Keywords

FormalPara Vernaculars:

Urd. : Darchoba , Darhald (stem wood) , Rasot (extract) , Zarishk (fruit) ; Hin. : Chitra , Darhalad (stem wood) , Jharki-halad , Kash-mal , Rasaut , Raswanti (extract), Raswat ; San.: Chitra , Dãruharidrã , Dãruniśã , Darvi , Katamkateri , Rasãñjana (dry extract), Pitã , Pitadãru , Parjanyã ; Ben.: Darhaldi , Daruharidra; Mal.: Kasturimanjal, Maramanjal , Maradarisina ; Mar.: Daruhalad ; Tam.: Kasturimanjal, Maramanjal , Mullabubla , Puttar ; Tel.: Daruharidra, Kasturipaspu , Manupasupu ; Ara.: Amber baarees (fruit); Eng.: Indian barberry , Nepal barberry , Root bark of berberis , Turmeric wood , Tree turmeric ; Ger.: Begrannter sauerdorn ; Gre.: Lofiyun ; Nep.: Chitra ; Per.: Darchob (stem wood), Darhald , Filzahrah , Zarishk (fruit).

FormalPara Description:

A deciduous evergreen shrub found in temperate and subtropical regions of Asia (north India, Nepal , Sri Lanka), Africa, Europe and North and South Americas. The roots of B. aristata  are considered as the official drug in the Ayurvedic Pharmacopoeia of India. However, in different parts of India, other species of Berberis, namely B. asiatica, B. chitria, and B. lycium are also used under the name of Daruharidra [24]. Rasout is the water extract of powdered stem or wood.LXXXI In India, Darhalad is available as pieces of 2.5–5.0 cm in diameter, covered by a soft, corky, light brown bark, with a hard layer of stony cells beneath, forming a complete coating of the stem. Rasot or rusot is the dark brown extract of the consistence of opium, having a bitter and astringent taste. Zarishk is a moist sticky mass of small black fruit; most of them abortive, but a few contain one or two oblong seeds about 0.4 cm long, with a thin roughish brown testa. Root bark is brittle, externally light-brown and corky, beneath which is a dark brown layer, with a greenish-yellow tinge, fibrous, and very bitter (Figs. 1 and 2).XL

Fig. 1
figure 1

Berberis aristata , Plant, L. Shyamal, WikimediaCommons; ShareAlike 3.0 Unported CC BY-SA 3.0, https://commons.wikimedia.org/wiki/File:BerberisAculeata.jpg; https://creativecommons.org/licenses/by-sa/3.0/deed.en

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Fig. 2
figure 2

Berberis aristata, Fruits, Buddhika.jm, WikimediaCommons; ShareAlike 3.0 Unported CC BY-SA 3.0, https://commons.wikimedia.org/wiki/File:Berberis_aristata_fruit.jpg; https://creativecommons.org/licenses/by-sa/3.0/deed.en

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FormalPara Actions and Uses:

Ibn-al-BaitarLXIX quoted Ghafiqi that the decoction of the root in wine or vinegar is beneficial for inflammation and pain of liver. Rose-water in which Zarishk has been soaked is preventive and curative as eye drops for chronic inflammation. Ibn al-Baitar also quoted Galen that it is beneficial for gastric ulcers, diarrhea and nosebleed in women. Galen assigned the temperament of moderately hot and dry 2° to this plant; some authors consider it cold 1° and dry 2°. Dioscorides mentioned it useful for cough and hemoptysis. In Iran, fruits of B. vulgaris are known as Zereshk. The tree is called Zarishk in Unani medicine, the bark is known as Dar-e-hald, and the resin obtained from the tree is called Rasaut . Externally, Rasaut is astringent, anti-inflammatory and counterirritant; and internally, astringent, blood purifier, and styptic; internally it is used after dissolving in rose-water.Footnote 1 Decoction of Zarishk as enema is beneficial for ulcerative colitis. KabeeruddinLXXVII mentions that Zarishk reduces excessive heat due to blood and yellow bile, reduces stomach and liver heat, and relieves thirst, nausea and vomiting. It is useful as antipyretic, antimicrobial, hepatoprotective, antihyperglycemic, anticancer, antioxidant, and antilipidemic agent. Bark and stem are tonic, diaphoretic, stomachic, antiperiodic, and gentle aperients, and used in malarial fevers, diarrhea, dyspepsia, dysentery, ague, during convalescence from fevers and acute diseasesLXXXI; the root is purgative.CV The extract and its formulations have also been used in the treatment of hemorrhoids, gynecological disorders, HIV-AIDS, osteoporosis, diabetes, wound healing, eye and ear infections, jaundice, skin diseases, and malarial fever [22], enlargement of spleen, leprosy, rheumatism, fever, morning/evening sickness, and snakebite [28]. In Ayurveda, the stem is used in the treatment of kapharoga, amatisara, medoroga, urustambha, karnaroga, mukharoga, netraroga, kandū, vrana, and meha.LX The alkaloid, berberine, isolated from the plant has also shown significant antimicrobial activity against bacteria, viruses, fungi, protozoans, helminths, and chlamydia; and is clinically used for bacterial diarrhea, intestinal parasitic infections, and ocular trachoma infections [2].

FormalPara Phytoconstituents:

The plant mainly contains isoquinoline alkaloids; major alkaloids identified are berberine, berberrubine, jatrorrhizine, ketoberberine, palmatine, dihydropalmatine or 7,8-dihydro-8-hydroxyberberine, berbamine and pakistanamine. Berberine, mainly reported from root and stem bark, was also identified in leaves along with chlorogenic acid [3]. Hydroalcoholic stem bark extract showed the presence of 25.44% alkaloids (the isoquinoline alkaloids: berbamine, berberine, reticuline, jatrorrhizine, palmatine and piperazine) [29].

FormalPara Pharmacology:

Aqueous-alcoholic (50%) root extract, mainly containing berberine, berbamine and palmatine, significantly lowered FBG in diabetic rats, without causing hypoglycemia. The glucokinase and G-6-PD activities were increased, and activity of glucose-6-phosphatase was decreased [25]. Berberine shows hypoglycemic activity comparable to metformin in diabetic mice [4]. Aqueous fruit extract exhibited a positive inotropic action, and activity-directed fractionation led to n-butanolic fraction (BF) with cardiotonic activity; that produced a dose-dependent positive inotropic action with little effect on HR. Pretreatment of atria with propranolol did not abolish the cardiotonic effect of BF, and carbachol partially reversed the effect, indicating that a cAMP-independent mechanism underlies the inotropic action [14].

Pretreatment of rats with hydroalcoholic bark extract produced significant anti-inflammatory and antigranuloma effects with significant reduction in proinflammatory markers, IL-1β, IL-6, TNF-R1, and COX-2 [20]. Hydroalcohol root extract inhibited growth of B. cereus, E. coli, S. aureus and A. flavus; while the stem extract was active against B. cereus and S. pneumoniae [26]. Ethanol and aqueous bark extracts inhibited growth of Shigella, with MIC and MBC between 125–500 and 300–600 µg/mL, respectively. Both extracts delayed the onset of castor oil-induced diarrhea and reduced the number of diarrheal episodes [17]. The extract significantly inhibits generation of ROS from H. pylori-infected gastric epithelial cells [33]. Hydroalcoholic stem bark extract exhibited synergistic effect with colistin, tigecycline and amoxicillin/clavulanate, and antagonism with ertapenem and meropenem [29], produced synergistic bactericidal effect against carbapenem-resistant E. coli [30], and ameliorated carbapenem-resistant E. coli-induced peritonitis in rats [31]. B. aristata extract protected rats against anti-TB drugs (INH, RIF, and PZA)-induced testicular damage [24]. Administration of aqueous-methanol extract to ovariectomized rats for 42-days exhibited antiosteoporotic effect, significantly increased uterine weight, femur BMD and lumber hardness, and increased serum levels of calcium and phosphorus [32]. Ethanol extract (i.p.) attenuated percent increase in weight gain due to tumor cell proliferation, increased survival time, reversed alterations in hematology of EAC-bearing mice [21]. Berberine also significantly inhibited incidence of tumors, induced by 20-MCA or NDEA in mice and rats, and increased their life span [1]. Topical instillation of aqueous extract showed potent anti-inflammatory activity against endotoxin-induced uveitis in rabbits [15].

Berberine exhibited antidepressant activity, and enhanced antimobility effect of subeffective doses of desipramine, imipramine, fluoxetine, venlafaxine, bupropion and tranylcypromine in forced-swim test of mice, and increased levels of NE, 5-HT and DA [19]. Chronic administration of berberine for 15-days significantly increased brain levels of NE, 5-HT, as well as DA; but at a higher dose of 10 mg/kg, i.p., only 5-HT and DA were significantly increased [18]. Berberine was effective against T. vaginalis, comparable to metronidazole [27], and markedly diminished parasitic load, improved hematological picture of L. donovani-infected hamsters, with less toxicity than pentamidine [13]. Berberine inhibits secretory responses of heat-labile enterotoxins of V. cholerae and E. coli, and also markedly inhibits secretory response of E. coli heat-stable enterotoxin; however it does not inhibit stimulation of adenylate cyclase by cholera enterotoxin [23]. Pretreatment with berberine for 2-days also prevented APAP- or CCl4-hepatotoxicity, and post-treatment with three successive oral doses reduced APAP-induced hepatic damage, but not the CCl4-hepatotoxicity [16].

FormalPara Clinical Studies:

Berberine has poor oral bioavailability due to the presence of P-glycoprotein in enterocytes—that extrudes berberine back into the intestinal lumen, thus limiting its absorption. Silymarin, derived from Silybum marianum, is considered a P-glycoprotein inhibitor by some. A pilot study of a combination product of B. aristata  extract and Silybum marianum extract (Berberol®) to twenty-six Italian type-2 diabetic patients with suboptimal glycemic control, showed significant reduction in HbA1c, basal insulin, TC, LDL-C, and TGs, after 90-days of treatment [12]. In another RCT of dyslipidemic, euglycemic patients, the same combination reduced TC, TGs and LDL-C, and increased HDL-C and insulin secretion after three-months of treatment. However, the lipid profile worsened when treatment was interrupted for two months, and improved again when the treatment was reintroduced [5, 6]. A comparative study of the standardized extract of B. aristata with the fixed combination containing the same standardized extract of B. aristata  plus standardized extract of S. marianum (Berberol®) showed similar improved fasting glucose, TC, LDL-C, TGs, and liver enzyme levels in both groups, except the HbA1c values were reduced to a greater extent by the fixed combination [11]. Addition of the combination (Berberol®) to statin regimen was effective in reducing doses of statins by half in dyslipidemic patients who could not tolerate high doses of statins, without affecting the lipid profile [8]. Similar results were reported in hypercholesterolemic, type-2 diabetic patients, wherein addition of Berberol® either as a single therapy or as an add-on therapy to low-dose statin or to ezetimibe reduced TGs, LDL-C, FBG, and HbA1c in a significant manner without inducing toxicity [10]. The combination also reduced fasting plasma glucose, insulin, and HOMA-index in euglycemic, dyslipidemic subjects, intolerant to high dosages of statins after six-months of treatment, with no reduction in levels of TC, LDL-C and TGs [9]. Addition of the combination to insulin therapy in type 1 DM patients resulted in reduction of insulin dose for the same level of glycemic control [7].

FormalPara Human A/Es, Allergy and Toxicity:

Harmful in individuals with phlegmatic constitution.LXXVII

FormalPara Animal Toxicity:

Oral LD50 of both ethanol and aqueous bark extracts were >5,000 mg/kg body weight in the acute toxicity studies with Swiss albino mice [15]. The no observed adverse effect level (NOAEL) of hydroalcoholic stem bark extract in rats was up to a dose of 2,000 mg/kg BW [31].

FormalPara CYP450 and Potential for Drug-Herb Interactions:

Hepatic mRNA levels of CYP1A1, CYP2B9, CYP2B10, CYP3A11, CYP4A10, and CYP4A14 are increased in STZ-diabetic mice. Berberine restores expression of CYP3A11, CYP4A10, and CYP4A14 to normal levels, but suppresses the expression of CYP2E1, an adverse hepatic event-associated enzyme. Berberine treatment alone increases the expression of CYP2B9 and CYP2B10 in primary mouse hepatocytes [4].

FormalPara Commentary:

Antidiabetic and antidyslipidemic effects obtained in RCTs of the combination of standardized extracts of B. aristata and S. marianum as adjunct to standard treatments are encouraging, and worthy of consideration in patients with suboptimal glycemic control.