Sphaeranthus indicus belongs to the family Asteraceae. It is also known as Gorakhmundi. It is a highly branched, strongly-scented annual herb with winged stem and toothed wings. Leaves are obovate-oblong, narrowed at the base, dentate and serrate. Flowers are compound heads, globose ovoid. The flowering time spans from November to January in Indian conditions. The medicinally useful parts are root, bark, leaves, flowers, and seeds.
The flowering and fruiting heads of the plant, Sphaeranthus indicus contains 3a-hydroxy-5a,9-dimethyl-3-methylene-3a,4,5,5a,6,7,8,9b-octahydro-3H-naphtho[1,2-b]furan-2-one (7-α-Hydroxy-4,11(13)-eudesmadien-12,6-olide or 7-hydroxyfrullanolide) as a major compound. It strongly inhibits pro-inflammatory cytokines.
Several other compounds have been reported from Sphaeranthus indicus like methyl chavicol, α-ionone, δ-cadinene, p-methoxycinnamaldehyde as major constituents and α-terpinene, citral geraniol, geranyl acetate, β-ionone, sphaerene, indicusene and sphaeranthol as minor constituents of essential oil (Perfum. Essent. Oil Record. 1959, 50, 765; Chem. Abstr. 1960, 54, 798Og); 7α-hydroxyeudesm-4en-6,12-olide, its β-isomer, dihydrolactone, a new sesquiterpene acid, 2-hydroxycostic acid, β-eudesmol and illicic acid (Jayant S. Sohoni et J. Chem, Soc., Perkin Trans, 1, 1988, 157-160); Eudesmanoids like 11-alpha-13-dihydro-3alpha,7alpha-dihydroxy-4,5-epoxy-6 beta,7-eudesmanolide, 11 alpha,13-dihydro-7alpha-acetoxy-3beta-hydroxy-6beta,7-eudesm-4-enolide and 3-keto-beta-eudesmol (Pujar P P et al, Fitoterapia. 2000 June; 71(3):264-8) and a sesquiterpene glycoside (Shekhani M S et al, 1990; Phytochemistry 29, 2573-2576).
Some of the non-patent literature of Sphaeranthus indicus is quoted below:
In a study evaluating the anti-inflammatory effects of Rubia cordifolia, Curcuma longa, Hemidesmus indicus, Azadirachta indica and Sphaeranthus indicus, Sphaeranthus was found to be more potent in suppressing the proinflammatory cytokines interleukin-8 (IL-8) and tumor necrosis factor α (TNF α) induced by the culture supernatant of Propionibacterium acnes in polymorphonuclear leukocytes (PMNL) and monocytes [Jain A et. al.; Phytomedicine. 2003 January; 10(1):34-8].
The petroleum ether extract from the flower heads of Sphaeranthus indicus Linn was found to be effective in increasing phagocytic activity, hemagglutination antibody titer and delayed type hypersensitivity when tested in mice. The petroleum extract showed a dose-response relationship. It was found that 200 mg/kg dose was the optimum dose. Sphaeranthus acts as an immunomodulatory agent, by stimulating both humoral and cellular immunity as well as phagocytic function. [Bafna A R et. al; J Herb Pharmacother. 2007; 7(1):25-37].
In a study, the effect of aqueous extract of Sphaeranthus indicus (300 mg/kg/day, i.p) against dexamethasone (10 mg/kg/day, s.c) induced changes in lipid profile in rat was investigated. S. indicus showed significant decrease in serum total cholesterol, triglyceride, LDL, VLDL and there was no significant change in the level of HDL. Atherogenic index also reduced significantly after S. indicus treatment thus indicating that, S. indicus has a potential lipid lowering effect [Tenpe C R et al; Biomed. Vol. 02 (4), 2008; 400-403].
Recently, in another study, the antihyperglycaemic effects of Sphaeranthus indicus in rats rendered diabetic by nicotinamide [120 mg kg(−1) i.p.] and streptozotocin (STZ) [60 mgkg(−1) i.p] was investigated. Oral administration of S. indicus for 15 days resulted in significant decrease in blood glucose levels and increases in hepatic glycogen and plasma insulin levels. Fasting normal rats treated with the alcoholic extract of S. indicus showed significant improvement in oral glucose tolerance test. Glibenclamide was used as a reference standard [Prabhu K S et al; J Pharm Pharmacol. 2008; 60(7): 909-16].
None of the above literature describes the amelioration of metabolic syndrome related biomarkers or its therapeutic effects against metabolic syndrome or disease conditions associated with metabolic syndrome by Sphaeranthus indicus. 
Aqueous extract of Sphaeranthus indicus has been used in Tenpe C R et al study, which do not contain significant quantities of 7-hydroxyfrullanolide, whereas the present inventive compositions contain lipophilic extract comprising 7-hydroxyfrullanolide as active compound. Hence the inventive compositions are different from those used in the Tenpe C R et al study. Similarly, alcoholic extract of roots and stolons has been used in Prabhu K S et al's study. However, the present inventive compositions are derived from flower heads, which contain predominantly 7-hydroxyfrullanolide and hence are different from those used in the Prabhu K S et al's study.
Some of the Patent literature of Sphaeranthus is quoted below:
PCT Publication WO07036900A2 relates to a novel herbal composition comprising an extract of flowering and fruiting heads of the plant, Sphaeranthus indicus containing 3a-hydroxy-5a,9-dimethyl-3-methylene-3a,4,5,5a,6,7,8,9b-octahydro-3H-naphtho[1,2-b]furan-2-one (7-Hydroxy-4,11(13)-eudesmadien-12,6-olide), as a bioactive marker. The said invention also relates to methods of manufacture of the said compositions.
Japanese Patent Publication JP07138180A2 relates to inhibitor of hyaluronidases containing an extract separated from at least one herb selected from the group consisting of Azadirachta indica, Cymbopogon nardus, Murraya koenigii, Sphaeranthus indicus, Ocimum sanctum, Tinospora cordifolia and Phyllanthus nuriri and its use as a cosmetic capable of preventing aging and preventing fine wrinkles and dryness of the skin.
PCT Publication WO06134609A2 discloses herbal anticancer agent comprising the extract of plant Sphaeranthus indicus or group of compounds obtained from the plant Sphaeranthus indicus. It also discloses a pharmaceutical composition comprising the said agent, methods for preparing the composition, methods of treating all kinds of cancer in mammals including human beings, methods of making the plant extract and methods for obtaining the active constituents.
PCT Publication WO06016228A2 relates to a compound or group of compounds present in an active principle derived from plants of the species Sphaeranthus, for the preparation of pharmaceutical formulations or food supplements for the prophylaxis and/or treatment of tumor diseases. The said invention furthermore relates to a novel method for the isolation of an active principle from Sphaeranthus plant parts which are effective in prophylaxis and/or treatment of cancers.
U.S. Pat. No. 7,344,738 provides pharmaceutical or medicinal preparation comprising a combination of two herbal compositions, including one comprising a mixture of the following herbs: Moringa oleifera, Boerhavia diffusa, Onosma bracteatum, Bauhinia variegata, Spheranthus indicus, Tecomella undulata, Chlorophytum borivilianum, Ficus racemosa, and Cyperus rotundus, or a mixture of the active ingredients that have been extracted from those herbs or chemically synthesized. The herbal preparation is effective for the treatment of a wide range of physiological and pathological conditions in the human body resulting from a weakened or deteriorating immune system.
Garcinia mangostana which is also used in the present novel composition belongs to the family Guttiferae. Garcinia consists of roughly 300 species of dioecious trees and shrubs distributed into South America (where they are also known as Rheedia), Africa, Madagascar, and Southeast Asia. Most of the species diversity in the genus is centered in Malaysia, with over two-thirds of the species in the genus being found there [http://www.mobot.org/MOBOT/Research/mangosteen/].
Mangostins are a major class of compounds in Garcinia mangostana. The structure of mangostin was established by Peter Yates et al. [Peter Yates, George H. Stout; J. Am. Chem. Soc.; 1958; 80(7); 1691-1700].
Several pharmacological activities have been reported for mangosteen like anti-inflammatory [Gopalakrishnan C et al., Indian J Exp Biol. 1980 August; 18(8):843-6], histaminergic and a serotonergic receptor blocking agent [Chairungsrilerd N et al., Planta Med. 1996 October; 62(5):471-2], anti-cancer agent [Ee G C et al., J Asian Nat Prod Res. 2008 May; 10(5):481-5], Anti-microbial [Sundaram B. M., et al.; Planta Med. 1983; 48:59-60], etc. and a lot of research is being conducted for exploring new activities.
Some of the non-patent literature of Garcinia is described below:
In an assay guided fractionation study, the different fractionations from lipophilic to hydrophilic using combined solvent extraction and Amberlite XAD2 adsorption chromatography was studied. The mangosteen pericarps extracts have been tested for alpha-amylase inhibition activity and it was concluded that xanthones does not have any inhibiting activity but the Oligomeric Proantho Cyanidins from the hydrophilic fraction are reported to be 56 times more effective in inhibiting alpha-amylase. [Eng Kiat Loo A, Huang D.; J Agric Food Chem. 2007 sNov 28; 55(24):9805-10].
It is of importance to know that in the above stated study [Eng Kiat Loo et al, 2007], the alpha-amylase inhibitory activity was attributed to oligomeric proantho cyanidins. It was further stated that xanthone fraction did not have any alpha-amylase inhibition activity. Hence the active compound(s) responsible for the activity of the extracts or fractions of this prior art article are different from those of the present invention.
In another study the investigators determined Aldose Reductase (ALR2) inhibitory effect of G. mangostana. α-Mangostin was found to be potent against ALR2. It was concluded that α-mangostin might be useful in preventing diabetic complications [Sri Fatmawatia et al., Biology, Chemistry, Pharmacology and Clinical Studies of Asian Plants Apr. 9-11, 2007, Surabaya, Indonesia].
A cursory review of prior art reveals that, there is no knowledge relating to the use of the composition comprising Sphaeranthus indicus and Garcinia mangostana for treating Metabolic Syndrome or for ameliorating metabolic marker proteins.
Metabolic Syndrome also known as Syndrome X, insulin resistance syndrome and DysMetabolic Syndrome is a condition, wherein a group of diseased states, which increase atherosclerosis, stroke and diabetes.
Metabolic Syndrome was first described by Reaven in 1988 [Reaven, (1988) Diabetes 37; 1595-1607] as a cluster of interrelated common clinical disorders, including obesity, insulin resistance, glucose intolerance, hypertension and dyslipidemia.
A criteria for diagnosing Metabolic Syndrome was established by The Adult Treatment Panel-III (ATP-III) of the National Cholesterol Education Program in 2001 [JAMA (2001), 285; 2486-2497]. Five Criteria were selected by this Panel to identify individuals with Metabolic Syndrome including abdominal obesity, impaired fasting glucose, high triglyceride (TG), low HDL cholesterol (HDL-C) concentrations and increased blood pressure. Metabolic Syndrome is diagnosed, if any three of the components are present in an individual.
A lot of research is being carried out over a decade to develop agents to control Metabolic Syndrome. The application of metabolic markers for the control of this syndrome has also been attempted.
People with Metabolic Syndrome are at high risk of coronary heart disease, other diseases related to plaque buildups in artery walls (e.g., stroke and peripheral vascular disease) and type-2 diabetes.
Some of the biological conditions are also considered as markers for Metabolic Syndrome, which include Hyperuricemia—[Vuorinen-Markkola H et al; J Clin Endocrinol Metab. 1994; 78(1):25-9.]; Hypertriglyceridemia [Grundy S M.; Am J Cardiol. 1998; 81(4A):18B-25B]; Hypoadiponectinemia [Stern N et al; J Cardiometab Syndr. 2007; 2(4): 288-94]; Microalbuminuria [Brahimi M et al; Arch Mal Coeur Vaiss. 2007; 100(8):673-6.].
Some of the patents are quoted below which refer to the treatment and curing of Metabolic Syndrome.
PCT Publication WO08086403A1 describes the identification and isolation of chromones and novel chromone compositions from plant sources that are effective in enhancing adiponectin production by adipocytes and regulating genes involved in fatty acid biosynthesis. The invention also include methods for the prevention and treatment of a variety of diseases and conditions including, but not limited to insulin resistance, glucose intolerance, hyperglycemia, Metabolic Syndromes, dyslipidemia, and hypertriglyceridemia.
PCT Publication WO08074935A2 relates to compositions and products that can be obtained from plants, such as extracts, fractions and/or molecules useful for preventing or treating metabolic disorders, obesity and/or diseases associated therewith such as the X syndrome (Metabolic Syndrome), type-2 diabetes, or for producing food additives for human beings or animals.
PCT Publication WO08093848A1 discloses a pharmaceutical product containing phosphatidylcholine derived from soybean for oral administration or for oral cavity application, a functional food and an oral composition which can prevent or ameliorate a disorder in the physical function induced by the increase in an inflammation marker, which can reduce the occurrence of Metabolic Syndrome or the risk of a disease and Metabolic Syndrome, and which can maintain or promote the healthy state.
Based on the information cited above and several other documents, the inventors of the present invention have felt the need of an effective natural composition which can efficiently be used for the control of Metabolic Syndrome and several other associated and related diseases.
According to our knowledge, there is no prior art relating to the usage of ingredients selected from the extracts, fractions or active compounds, phytochemical(s) or mixtures thereof derived from Sphaeranthus indicus and their compositions in combination with ingredients selected from the extracts, fractions or active compounds, phytochemical(s) or mixtures thereof derived from Garcinia mangostana for the amelioration of for the control, prevention and treatment of disease conditions associated with or related to obesity, metabolic Syndrome and other metabolic disorders.
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