Available online through - IJRAP · Crocus sativus (Common name: Saffron) is a native of south Europe and is cultivated in Spain, France, Italy, Greece, India and China (Figure 4)

Darji Vinay Chhanalal et al / IJRAP 2011, 2 (1) 84-89

International Journal of Research in Ayurveda & Pharmacy, 2(1), Jan-Feb 2011 84-89

Review Article Available online through www.ijrap.net ISSN 2229-3566

NATURAL AGENTS FOR INFLAMMATORY BOWEL DISEASE

Darji Vinay Chhanalal1*, Bariya Aditi Hemrajbhai2, Deshpande Shrikalp Shrikant3 1Department of Pharmacology, Sharda School of Pharmacy, Pethapur, Gandhinagar - 382610, Gujarat, India

2Department of Pharmacology, Kalol Institute of Pharmacy, Kalol, Gandhinagar - 382721, Gujarat, India 3Department of Pharmacology, K.B. Institute of Pharmaceutical Education & Research, Gandhinagar - 382023,

Gujarat, India

Received on: 29/12/2010 Revised on: 26/01/2011 Accepted on: 12/02/2011

ABSTRACT Inflammatory bowel disease (IBD) is a chronic inflammatory disease of gastrointestinal tract. It comprises the two conditions, Crohn’s disease and ulcerative colitis, characterized by chronic recurrent ulceration of the bowel. Conventional drugs for colitis treatment include aminosalicylate, corticosteroids,antibiotics & immunomodulators. 5- Amino salicylic acid having side effects in 30% of the patients. Systemic corticosteroids producing incidence of complication is 4.3%. Antibiotic therapy is beneficial in 70% of the patients & Immunomodulators having 50 to 70% beneficial effects. This report shows that there is no any appropriate treatment available to treat IBD without side effects. A natural agent with reduced or no toxicity is therefore essential. In nature there are so many types of natural agents which are used as protective agents in IBD. This article emphasizes many natural products obtained from plant & other sources, which possess potent activity against experimentally induced IBD. KEYWORDS: Natural agents, Inflammatory bowel disease (IBD), Ulcerative colitis.

*Corresponding author Darji Vinay Chhanalal, Department of Pharmacology, Sharda School of Pharmacy, Pethapur, Gandhinagar-382610, Gujarat, India E-mail: [email protected] INTRODUCTION Inflammatory bowel disease is a chronic inflammatory disease of gastrointestinal tract. Inflammatory bowel disease comprises the two conditions, Crohn's disease and ulcerative colitis, characterized by chronic recurrent ulceration of the bowel and of unknown etiology. The pathogenesis likely involves genetic, environmental, and

immunologic factors.1 Although the incidence and prevalence of ulcerative colitis and Crohn's disease are beginning to stabilize in high-incidence areas such as northern Europe and North America, they continue to rise in low-incidence areas such as southern Europe, Asia, and much of the developing world. As many as 1.4 million persons in the United States and 2.2 million persons in Europe suffer from these diseases. In India, ulcerative colitis was first reported in 1964 and Crohn's disease was considered almost nonexistent till 1986. During the last 10 years, Crohn's disease is being reported more frequently from different parts of India, especially southern India.2 Accordingly, a number of animal models with defined knockouts of inflammatory factors such as IL-2, IL-10,

and the T cell receptor, as well as seemingly unrelated

molecules, such as the multidrug resistance protein appear to result in bowel inflammation.3 Several cytokines including TNF-a and IL-1b, have been shown to be upregulated in inflammatory bowel disease and serve to amplify and perpetuate tissue damage. Furthermore, chemokines are also upregulated, thus

providing a continuous signal for the influx of leukocytes.4 There is greatly increased production rates

of nitric oxide (NO) into the colonic lumen of patients with inflammatory bowel disease and provided evidence for the hypothesis that the enzyme, inducible NO synthase (iNOS), is the source of excess NO production.5 Management of inflammatory bowel disease involves the use of 5-aminosalicylic acid and immunosuppressive agents such as corticosteroids and 6-mercaptopurine as well as its precursor azathioprine.6 Long term use of glucocorticoids is associated with high rates of relapse and unacceptable toxicity as well as a significant number of patients are resistant or intolerant to thiopurines. Novel agents such as monoclonal antibodies against TNF-a have been developed and demonstrate clinical



efficacy. However, these agents are expensive and not without side effects. Consequently, there is a need for alternative agents that may be equally or more effective

as well as being cheaper. Therefore a natural agent with reduced or no toxicity is essential. Numerous plant products are now used for the remedy of IBD. Some medicinal plants and their products, including vegetables, fruits and crops may prevent from IBD (Table 1). Most of these plants possess the activity against IBD by their Anti-oxidant mechanism. Natural agents useful in IBD Punica granatum Punica granatum Linn is a native of Afghanistan, Baluchistan and Persia, apparently wild in warm valleys in outer parts of Western Himalaya, hilly tracts. It belongs to family Punicaceae (Figure 1). It posses the various activities like Antidiarrhoeal, Anthelmintic, Antibacterial, Antifungal, Antifertility, Spasmogenic, Antioxidant, Analgesic & Antidiabetic.7 Punica granatum was tested for 2, 4 - dinitro benzene sulfonic acid (DNBS) induced colitis, and antioxidant activity was evaluated to clarify its possible mode of action. Experimental colitis was induced by DNBS (120 mg/kg) intrarectally. Punica granatum fruit juice (4 ml/kg) orally was given as a treatment for a 18 days & it was found that Punica granatum fruit juice (4ml/kg) was significantly effective against experimentally induce IBD.8 Vaccinium ashei Vaccinium ashei commonly known as Blueberry (Figure 2) is native to the southeastern U.S. where they occur in mixed woods, on high banks along streams or rivers, and in pine flatwoods communities. It belongs to family Ericaceae. Many of the heath-promoting properties of blueberries are thought to be attributable to anthocyanins that structurally belong to the natural products of flavonoids. Anthocyanins from blueberries are also used as anti-inflammatory, antimutagenic and rhodophylactic agents and the principal therapeutic benefits attributable to anthocyanins include antioxidant protection and maintenance of DNA integrity. Anthocyanins extract of blueberry was tested against trinitrobenzene sulfonic acid (TNBS)-induced inflammatory bowel disease (IBD) model of mice. Colitis was induced by intracolonic injection of 0.5 mg of TNBS dissolved in 50% ethanol–phosphate buffered solution. Anthocyanins extract of blueberry rendered strong protection against TNBS-induced colonic damage at a dosage of 40 mg/kg.9 Emblica officinalis Emblica officinalis (family: Euphorbiaceae) is an herbal plant widely used in many of the indigenous medical

preparations against variety of the diseases (Figure 3). It is commonly known as Aamla & found throughout India till the height of 4500 feet. It has potent antimicrobial, anti-diabetic, antitussive, adaptogenic, antioxidant, antitumour, radioprotective, antiulcerogenic, analgesic, anti-pyretic and anti-inflammatory activities of. Protective effect of methanolic fruit extract of Emblica officinalis (MEO 200 mg/kg) on acetic acid induced ulcerative colitis was evaluated in male Wistar rats. Colitis was induced by intracolonic instillation of 2 ml of 4% v/v acetic acid solution. The effect was assessed on the basis of macroscopic score, wet weight/length ratio of colonic tissue, biochemical changes and histopathological studies. Induction of colitis by acetic acid produced severe ulceration, edema and inflammatory cells infiltration in colonic tissues and increased levels of serum marker enzyme lactate dehydrogenase (LDH). Pretreatment with MEO (200 mg/kg) decreased serum LDH and restored histopathological changes near to normal. Result indicates that MEO can protect against acetic acid induced ulcerative colitis and may be beneficial in patients with inflammatory bowel disease. This protective effect may, at least in part, be due to their anti-inflammatory and/or antioxidant actions.10 Crocus sativus Crocus sativus (Common name: Saffron) is a native of south Europe and is cultivated in Spain, France, Italy, Greece, India and China (Figure 4). Cultivation in India is mostly confined to the table-land of Pampur (5,300 ft. above sea level) in Kashmir and Kishtwar in Jammu. It belongs to family Iridaceae & main chemical constituent of Crocus sativus is Crocetin. Extensive research has been conducted on Crocetin, and it has been shown that it can inhibit tumor promotion, has hepatoprotective activity, is antidiabetic, has antioxidative & anti-inflammatory activities, is useful in cardiac diseases and have antiapoptic activities. Protective effect of crocetin was evaluated in 2, 4, 6- trinitrobenzene sulfonic acid (TNBS) induced inflammatory bowel disease (IBD) in mice model. Treatment of TNBS induced (60 mg/ml in 30% ethanol) mice with crocetin (50 mg/kg/day) for 8 days significantly reduced the symptoms of IBD & regulates the various biochemical levels. Crocetin showed its protective effect in TNBS induced colitis by down regulation of NFkB.11 Curcuma longa Turmeric the common name for Curcuma longa (Figure 5) is an Indian spice derived from the rhizome of the plant and has a long history of use in Ayurvedic medicine as a treatment for inflammatory conditions. Curcuma longa is a perennial member of the



Zingiberaceae family and is cultivated in India & other parts of Southeast Asia.12 Curcuma longa Linn, is widely used as a food flavouring and colouring agent in the Asian diet. Its yellow colour is imparted by curcumin (diferuloylmethane), a polyphenolic pigment. Curcumin exhibit a variety of pharmacological effects including anti-inflammatory, antitumour, anti-HIV and anti-infectious activities. Protective effects of curcumin, an anti-inflammatory and antioxidant food derivative, was evaluated on 2, 4, 6- trinitrobenzene sulphonic acid-induced colitis in mice, a model for IBD. Dose – response studies revealed that pretreatment of mice with curcumin (50 mg/kg daily for 10 days) significantly ameliorated the appearance of diarrhoea and the disruption of colonic architecture. There was a significant reduction in the degree of both neutrophil infiltration (measured as decrease in myeloperoxidase activity) and lipid peroxidation (measured as decrease in malondialdehyde activity) in the inflamed colon. Curcumin also reduced the levels of nitric oxide (NO) and O2- associated with the favourable expression of Th1 and Th2 cytokines and inducible NO synthase. These findings suggest that curcumin or diferuloylmethane, a major component of the food flavor turmeric, exerts beneficial effects in experimental colitis and may, therefore, be useful in the treatment of IBD.13 Camellia sinensis Camellia sinensis (Tea) belongs to family Theaceae is one of the most commonly consumed beverages in the world (Figure 6). It is rich in polyphenolic compounds, collectively known as the tea flavonoids. It is native to mainland China, South and Southeast Asia, but it is today cultivated across the world in tropical and subtropical regions.14 Epigallocatechin gallate (EGCG) derived from Camellia sinensis provides protective effect in TNBS induced colitis. Pretreatment with EGCG (30 mg/kg for 10 days) significantly prevents the TNBS induced IBD in rats. EGCG ameliorate acute experimental colitis by suppression of superoxide generation from colonic tissue.15 Thyme vulgaris L. & Origanum vulgare L Thymus vulgaris L. (Thyme) (Figure 7) and Origanum vulgare L. (Oregano) (Figure 8) are aromatic plants of the Mediterranean flora commonly used as spices and for medicinal purposes. Both plants are belongs to family of Limiaceae. Thyme is traditionally used for its antiseptic, antispasmodic, and antitussive effects. Furthermore, thyme possesses antimicrobial, antifungal, antioxidative, and antiviral properties. The essential oil derived from thyme is a mixture of monoterpenes and one of the main compounds of this oil is a natural terpenoid thymol . Thymol exhibits multiple biological activities including

anti-inflammatory, immunomodulating, antioxidant, antibacterial, antifungal, and free radical scavenging properties. Oregano is recognized for its potential therapeutic role because of its diaphoretic, carminative, antispasmodic, antiseptic, and tonic properties. Oregano similar to thyme, evinces antioxidant and antimicrobial activities and some reports deal with its antimutagenic and anticarcinogenic effects. Oregano essential oil is obtained by steam distillation of O. vulgare and its major compounds are carvacrol and thymol. Oregano essential oil is known to possess antimicrobial, antifungal, and antioxidant activities. Combination of thyme and oregano essential oil (0.2% thyme and 0.1% oregano oils) significantly decreases the level of IBD in TNBS-induced colitis in mice. Administration of thyme oil in combination with oregano oil could be more effective in improvement of trinitrobenzene sulphonic acid (TNBS)-induced colitis than the separate administration of these essential oils.16 Aegle marmelos Aegle marmelos Linn. (Syn: Bilva, Family: Rutaceae) is distributed throughout the deciduous forests of India, ascending to an altitude up to 1200 m in the western Himalaya and also in Andaman Islands. Because of its use in worship, it has been cultivated all over, particularly in the vicinity of Shiva temples (Figure 9). It posses the various activities like hypoglycemic, spasmogenic, antiviral, cardiac stimulant, antiemetic, anthelmentic, antibacterial (seed oil), antidiarrhoeal, antioxidant & anti-inflammatory in various experimental animals. Aegle marmelos was tested for 2, 4 - dinitro benzene sulfonic acid (DNBS) induced colitis, and antioxidant activity was evaluated to clarify its possible mode of action. Experimental colitis was induced by DNBS (120 mg/kg) intrarectally. Methanolic fruit extract of Aegle marmelos (200 mg/kg) orally was given as a treatment for a 18 days & it was found that Aegle marmelos extract (200 mg/kg) was significantly effective against experimentally induce IBD.17 Ficus bengalensis Ficus bengalensis (Banyan tree), is a large tree with aerial Roots & it belongs to family Moraceae (Figure 10). It grows wild in lower Himalayas and is found all over India. Different parts of the tree have been found to possess medicinal properties: leaves are good for ulcers, aerial roots are useful in treating gonorrhea, seeds and fruits are used as cooling agent and tonic as well. The water extract of FB bark has been reported to possess hypocholesterolaemic and hypolipidaemic effects.18

Effects of ethanol extract of Ficus bengalensis Linn. bark (AEFB) were studied on 2,4,6-trinitrobenzenesulfonic acid (TNBS, 0.25 ml 120 mg/ml in 50% ethanol



intrarectally, on first day only) induced IBD in rats. The effects of co-administration of prednisolone (2 mg/kg) and AEFB (250, 500 mg/kg) for 21 days were evaluated. Animals sacrificed at end of the experiment and various histopathological parameters like colon mucosal damage index (CMDI) and disease activity index (DAI) were assessed. In the colon homogenate malondialdehyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD), and nitric oxide (NO) levels and in mesentery % mast cell protection was also measured. Rats treated with only TNBS showed more score of CMDI and DAI, higher MDA, NO, MPO, and lower SOD activity as compared to the control group. Treatment with AEFB significantly declined both indices scores and decreased the MPO, MDA, NO, and increased the SOD activity. AEFB also increased the % mast cell protection compared to alone TNBS-treated animals. AEFB has a significant protective effect in the IBD in rats that is comparable to that of prednisolone and may be because of the presence of flavonoids, terpenoids, and phenolic compounds.19 Brassicca oleraceae & Carica papaya Brassica oleracea (Kale) var. gongylodes (Brassicaceae) commonly known as Knol-Khol (Figure 11), kale is rich in the antioxidant vitamins C, E and carotene and are good sources of dietary fiber. They also contain sulphoraphanes and other isothiocyanates, which are believed to stimulate the production of protective enzymes in the body. Brassica oleraceae is reported as antihyperglycaemic & antioxidant agent.20 Carica papaya (Papaya) is a plant belongs to family of Caricaceae (Figure 12). The use of Carica papaya L. in traditional medicine relies on Papain. The active principle exerts an ulcer protective effect. The Carica papaya possesses antioxidant, antimicrobial & anti-inflammatory activities.21 Rats received, orally, 500 mg/kg of rat weight of three treatments of dried vegetables: papaya, kale and the mixture of both vegetables (60% of kale plus 40% of papaya) in TNBS induced colitis study. In the prebiotic study, after two weeks of treatment, bacteria counts were determined. In the anti-inflammatory study, after the two weeks of treatment, colitis was induced by intracolonic administration of TNBS, and one week after, damage score and biochemical parameters were evaluated. Only the administration of the mixture was able to modulate the bacterial flora in healthy rats, as well as in rats with colitis induced by TNBS. In addition, the mixture showed intestinal antiinflammatory effect in the colitic rats. This effect was evidenced by a reduction in damage score, by the colonic iNOS expression downregulated, by the decrease in the production of the TNFα and IL-1β

and by the decrease in the MPO activity. The combination of both vegetables showed prebiotic and anti-inflammatory effects in the TNBS model of rat colitis, when compared to each single vegetable alone.22 Glycyrrhiza glabra Glycyrrhiza glabra Linn. of the family Leguminosae (Figure 13), is a genus of perennial herbs and under shrubs distributed in the subtropical and warm temperate regions of the world, chiefly in the Mediterranean countries and China. The dried, peeled or unpeeled underground stems and roots constitute the drug known in the trade as liquorice. The roots and rhizomes possess demulcent, antiinflammatory, antistress, anti depressive and expectorant property and useful in the treatment of peptic ulcer.23 Diammonium Glycyrrhizinate (DG) is a one of the important constituent extracted and purified from Glycyrrhiza glabra. Diammonium Glycyrrhizinate Significantly (P < 0.01) reduces the inflammatory injury in acetic acid induced colitis in rats. This may occur via suppression of NF-κB, TNF-α and ICAM-1 in colonic mucosa.24 REFERENCES 1. Sartor RB. Current concepts of the etiology and pathogenesis of

Ulcerative colitis and Crohn's disease. Gastroenterol Clin North Am 1995; 24:475-85.

2. Desai HG, Gupta PA. Increasing incidence of Crohn's disease in India: Is it related to improved sanitation? Indian J Gastroenterol 2005; 24:23-4.

3. Panwala CM, Jones JC, Viney JL. A novel model of inflammatory bowel disease: mice deficient for the multiple drug resistance genes, mdr1a, spontaneously develop colitis. J Immunol 1998; 161:5733-44.

4. Papadakis KA, Targan SR. The role of chemokines and chemokine receptors in mucosal inflammation. Inflamm Bowel Dis 2000; 6:303-13.

5. Perner A, Nordgaard I, Matzen P. Colonic production of nitric oxide gas in Ulcerative colitis, collagenous colitis and uninflamed bowel. Scand J Gastroenterol 2002; 37:183-8.

6. Hanauer SB, Meyers S. Practice guidelines: management of Crohn’s disease in adults. Am J Gastroenterol 1997; 92:204-11.

7. Sharma PC, Yelne MB, Dennis TJ. Database on Indian Medicinal Plants used in Ayurveda, 2005; 1:177-82.

8. Darji VC, Bariya AH, Deshpande SS, Patel DA. Effect of Punica granatum fruits in inflammatory bowel disease. Journal of Pharmacy Research 2010; 3(12):2850-2.

9. Lin-Hua Wu, Zeng-Lai Xu, Di Dong, Shan-An He, Hong Yu. Protective Effect of Anthocyanins Extract from Blueberry on TNBS-induced IBD Model of Mice. eCAM 2010; 1-8.

10. Deshmukh CD, Veeresh B, Pawar AT. Protective effect of Emblica officinalis fruit extract on Acetic acid induced Colitis in rats. Journal of Herbal Medicine and Toxicology 2010; 4(2):83-7.

11. Hamid AK, Zhiyu Q. Crocetin reduces TNBS-induced experimental colitis in Mice by downregulation of NFkB. Saudi J Gastroenterol 2009; 15(3):181-7.

12. Julie SJ. Anti-inflammatory properties of Curcumin- A major constituent of Curcuma longa: A review of preclinical and



clinical research. Alternative Medicine Review 2009; 14(2):141-53.

13. Ukil A, Maity S, Karmakar S, Datta N, Vedasiromoni JR , Pijush KD. Curcumin, the major component of food flavour turmeric, reduces mucosal injury in trinitrobenzene sulphonic acid-induced colitis. British J Pharmacology 2003; 139:209-18.

14. Das D, Mukherjee S, Mukherjee M, Das AS, Mitra C. Aqueous extract of black tea (Camellia sinensis) prevents chronic ethanol toxicity Current Science, 2005; 88(6):952-61.

15. Miyako M, Noboru H. Protective effect of Epigallocatechin gallate on acute experimental colitis. J of Health Science, 2005; 51(3):362-4.

16. Alexandra B, Stefan C, Stefan J, Gabriela I, Pavol R, Juraj K. Effects of a Combination of Thyme and Oregano Essential Oils on TNBS-Induced Colitis in Mice. Mediators Inflamm, 2007; 2007:23296.

17. Gandhi TR, Darji VC, Solanki RP, Patel KV. Effect of Aegle marmelos Linn. (Rutaceae) fruits in inflammatory bowel disease. Indian drugs, 2009; 46(6):460-4.

18. Mahalingam G, Krishnan K. Antidiabetic and ameliorative potential of Ficus bengalensis bark extract in Streptozotocin induced diabetic rats. Indian J Clin Biochem, 2008; 23(4):394-400.

19. Manish AP, Paras KP, Manish BP. Effects of ethanol extract of Ficus bengalensis (bark) on inflammatory bowel disease. Indian J of Pharmacology, 2010; 42(4):214-8.

20. Rasal VP, Shetty BB, Sinnathambi A, Yeshmaina S, Ashok P. Antihyperglycaemic And Antioxidant Activity Of Brassica Oleracea In Streptozotocin Diabetic Rats. The Internet J of Pharmacology. 2006; 4(2).

21. Shivananda BN, Lexley PP, Dala M. Wound healing property of Carica papaya L. in experimentally induced diabetic rats. Indian J of Exp Biology, 2007; 45:739-43.

22. Cibele LA, Monica C, Desiree C, Maria ER et al. Effect of kale and papaya supplementation in colitis induced by trinitrobenzenesulfonic acid in the rat. The European e-journal of clinical nutrition & metabolism 2010; 5(3):111-6.

23. Muralidharan P, Balamurugan G, Venu Babu. Cerebroprotective effect of Glycyrrhiza glabra Linn. root extract on hypoxic rats. Bangladesh J Pharmacol 2009; 4: 60-4.

24. Hao Yuan, Wan-Sheng Ji, Ke-Xiang Wu, Jian-Xin Jiao et al. Anti-inflammatory effect of Diammonium Glycyrrhizinate in a rat model of ulcerative colitis. World J Gastroenterol 2006; 12(28):4578-81.

Table 1: Natural agents proved in IBD

Sr No. Name of the plant Common

Name Family Part Used Imp. Chemical Const.

1. Punica granatum Dadima Punicaceae Fruit Ellagic & Gallic acid,

2. Vaccinium ashei Blueberry Ericaceae Fruit Anthocyanins

3. Emblica officinalis Amla Euphorbiaceae Fruit Vitamin C

4. Crocus sativus Saffron Iridaceae Flower Crocetin

5. Curcuma longa Turmeric Zingiberaceae Rhizome Curcumin

6. Camellia sinensis Tea Theaceae Leaves Epigallocatechin

7. -Thyme vulgaris L. -Origanum vulgare L.

-Thyme -Oregano Limiaceae Leaves &

Flowers -Thymol - Carvacol

8. Aegle marmelos Bilva Rutaceae Fruit Marmelosin, Tannic acid

9. Ficus bengalensis Banyan tree Moraceae Bark Tannins

10. -Brassicca oleraceae -Carica papaya

-Kale -Papaya

-Brassicaceae -Caricaceae

-Leaves -Fruit

-Norisoprenoids -Papain

11. Glycyrrhiza glabra Liquorice Leguminosae Root Diammonium glycyrrhizinate

12. Ginkgo biloba Maidenhair Tree Ginkgoaceae Leaves Flavanoid glycosides,

Ginkgolides

13. Polygala vulgaris Polygalae Polygalaceae Root Saponins

14. Rheum tanguticum Rhubarb Polygonaceae Root Resin, Tannic & Gallic acid

15. Royal jelly Royal jelly --- Jelly B-complex vitamins

16. Coptidis japonica Japanese goldtread Ranunculaceae Rhizome Berberine

17. Propolis --- --- Wax Resin, Wax

18. Natural Honey --- --- Honey Glucose, Fructose



Figure 1: Punica granatum (Punicaceae) Figure 5: Curcuma longa (Zingiberaceae) Figure 9: Aegle marmelos (Rutaceae)

Figure 2: Vaccinium ashei (Ericaceae) Figure 6: Camellia sinensis (Theaceae) Figure 10: Ficus bengalensis (Moraceae)

Figure 3: Emblica officinalis (Euphorbiaceae) Figure 7: Thyme vulgaris L. (Limiaceae) Figure 11: Brassicca oleraceae (Brassicaceae)

Figure 4: Crocus sativus (Iridaceae) Figure 8: Origanum vulgare L. (Limiaceae) Figure 12: Carica papaya (Caricaceae)

Documents

Available online through - IJRAP · Crocus sativus (Common name: Saffron) is a native of south Europe and is cultivated in Spain, France, Italy, Greece, India and China (Figure 4)