Fumaria indica L.

Scientific Name: Fumaria indica L. Synonyms: Fumaria parviflora auct. Non Lam. Burkill, Fumaria parviflora ssp. vaillanii (Lois.) Hook.f. & Thomas, Fumaria vaillanii var. indica Hausskn. Family: Subfamily: Fumarioideae Tribe: Fumarieae Subtribe: Fumariinae Genus: Fumaria Specie s: indica Common Name: Fumaria, Pitpapra, Shahtrah, Common fumitory Part used: whole plant Plant Description: Fumaria indica is a delicate much-branched annual herb with clusters of tiny pale-pinkish to whitish flowers, each 5-6 mm long. Sepals are minute. Upper petal has short, somewhat down-curved sac-like spur. Flower-stalks are erect, as long as or slightly shorter than the lace-shaped bracts. Leaves are 2-3 times cut into narrow pointed segments, about 1 mm broad. Stems are glaucous, leafy, 5-30 cm long. Fruit is round, about 2 mm. Chemical Constituents: narceimine, (-)-tetrahydro-, narlumidine, methyl fumarate, , bicuculine, and fumariline. Papraine, Fumarizine, Papracinine, Paprarine, Paprafumine, Papracine, Papraline, Paprazine, Noroxyhydrastinine, Oxy-hydrastinine, 3-N- methylo-corydaldine, Fumariflorine, Stylopine, Cryptopine, 8-oxocoptisine, Bisnorargemonine, Lastourvilline, (-)-β-hydrastine, N-methylhydrastine, Fumaramine, Parfumine, Fumaritine, Fumaritine N-oxide, N-Feruloyltyramine. Structures of chemical constituents of Fumaria indica L.

Narceimine (-)-Tetrahydrocoptisine Methyl fumarate

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Protopine Bicuculine Fumariline

Fumaritine N-Feruloyltyramine Stylopine

Cryptopine Noroxyhydrastinine

Actions of Herb: Anti-inflammatory, Anti-nociceptive, anthelmintic, antipyretic, hepato- protective , hypoglycemic, antidyspeptic, blood purifier, cholagogue, diaphoretic, sedative, antifungal, anti-periodic, carminative, restorative, anti-infective, appetizer, aperient. Medicinal Uses: It is used in the treatment of constipation, diarrhea, fevers and blood disorders.Its use is also been recommended in case of chronic skin diseases, urinary diseases and cough.It is used in syphilis, scrofula, leprosy, gall bladder disease and given in ague and jaundice. The plant is used to purify blood in cutaneous disease and liver obstruction. Externally used for the treatment of boils, sores and abscesses due to its mucilage content. Side Effects: GI complaints, flushing, bleeding, drowsiness, sedation, eye problem, trembling, convulsions, death. Contraindications: Pregnancy and lactation; long treatments are contraindicated, cardiovascular diseases, respiratory diseases, epilepsy, glaucoma, biliary tract infection, gall stones, jaundice. Dosage: Plant can be taken as an infusion 2-4 g per 200 ml of water, thrice a day. Do not prolong the treatment more than 15 days. To treat muscle spasms associated with stomach and intestinal disorders, 250-milligram capsules have been taken by mouth. To treat skin problems, a 1:5 tincture of Fumaria in 25% alcohol has been taken by mouth in doses of 1-2 milliliters three times daily. Doses of 1-4 milliliters of a 1:5 liquid extract of

254 Fumaria in a 45% alcohol solution have been taken by mouth. Various topical preparations containing Fumaria have been applied to the skin. To treat irritable bowel syndrome, 1,500 milligrams of Fumaria has been taken daily in three divided doses for 18 weeks. Drug interactions Interactions with Drugs : Fumaria may increase the risk of bleeding when taken with drugs that increase the risk of bleeding. Some examples include aspirin, anticoagulants (blood thinners) such as warfarin (Coumadin®) or heparin, antiplatelet drugs such as clopidogrel (Plavix®), and nonsteroidal anti-inflammatory drugs such as ibuprofen (Motrin®, Advil®) or naproxen (Naprosyn®, Aleve®). Fumaria may increase the amount of drowsiness caused by some drugs. Examples include benzodiazepines such as lorazepam (Ativan®) or diazepam (Valium®), barbiturates such as phenobarbital, narcotics such as , some antidepressants, and alcohol. Caution is advised while driving or operating machinery. Fumaria may also interact with acne medication, agents that may treat muscle spasms, anticancer agents, antifungal agents, anti-inflammatory agents, anti-parasitic, antipyretics (agents that may reduce fever), antiviral agents, central nervous system (CNS) depressants, cholinesterase inhibitors, and heart health agents. Interactions with Herbs and Dietary Supplements Fumaria may increase the risk of bleeding when taken with herbs and supplements that are believed to increase the risk of bleeding. Multiple cases of bleeding have been reported with the use of Ginkgo biloba , and fewer cases with garlic and saw palmetto. Numerous other agents may theoretically increase the risk of bleeding, although this has not been proven in most cases. Fumaria may increase the amount of drowsiness caused by some herbs or supplements. Fumaria may also interact with acne-treating herbs and supplements, anticancer herbs and supplements, antifungal herbs and supplements, anti-inflammatory herbs and supplements, anti- parasitic herbs and supplements, antipyretics (herbs and supplements that may reduce fever), central nervous system (CNS) depressants, cholinergics, heart health herbs and supplements, and herbs and supplements that may treat muscle spasms. Physico-chemical parameters of the study drugs Physico-chemical parameters like foreign matter, moisture content (Loss on Drying), pH, total ash, acid insoluble ash, water soluble extractive, alcohol soluble extractive values of F. indica were determined. Table: Physico-chemical parameters of Fumaria indica

Parameter F. indica pH value 6.5 Loss on drying 12.036 % Ash value 24.962 % Acid insoluble ash 5.530 % Water soluble extractive value 29.571% Alcohol soluble extractive value 17.661 % Proshanta M, Harisha CR, Shukla VJ.A comparative pharmacognostical & phytochemical study on different plant sources of Parpatak. 2014. World Journal of Pharmaceutical Research. 3(4): 1531-1548 .

255 Macroscopic characteristics The drug consists of crumpled stems and leaves. The dried leaves and stems are dull green in color and on crushing emit peculiar pungent odor and bitter taste. Stem is herbaceous, branched, angular and striated longitudinally. Leaves are simple and divided into narrow and flat segments. Leaf margin is entire with acuminate apex. Fruit is a nut globose and one-seeded. Microscopic characters Stem: Transverse section of stem shows single layer of epidermis covered by thin cuticle. One to three layered collenchymatous cells are present beneath the epidermal layer. Cortical parenchyma consists of several layers of polygonal cells. Patches of sclerenchymatous cells are present in the cortical region. Conjoint collateral and open vascular bundles are arranged in a ring. Parenchymatous pith is present in the center of stem.

Figure: Transverse section of stem Proshanta M, Harisha CR, Shukla VJ.A comparative pharmacognostical & phytochemical study on different plant sources of Parpatak. 2014. World Journal of Pharmaceutical Research. 3(4): 1531-1548. Leaf petiole: The transverse section of the leaf cetiole shows that the outermost surface of epidermal layer is covered with thin cuticle. Epidermis is followed by 2- 3 layers of collenchymatous cells. Below the collenchymatous layers spongy parenchyma with small air spaces is present. Ranunculaceous stomata are present in the epidermis. Stele shows separate vascular bundles consisting of xylem and phloem tissues. Leaf: Transverse section of leaf shows that epidermis consists of single layer of parenchymatous cells covered with thin cuticle. Below the epidermi mesophyll is differentiated into 1-2 layered palisade parenchyma and 2-3 layered loosely arranged spongy parenchyma with small intercellular spaces. Conjoint collateral vascular bundles are present in the center of midrib and are enclosed in several layers of parenchymatous cells. Ranunculaceous stomata are present epidermis.

Figure: Transverse section of Leaf petiole × 80. B. A portion of Leaf lamina × 60

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Figure: Transverse section of leaf through mid-rib Proshanta M, Harisha CR, Shukla VJ.A comparative pharmacognostical & phytochemical study on different plant sources of Parpatak. 2014. World Journal of Pharmaceutical Research. 3(4): 1531-1548. Root: Transverse section of the root revealed circular outline. 2-4 layers of cork cells and cortex cells 4-6 layered. Endodermis was not distinct; secondary phloem was well developed and consisted of sieve tube, companion cells and phloem parenchyma; central core of F. indica root revealed a wide zone of xylem comprising of vessels, tracheids and fibers. Vessels were found in radial rows having reticulate and spiral thickening, medullary ray were observed to be broad and radiating, fibers moderately long, thick walled, having narrow lumen and blunt tips.

Figure: TS section of root Proshanta M, Harisha CR, Shukla VJ.A comparative pharmacognostical & phytochemical study on different plant sources of Parpatak. 2014. World Journal of Pharmaceutical Research. 3(4): 1531-1548. Powdered drug of stem is yellowish green in color with unpleasant odor and bitter taste. Distinguishing microscopic characters are epidermis with thin cuticle, thick walled collenchymatous cells and polygonal parenchymatous cells. Annular and spiral vessels are also seen in the powdered drug. Powdered drug of leaf is dull green in color with pungent odor and bitter taste. Microscopic study shows epidermis with ranunculaceous stomata, parenchymatous cells, palisade parenchyma and vasicentric parenchymatous cells. Spiral, pitted and annular vessels are also seen in the powdered drug .

Figure: Powdered drug of Fumaria indica Stem × 250A. Epidermis with thin Cuticle, B. Collenchymatous cells, C. Sclerenchymatous cells, D. Parenchymatous cells, E. Annular vessel, F. Spiral vessel

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Figure: Powdered drug of Fumaria indica Leaf × 250 A. Epidermis with Ranunculaceous Stomata, B.Parenchymatous cells, C. Palisade Parenchyma with Epidermis, D. Vasicentric Parenchymatous cells in longitudinal view, E. Spiral vessel, F. Pitted vessel, G. Annular vessel

Proshanta M, Harisha CR, Shukla VJ.A comparative pharmacognostical & phytochemical study on different plant sources of Parpatak. 2014. World Journal of Pharmaceutical Research. 3(4): 1531-1548. Chemical Identification Tests The presence of different chemical constituents in rhizome of F. indica, identified by reactions with various chemical reagents was triterpenes, tannin, and carbohydrate. Table: Chemical Identification Tests of F. indica Chemical Constituents F. indica Alkaloids ++ Anthraquinone glycosides - Carbohydrates + Cardiac glycosides - Coumarin glycosides +++ Flavonoids + Tannins ++ Terpenoids + Note: + = present; ++ = moderately present; +++ = abundantly present; - = absent Proshanta M, Harisha CR, Shukla VJ.A comparative pharmacognostical & phytochemical study on different plant sources of Parpatak. 2014. World Journal of Pharmaceutical Research. 3(4): 1531-1548. Thin layer Chromatography of F. indica extract Thin layer chromatography of F. indica extract was performed in two different solvent systems. In ethylacetate-methanol-water solvent system in the ratio of 100:16.5:13.5 (254nm: 0.131, 0.47, 0.69; 366nm: 0.20, 0.31, 0.45, 0.63, 0.71) and chloroform-methanol-water in the ratio of 80:20:2 (254nm: 0.048, 0.47, 0.59; 366nm: 0.042, 0.38, 0.62, 0.72) solvent systems. The TLC plates were observed under UV light at 254 and 366 nm. The distances of spots are measured after spraying with Vanillin-Sulphuric acid reagent.

Figure: TLC plates of F. indica under 254 and 366 nm UV Light.

258 Figure; Fourier Transform Infra-red Spectroscopy of F. indica extract

Figure: High Performance Liquid Chromatography of F. indica extract

Analgesic Activity In acetic acid induced writhing test Aspirin as 300 mg/kg orally was used as a reference compound. The crude extract of F. indica showed significant dose related inhibition of number of writhes. In vehicle treated (control) animals mean number of writhes induced by intra- peritoneal injection of acetic acid was 131, which was reduced to 72.8, 55, and 48.9 in animals treated with 200, 300 and 500 mg/kg oral doses of the test substance respectively. The results of writhing test were highly significant and comparable with aspirin, which produced 40.4 writhes. The % inhibition of writhes with the 200, 300 and 500 mg/kg doses of crude extract were 44.4 %, 58.01% and 62.7 % whereas with aspirin it was 71.11 %. In the hot plate activity of crude extract of F. indica dose dependent increase in the tail flick time was observed. It showed highly significant result at 500 mg/kg (at 3 rd hour tail flick time of 500 mg/kg crude extract was 0.45 seconds and Aspirin 300 mg/kg showed 0.33 seconds). Table: Acetic acid induced writhing test in crude extract of Fumaria indica Treatment Dose(mg/kg) Mean No. of writhes % of inhibition Control 0.5ml saline 131±3.38 - Crude Extract 200 55±1.96 44.42* Crude Extract 300 48.9±2.16 62.7 Crude Extract 500 72.8±3.36 58.01 Aspirin 300 40.4±1.27 64.2* Each value is the mean ± S.E.M. of five determinations. * P < 0.05, Dunnet test as compared to control

259 Table: Hot plate activity of crude extract of Fumaria indica variation in flicking time Group 0 1 2 3 Control 0.19±0.014 >0.22 >0.22 >0.22 500 0.19±0.04 0.35±0.05 0.41±0.06 0.45±0.01* 300 0.20 ±0.03 0.31±0.02 0.36±0.04 0.33±0.04 200 0.19±0.06 0.32±0.04 0.30±0.04 0.28±0.07 100 0.19±0.04 0.26±0.03 0.22±0.02 0.19±0.05 50 0.20±0.03 0.23±0.03 0.22±0.03 0.18±0.02 Aspirin 0.18±0.02 0.39±0.03* 0.44±0.04* 0.33±0.08 Each value is the mean ± S.E.M. of five determinations. * P < 0.05, Dunnet test as compared to control Gross behavior and Neuro-pharmacological activity: In gross behavior activity of F. indica crude extract showed decrease in the motor activity and slight irritation at 500 mg/kg. Table: Behavioral profile of Fumaria indica Parameters Dose mg/kg Diazepam Imipramine 500 300 200 100 2mg/kg 10mg/kg Nystagmus +3 +2 +1 +2 +1 - Vocalization ------Piloerection +1 +1 - - - + Micturition + + + - - + Irritability +2 + - - - - Disorientation/Staggeringgate + - - - - + Aggressiveness + + +s - - +s Motor activity(Decrease) +2 + + + + - Pain response + + + + + + Ataxia - - - - - + Tail erection + + - - - + Tremor +1 - - - - +2 In all neuro-pharmacological tests Diazepam as 2 mg/kg and Imipramine were used as the reference drugs. Crude extract of F. indica was tested in three doses as 200, 300 and 500 mg/kg orally. The control group was treated with 0.5 ml saline orally. Mean number of squares crossed by the rats with all the four paws was 159.8 for control group, 91, 115 and 121 for 500, 300 and 200 mg/kg of crude extract of F. indica respectively and 31 for diazepam. This showed that the open field activity was diminished, which postulates that the test substance has passive and sedative activity. The results were more significant at 500 mg/kg oral dose of F. indica . In Exploratory activity there was significant decrease in the head dip response at 500 mg/kg. Drug treated animals showed passive mood and decreased activity. Like open field and head dip test the activity was also decreased in cage cross and rearing test. Diazepam showed an average of 09 and 14 numbers of cage cross and rearing activities whereas with 500, 300 and 200 mg/kg oral doses of crude extract the mean number of cage cross activity was 15, 17 and 20 respectively. The mean number of rearing activity for control group was 39.17. Time taken to travel iron rod was significantly increased, which shows muscle relaxant activity of F. indica. The mean time taken to travel iron rod by control group was 22 seconds, which was

260 increased to 28 seconds in animals treated with 500 mg/kg of crude extract. The mean time of animals treated with 300 and 200mg/kg of F. indica was 50and33seconds respectively The mean activity time in water tub of animals treated with F. indica (2.41 minutes for 500 mg/kg and 2.56 minutes for 300mg/kg and 2.34 minutes for 200 mg/kg) and diazepam (2.52 minutes) was decreased as compared to the control group (3.45 minutes). This finding intimates that F. indica possesses both sedative and muscle relaxant activities. Table: Assessment of Neuro-pharmacological activities Fumaria indica Treatmen Dose Open field Head Cage Rearing Mobility Tractio t mg/kg dip cross test (min) time(sec) n test orally Control 0.5ml 159.8±4.6 34±3.75 35. 7±1.54 39.17±0.9 3.45±1.1 22 ±0.05 3 2 Crude 500 91±3.85 15±2.56 15±2.56 15.17±1.5 2.41±1.4 28± 0.07 Extract 1 5 Crude 300 115±2.34 20±2.24 17± 2.58 31± 0.51 2.56±1.0 50±0.02 Extract 3 Crude 200 121±2.34 18± 1.14 20±1.71 12±1.52 2.34±1.0 33±1.13 Extract 1 Diazepam 2 31±2.12 05±0.09 09±1.12 14±1.12 2.1±1.3 180±3.1 2 Imipramine 15 166±3.2 45±1.42 39±1.6 55±2.5 4.4±2.1 06±0.09

Smooth muscle relaxant activity The major of F. indica , Protopine (0.5-5.0 g/ml) produced a moderate to marked relaxation of the separated ileum of guinea-pig, rabbit and albino rat in vitro . Hepato-protective activity F. indica exhibited hepato-protective activity against carbon tetrachloride, paracetamol and rifampicin induced heptatotoxicity in albino rats. The petroleum ether extract of F. indica against carbontetrachloride, total aqueous extract of F. indica against paracetamol, and methanolic extract of F. indica against rifampicin induced hepatotoxicities revealed decline in the elevated levels of the biochemical parameters in a manner similar to that of silymarin showing its probable hepato-protective agent. Spasmogenic and spasmolytic effect The crude extract of F. indica contains cholinergic and calcium channel blocker constituents, due to which it exhibits spasmogenic and spasmolytic effects invitro that may support the use of F. indica for the treatment of constipation and diarrhea in complementary and alternative system of medicine. Anti-inflammatory activity F. indica extract revealed significant dose dependent anti-inflammatory activity in acute and chronic cotton models of inflammation in experimental animals. Anti-bacterial activity F. indica exhibited significant antibacterial activity against certain bacterial strains like Enterobacter aerogenes , Escherichia coli , Klebsiella pneumonia , Proteus mirabilis , Proteus vulgaris , and Salmonella typhimurium . F. indica showed lower anti-fungal activity as compared to its anti-bacterial activity against following fungal strains A. flavus , C. albicans and C. kruesie .

261 Table: Anti-microbial activity of Fumaria indica extract

Table: The minimum inhibitory and minimum bactericidal concentration of F. indica methanolic extract

Khan A, Tak H, Nazir R, Lone BA, Parray JA. 2014. In vitro Anthelmintic and Antimicrobial of Methanolic Extracts of Fumaria indica . Clin Microbial 3(5): 1-5. F. indica showed significant anti-fungal activity against spore germination of some plantpathogenic fungi like Alternaria , Collectotrichum and Curvularia species. Anti-oxidant activity The anti-oxidant potential of F. indica was assessed by four methods: DPPH free radical scavenging activity, total anti-oxidant activity, FRAP assay and ferric thiocyanate assay along with determination of their total phenolics. 83.41± 1.23% inhibition of DPPH radical was observed at 250 g/ml concentration of ethyl acetate soluble fraction of F. indica . The IC50 of the same fraction was found 79.15±0.87 g/ml; highest total anti-oxidant activity (1.029±0.08); highest FRAP value (249.66±1.83 g of trolox equivalents); highest total phenolic contents (123.23±0.41) as well as highest value of inhibition of lipid peroxidation, that is, 51.16±1.48% at concentration of 500 g/ml. Clinically proven efficacy of F. indica F. indica is used in Europe for treatment of chronic eczema and psoriasis. German Commission E recommends its use due to its spasmolytic activity for alleviating gastro-intestinal and liver disorders (Fumitory. Bundesanzeiger, no 173. Cologne, Germany, 1986).

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