designed to determine the ability of baical skullcap to inhibit various human cancer cells in vitro, S. baicalensis demonstrated a significant dose-dependent, growth inhibition on squamous cell carcinoma, breast cancer, hepatocellular carcinoma, prostate carcinoma and colon cancer cell lines (Ye et al 2002). Prostate and breast cancer cells were particularly sensitive. Baical skullcap has also been shown to arrest mouse leukaemia cell proliferation in vivo (Ciesielska et al 2002, 2004). Inhibition of PGE2 synthesis via suppression of COX-2 expression may be responsible for its anticancer activity (Ye et al 2002). Differences in the biological effects of baical compared with baicalein suggest synergistic effects among components in baical (Zhang et al 2003). Another study has shown complete inhibition of acute lymphatic leukaemia, myeloma and lymphoma cell lines in vitro (Kumagai et al 2007). Baicalein, baicalin and wogonin have been shown to reduce proliferation of human bladder cancer cell lines in a dose-dependent manner, but baicalin exhibited the greatest antiproliferative activity. In an in vivo study baical skullcap extract had a significant inhibition of tumour growth (P < 0.05) (Ikemoto et al 2000).
Baical skullcap significantly inhibited prostate-specific antigen production and reduced PGE2 synthesis via direct inhibition of COX-2 activity in vitro (Ye et al 2007). The extract also reduced cyclin D1, resulting in a G1 phase arrest, and inhibited cyclin-dependent kinase 1 (cdk1) expression and kinase activity leading to a G2/M cell cycle arrest. An animal study reported a 50% reduction in tumour volume after 7 weeks (Ye et al 2007). Another study found that baicalein, wogonin, neobaicalein and skullcap-flavone inhibited prostate cancer cell proliferation in vitro (Bonham et al 2005). Additionally, the in vivo phase of the study found that baicalein (20 mg/kg/day) reduced the growth of prostate cancer xenografts in mice by 55% after 2 weeks.
Wogonin inhibited PMA-induced COX-2 protein and mRNA levels in human lung epithelial cancer cells (Chen et al 2008). It appears that this was due to activator protein 1 (AP1) inhibition.
Adjunct to chemotherapy
In experiments with murine and rat transplantable tumours, baical skullcap extract treatment improved cyclophosphamide and 5-fluorouracil-induced myelotoxicity and decreased tumour cell viability (Razina et al 1987). Wogonin has also demonstrated the ability to hasten etoposide-induced apoptotic cell death (Lee et al 2007). Another in vitro study found that wogonin increased apoptosis and induced cell cycle arrest at the G2/M phase (Himeji et al 2007).
Prevention of metastases
The advancement of Pliss’ lymphosarcoma in rats is associated with disorders of platelet-mediated haemostasis, presenting with either lowered or increased aggregation activity of platelets. Extract of baical was shown to produce a normalising effect on platelet-mediated haemostasis whatever the pattern of alteration. This activity is thought to be important for antitumour and, particularly, metastasis-preventing effects (Razina et al 1989).
Experiments in mice inoculated with metastasising Lewis lung carcinoma showed that the antitumour and antimetastatic effects of cyclophosphamide are potentiated by baical, rose root (Rhodiola rosea), licorice (Glycyrrhiza glabra), and their principal acting components, baicalin, paratyrosol and glycyrrhizin (Razina et al 2000).
Chemoprevention
Baicalein prevents chemically-induced DNA damage in a cell culture model (Chan et al 2002).
Anti-angiogenesis
Baicalein and baicalin have demonstrated anticancer activity against several cancers in vitro. The flavonoids have also been shown to be potent inhibitors of angiogenesis in vitro and in vivo. Baicalein was found to be more potent than baicalin (Liu et al 2003).
Cytochrome Inhibition
Baical flavonoids inhibit hepatic cytochromes CYP1A2 and CYP3A2 in vitro and in vivo (Kim et al 2002, de Boer et al 2005).
CLINICAL USE
Baical skullcap is an ingredient in the very popular traditional Chinese/Japanese formulation, Minor Bupleurum Combination, also known as Xiao Chai Hu Tang (Chinese) and Sho-saiko-to (Japanese). Minor Bupleurum Combination has been used in China for about 3000 years for the treatment of pyretic diseases.
Minor Bupleurum Combination (Sho-saiko-to) is now a prescription drug approved by the Ministry of Health and Welfare of Japan and widely used in the treatment of chronic viral liver diseases. Since 1999, Sho-saiko-to has been administered to 1.5 million patients with chronic liver diseases, because it can significantly suppress cancer development in the liver (Yamashiki et al 1999). Sho-saiko-to is also used for the treatment of bronchial asthma in Japan (Nakajima et al 2001). As such, many studies have been conducted with the herbal combination making it difficult to determine the role of baical skullcap as a stand-alone treatment.
Minor Bupleurum Combination (Sho-saiko-to, Xiao Chai Hu Tang)
Bupleurum falcatum (bupleurum)
Scutellaria baicalensis (baical skullcap)
Pinellia ternata (pinellia)
Panax ginseng (Korean ginseng)
Zizyphus jujuba (zizyphus)
Glycyrrhiza uralensis (Chinese licorice)
Zingiber officinale (ginger)
Respiratory infection
Sixty patients with respiratory infection (mainly nosocomial pneumonia) were treated either by injection of baical compound or piperacillin sodium (IV). The total efficacy was evaluated after treatment for 1 week.
Total effective treatment rates were 73.3% for baical compared with 76.7% in the antibiotic treatment group.
Body temperature was decreased similarly and symptoms disappeared or were relieved in 11.67 ± 6.75 days with the herb and 11.53 ± 7.30 days with the antibiotic.
In the piperacillin sodium group, fungal infections occurred in 4 of 30 patients, but there were none in the baical treatment group (Lu 1990).
Bone marrow stimulation during chemotherapy
Haemopoiesis was studied in 88 patients with lung cancer during combination treatment with chemotherapy and a S. baicalensis extract. Administration of the plant preparation was associated with haemopoiesis stimulation, intensification of bone marrow erythrocytopoiesis and granulocytopoiesis, and increased numbers of circulating precursors of erythroid and granulomonocytic colony-forming units (Goldberg et al 1997).
Epilepsy (in combination with other herbs)
Saiko-keishi-to, a spray-dried decoction of bupleurum (cinnamon, peony, ginger, licorice, ginseng, pinellia, zizyphus and baical) was administered to 24 people with epilepsy who had frequent uncontrollable seizures (3–5 seizures per day in the most severe case and 5 seizures per month in the mildest case) of various types, despite treatment with pharmaceutical anticonvulsants. Of them, 6 were well controlled with Saiko-keishi-to whereas 13 experienced improvement and 3 showed no effect. No patients experienced worsening of their condition. Two patients dropped out during treatment (Narita et al 1982).
Chronic active hepatitis (in combination with other herbs)
In a double-blind, multicentre clinical study of 222 patients with chronic active hepatitis, Sho-saiko-to was found to significantly decrease AST and ALT values compared with placebo. The difference between the treatment and placebo groups in the mean value was significant after 12 weeks. In patients with chronic active hepatitis type B (HB), a tendency towards a decrease of HB e antigen and an increase of anti-HB e antibodies was also observed. No remarkable side effects were noticed (Hirayama et al 1989).
Liver fibrosis (in combination with other herbs)
Minor Bupleurum Combination (Sho-saiko-to) has been shown to play a chemopreventive role in the development of hepatocellular carcinoma in cirrhotic patients in a prospective study, and several studies have demonstrated the preventive and therapeutic effects of Sho-saiko-to on experimental hepatic fibrosis (Shimizu 2000). Sho-saiko-to has been shown to inhibit the activation of hepatic stellate cells, the major collagen-producing cells. Sho-saiko-to has a potent antifibrotic effect by inhibiting oxidative stress in hepatocytes and hepatic stellate cells. It is proposed that the active components are baicalin and baicalein, because they both have chemical structures very similar to silybinin, the active compound in Silybum marianum (St Mary’s thistle), which exhibits antifibrotic activities.
OTHER USES
Because of its wide range of pharmacological effects, baical skullcap is used for many different indications. Although controlled trials are not yet available to determine its effectiveness, evidence from in vitro and animal studies provides a theoretical basis for the following uses:
chronic inflammatory conditions such as asthma, arthritis and allergies (anti-allergic and anti-inflammatory effects)
hepatitis (as a hepatoprotective agent)
common infections such as the common cold (antimicrobial and immunostimulant effects)
nausea and vomiting (anti-emetic effect)
mild hypertension (hypotensive activity demonstrated in several animal models).
In practice, baical skullcap is used in combination with other herbs for these conditions.
DOSAGE RANGE
Dried herb: 6–15 g/day (Bensky & Gamble 1986).
Liquid extract (1:2): 30–60 mL/week or 4.5–8.5 mL/day in divided doses.
ADVERSE REACTIONS
There have been several case reports of Sho-saiko-to-induced interstitial pneumonia (Liu et al 2002). One case of Sho-saiko-to-induced pneumonia in a patient with autoimmune hepatitis was reported (Katou et al 1999); however, direct toxicity is very low.
Toxicity studies of three different traditional Chinese/Japanese formulations containing baical suggest a very low acute or subchronic toxicity for the herbs in them. The studies found no herb-related abnormalities such as changes in body weight or food consumption, abnormalities on ophthalmological and haematological examination, urinalysis and gross pathological examination, changes in organ weights or optical microscopic examination (Iijima et al 1995, Kanitani et al 1995, Kobayashi et al 1995, Minematsu et al 1992, 1995). The acute lethal activity of wogonin is low, with an LD50 of 3.9 g/kg (Kwok et al 2002).
SIGNIFICANT INTERACTIONS
There are reports of baical flavonoids interacting with P450 enzymes. Baical flavonoids inhibit hepatic CYP1A2 (Kim et al 2002) and CYP2E1 expression (Jang et al 2003). Theoretically, inhibition of CYP1A2 and CYP2E1 may affect certain medical drugs metabolised by these P450 enzymes. There are, however, no clinical reports of such herb–drug interactions.
Sho-saiko-to during interferon therapy
Sho-saiko-to, as well as interferon, is used for the treatment of chronic hepatitis. There have been reports of acute pneumonitis due to a possible interferon–herb interaction. Pneumonitis, also called extrinsic allergic alveolitis, is a complex syndrome caused by sensitisation to an allergen. The mechanism of the Sho-saiko-to–interferon interaction seems to be due to an allergic–immunological mechanism rather than direct toxicity (Ishizaki et al 1996) — contraindicated.
Cyclosporin
A decoction of S. baicalensis has been reported to significantly decrease plasma levels of cyclosporin in rats. The co-administration of these two substances should be avoided until further research is available (Lai et al 2004).
Warfarin/anticoagulants
Increased risk of bleeding is theoretically possible — use with caution.
CONTRAINDICATIONS AND PRECAUTIONS
Baical skullcap and the formulation Sho-saiko-to (Minor Bupleurum Combination, Xiao Chai Hu Tang) are contraindicated during interferon therapy. Baical is contraindicated in cold conditions in TCM.
PREGNANCY USE
Baical is used in TCM for restless fetus (threatened abortion) and toxaemia of pregnancy. A recent animal study found that baical skullcap combined with Atractylodes macrocephala had an anti-abortive effect through inhibition of maternal–fetal interface immunity. The herbs prevented lipopolysaccharide-induced abortion by reducing natural killer cells and interleukin 2 activity (Zhong et al 2002). Although this is encouraging, safety in pregnancy is still unknown.
PATIENTS’ FAQs
What can this herb do for me?
Baical skullcap may be useful as an adjunctive therapy during cancer treatment to reduce nausea and immune suppression. Baical skullcap may also be beneficial in the treatment of vascular disorders, allergies, liver disease and infections, hypertension and arthritis; however, effectiveness is largely unknown.
When will it start to work?
For acute allergic and infectious conditions, the beneficial effects of baical skullcap should be noticeable within a few days. For chronic diseases, long-term use is recommended.
Are there any safety issues?
Baical skullcap is a safe and non-toxic herb, which is used in both acute and chronic conditions. It should only be used during pregnancy on the recommendation of a healthcare practitioner. Baical and the formulation Sho-saiko-to (Minor Bupleurum Combination known as Xiao Chai Hu Tang in Mandarin) are contraindicated during interferon therapy.
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