Herbal Medicines Potential Therapeutic Agents with Minimal Side Effects

Indigenous medicines, especially of plant origin, are used extensively for the treatment of various diseases. With lack of safe and effective treatment for liver diseases, researchers have been looking for alternative therapies that curb symptoms with minimum adverse effects on patients. Silybum marianum (milk-thistle) [15] and its extracts have been used since the times of ancient Greece for medicinal purposes. It is now currently used widely in Europe for liver disease, and is readily available in the United States from alternative medicine outlets and outdoor markets. Studies on effect of silymarin, an extract of milk-thistle, in preventing complications of chronic hepatitis virus infection at a dose of 140 mg three times daily suggest there is a need for optimization (e.g. single dosage, dose doubling), as efficacy could not be established. Silymarin may benefit the liver by promoting the growth of certain types of liver cells, demonstrating a protective effect, inhibiting inflammation and fighting oxidation. Similar studies have been reported from China, Africa, Arabia and India.

As well as milk-thistle, several hundred other plants are reported to have hepa-toprotective properties [18], and a number of studies have been conducted taking into consideration valid scientific, clinical, and research parameters. These plants include Cochlospurmum planchonii [17], Zingiber officinale [19], Nardostachys jata-mansi (jatamansi) [20], Swertia chirata (chirayata) [21, 22], Cichorium intybus. (chicory) [23], Hyprophilia auriculata (talamakhana] [24], Apiumgraveolens (celery), Teph-rosia purpurea (sharpunkha) [25], Plumbazo zeylanica (chitrak) [25], Solanum nigrum (makove) [26], Tinospora cardifolia (guduchi) [27] Terminalia belerica (bibhi-take) [28], Boerhavia diffusa (punarnava) [29], Eclipta alba (bhringraj) [30], Androgra-phis peninculata (kalmegh) [31], Allium sativa (garlic) [32], Glycyrrhiza uralensis (liquorice) [33], Camellia sinensis (green tea) [34], Curcuma longa (turmeric) [35], Picrorhiza kurroa (katuki) [36], Oldenlandia corymbasa, Asteracantha longifolia, Cassia occidentalis, Embelia ribes, Trachyspermum ammi, and Capparis spinosa.

Some of the constituents isolated from these hepatoprotective plants and reported to have antihepatotoxic activity include kaempferol, caffeic acid, ferulic acid, and p-cumaric acid (Capparis spinosa), azelaic acid, alpha-amyfrin, taraxerone, baurenyl acetate, beta-sitosterol, and daucosterol (Cichorium intybus), nigrumnins I and II (Solanum nigrum), arjunetoside, oleanolic acid, arjunic acid, and arjunaphthanolo-side (Terminalia arjuna), andrographolide (Andrographis paninculata), silybin and silymarin (Silybum marianum), kutkoside and picroside I and II (Picrorhiza kurroa), gomishins (Schizandra achinensis), wuweizisuc and schisandrin A (Schizan-dra chinensis), glycyrrhizin and glycyrrhizinic acid (Glycyrrhiza glabra), saikosapo-nins (Bupleurum falcatum), sarmantosins (Sedum sarmentosum), catechin (Anacar-dium occidentalis), ursolic acid (Eucalyptus spp.), curcumin (Curcuma longa), and fumaric acid (Sida cardifolia).

In India hundreds of medicinal plants are used alone or in different combinations in the preparation of around three dozen patented herbal formulations [37]. A large number of plants have been studied in last couple of years for their antihe-

patotoxic potential. However in most cases, the mechanism of their hepatoprotec-tive effect still remains to be ascertained. Most of the plants have been shown to stimulate secretion of bile fluid (choleretic) and salt (chologogue) in experimental animals [37]. Potent hepatoprotective plants such as Andrographis paniculata and Trichopus zeylanicus also stimulate biliary function in normal rats [38, 39]. In general, the therapeutic values of drugs are evaluated in model animals by inducing the disease and comparing the parameters of model drugs with those of active ingredients or extracts. Formulations may also be prepared using active ingredient or excipients from natural sources in the preparation of drug delivery system for studies on efficacy. Sometimes simple powdered forms of parts of herbs are also used in clinical studies.

Detailed efficacy and toxicity studies in experimental animals should be followed by clinical trials. Biochemical and other in vitro assays are required to determine the mechanism of action of these herbal products. To assess any toxic activity, in vivo and in vitro test systems are used. Identifying the hepatoprotective efficacy of drugs is not easy as this activity for a given drug may be different against different toxins [40]. Thus the efficacy of each drug has to be tested against hepatotoxins that act by different methods. Currently available data show that a few plants are promising hepatoprotective agents. These include Capparis spinosa (kaempferol), Picro-rhiza kurroa (picroliv), Andrographis paninculata (andrographolide), and Silybum marianum (silymarin). Kumars and Mishra have documented the hepatoprotective activity of fumaric acid from Sida cardifolia [41]. Ursolic acid, which occurs in many plants, also shows hepatoprotective properties [42, 43].

Although some herbal medicines are effective in the treatment of diseases against which modern medicines are inefficient, very often these drugs are unscientifically exploited and improperly used. Numerous plants and polyherbal formulations are used for the treatment of liver diseases. However, in most of the severe cases, the treatments are not satisfactory. Experimental evaluation in most cases has been incomplete and insufficient and the therapeutic values have been tested against chemically induced subclinical levels of damage in rodents. Even common dietary antioxidant and micronutrients such as tocopherol [44], ascorbic acid [45], beta-carotene [45], glutathione, uric acid, and bilirubin, and proteins such as ceru-loplasmin can provide protection from liver damage.

The synergistic action of various ingredients of a polyherbal formulation for holistic and long-lasting cure of hepatic disorder might help in regulating the metabolism, which is one of the factors responsible for longevity. Various experimental and clinical studies by different researchers have been well documented in this subject field. Khanfar et al. isolated and identified the active ingredient of Capparis spinosa as "beta 3-methyl-2-butenyl-beta-glucoside" [47]. "p-Methoxy benzoic acid" isolated from Capparis spinosa was found to possess potent hepatoprotective activity against CCl4-, paracetamol- (in vivo), and thiacetamide galactosamine- (in vitro) induced hepatotoxicity [48]. Al-Said et al. demonstrated the strong anti-inflammatory activity of Capparis spinosa, which was comparable to that of oxyphenbutazone [49, 50]. Bonina et al. documented a significant antioxidant activity of Capparis spinosa and also identified flavonols (kaempferol and quercetin derivatives) and hy-

droxycinnamic acids (caffeic acid, ferulic acid, p-cumaric acid, and cinnamic acid) as major antioxidants from Capparis spinosa [51]. Mahasneh observed potent antimicrobial and antifungal activity of Capparis spinosa [52, 53].

He and co-workers isolated 2,3,4,9-tetrahydro-14-pyrido [3,4-b] indole-3-carboxyl-ic acid, azelaic acid, and daucosterol as the major constituents of Cichorium intybus [54], and Du et al. identified the other constituents as alpha-amyrin, taraxerone, baurenyl acetate, and beta-sitosterol [55]. Aktay et al. and Zafar et al. observed the hepatoprotective effect (confirmed by histopathological examination) of Cichorium intybus against CCl4-induced hepatotoxicity and reported significant prevention of the elevation of malondialdehyde formation (plasma and hepatic) and enzyme levels (aspartate aminotransferase (AST) and alanine aminotransferase (ALT)) [23, 56]. Ahmed et al. screened Cichorium intybus for antihepatotoxic activity and measured the degree of protection using biochemical parameters (AST, ALT, alkaline phosphatase (ALP), and total protein (TP)). Potent antihepatotoxic activity comparable to silymarin was observed with almost complete normalization of the tissues (as neither fatty accumulation nor necrosis was observed on histopathological studies) [57]. Mun et al. studied the effects of Cichorium intybus on the immunotox-icity of ethanol and reported a significant increase in the number of circulating leukocytes, the weight of concerned organs (liver, spleen, and thymus), number of splenic plaque-forming cells, hemagglutination titers, and the secondary IgG antibody response. A significant increase in delayed-type hypersensitivity reaction, phagocytic activity, natural killer cell activity, cell proliferation, and interferon-gamma secretion was also observed [58]. Sultana et al. reported that the presence of Cichorium intybus in the reaction mixture containing calf thymus DNA and a free radical-generating system protects DNA against oxidative damage to its sugar moiety.

All these studies suggest that the observed hepatoprotective effects might be due to the ability to suppress the oxidative degradation of DNA in the tissue debris [59]. Gurbuz et al. observed significant cytoprotection against ethanol-induced damage and these results were further confirmed by using histopathological techniques [60]. Aminghofran et al. reported the capacity of Cichorium intybus to enhance the proliferation of lymphocytes after stimulation with allogenic cells [61]. Kim et al. investigated the effect of Cichorium intybus on mast cell-mediated immediate-type allergic reactions and observed inhibition of the systemic anaphylactic reaction and a reduction of plasma histamine levels [62].

Ikeda et al. identified saponin (nigrumnins I and II) as the active ingredients of Solanum nigrum [63]. Solanum nigrum was investigated for its hepatoprotective activity against CCl4-induced hepatic damage and Raju et al. observed remarkable hepatoprotective activity confirmed by evaluated biochemical parameters (AST, ALT, ALP, and TP) [64]. Moundipa et al. studied the effects of Solanum nigrum on hepatotoxicity and reported increased level of activity of aminopyrine, N-dimethy-lase, uridine diphosphate, glucuronyl transferase and glutathione-S-transferase, without any alteration in levels of ALP, ALT, and gamma-glutamyltransferase levels in the serum [65]. Prasant Kumar et al. tested Solanum nigrum in vitro for its cy-toprotective activity against gentamicin-induced toxicity and observed significant inhibition of cytotoxicity, along with hydroxyl radical scavenging potential, which might be the mechanism of cytoprotection [66]. Qureshi et al. reported the antifungal activity of Solanum nigrum [67]. Perumal Samy et al. demonstrated the potent antibacterial activity of Terminalia arjuna [68].

Ali et al. demonstrated that arjunaphthanoloside from Terminalia arjuna decreases inducible nitric oxide synthase levels in lipopolysaccharide-stimulated peritoneal macrophages [69]. Jafri et al. reported significant hepatoprotective effects of Cassia occidentalis in chemically induced liver damage [70]. Bin-Hafeez et al. showed that Cassia occidentalis modulated hepatic enzymes and provided hepatop-rotection against induced immunosuppression [71]. Harnyk et al.. demonstrated the clinically beneficial effects of Achillea millefolium in the treatment of chronic hepatitis [72]. Kriverko et al. reported clinical improvements in chronic hepatochol-ecystitis and angiocholitis with Achillea millefolium [73]. Lin et al. observed antihe-patoma activity of Achillea millefolium [74]. Devarshi et al. studied Mandura bhasma for its hepatoprotective properties in hepatitis induced by CCl4 and observed prevention of CCl4-mediated changes in enzyme activities, which suggest the hepatoprotective role of the plant [75].

The synergistic action of a polyherbal formulation (hepatoprotective, antimicrobial, antioxidant, and anti-inflammatory) could bring about holistic cure and treatment.

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