CHAPTER ONE
1.0 INTRODUCTION
Bitters as well as other medicinal plants have been the companions of man since time immemorial (Adaramoye, 2008). They occupy a central and integral place in modern herbal therapeutic medicine because of their efficacy and lesser toxicity compared synthetic drug. Many herbal remedies including bitters have been believed or known to be effective in management of dyslipidemia.
Dyslipidemia is a leading cause of coronary heart disease (CHD) and other related cardio- vascular disorders (CVDs). It is known that the occurrence of CHD is positively correlated with high total cholesterol and even more strongly with low density lipoprotein cholesterol. In contrast LDL Cholesterol, high level of HDL cholesterol has been associated with a decreased risk for heart disease (Clark et al, 2012). Efforts therefore have extensively been directed towards to reduce the risk of CVDs through the regulation of cholesterol (Adaramoye, 2008).
Kaka bitters like most other bitters is claimed to be an effective therapy for the management of abnormal blood lipid metabolism. However, there is a dearth of scientific data to support the folkloric use of this bitters in the treatment of abnormal lipid-related diseases (Adaramoye, 2008).
The present study therefore, was designed to provide scientific proof of the use of Kaka bitters in the management of dyslipidemia.
1.1 LITURATURE REVIEW
1.1.1 BITTERS – An Overview
1.1.1.1 HISTORY OF BITTERS
BIBLICAL VIEW
Mentions of herbal bitters with therapeutic effects were made in the Christian Holy Bible bitters. The Psalmist, king David talked about the “herb for the service of man… which strengthened man’s heart” (Psalm 104: 14, 15 KJV). Apostle Paul mentioned “wine (liquor) for thy stomach’s sake (i.e. aperitif, digestif, carminative, etc.) and thine own infirmities (who knows, may be antimicrobial, anti-genotoxic, astringent, diuretic or laxative involving infirmities) 1 Timothy 5:23. The name “bitters” to mean these drinks was used in different bible passages including James 3:11.
CONTEMPORARY VIEW
It is in literature that the Angostura bitters was first compounded by a German physician, Dr. Johann Gottieb Benjamin Siegert in Venezuela in 1824 as a cure for sea sickness and had been discovered long before this. The bitter was reported to have effects of settling mild case of nausea, and also an apertif, digestive and carminative properties. The origin of herbal bitters has been tracked down to more than 5,000 years ago, possibly due to the opening of trade route with China (Oyewo et al, 2013b).
1.1.1.2 GENERAL MEDICINAL PROPERTIES OF BITTERS
Bitters generally are known to have
1.1.1.3 CHEMISTRY OF BITTERS
Bitters are many from different herbal extract, many of these plants are from the plant family, Asteraceae, which often sesquiterpene lactones. The primary active ingredients in most bitters include saponin, tannin, flavonoid, etc. That of blessed thistle is a bitter tasting sesquiterpene lactone called cnicin (Alam et al, 2011). The bitter principles in artichoke, burdock and milk thistle for instance are flavonolignans. Other glycosides such as those from bitter-fasting flavonoid glycosides such as those from bitter orange peel including neohesperidin and naringin (Kareem et al, 2009).
1.1.1.4 MECHANISM OF ACTION OF BITTERS
Bitter generally use bitter taste to elicit their effects. They act on the tongue receptor where their effects are carried to the various area of the brain and further their signal they create are been interpreted and messages are appropriately sent out for their effect, for instance bitters elicit their effects as aperitifs by acting on the hypothalamus and increasing peristalsis.
There are fine distinct tastes that can be registered by the taste buds, viz: sally, sweet, bitter, sour, and umani or “savory”.
The bitter taste from bitters (a long sweet and umani taste) unlike salty and sweet bud taste which are sense by the taste bud through ion channels triggered by electronically charged particles, ions or certain food, are sensed by the taste bud through G-protein coupled receptors, a more sophisticated mechanism that is not well understand as that of ion channels. The compounds in bitters trigger certain molecules that close potassium ion channels, creating an action potential. Three cranial nerves are responsible for carrying the action potential initiated in taste buds to brain, where taste is ultimately registered. The facial nerve carries signals from the front two-thirds of the tongue and the vagus from the soft platelet and epiglottis.
1.1.2 BLOOD LIPIDS
1.1.2.1 INTRODUCTION
Plasma lipid consist of triacylglycerol (16%), phospholipids (30%), cholesterol (14%), and cholesteryl esters (36%) and much smaller fraction of unesterified long-chain fatty acid (4%) (Murray et al, 2003). This later fraction the free fatty acid is metabolically the most active in plasma lipid (Murray et al, 2003). Blood lipids such as triglycerides, phospholipids, and cholesterol possess oil nature and are not soluble (or sparing soluble) in blood. They are found noncovalently to protein to form lipoprotein (Voet and Voet, 2011). Lipoproteins are spherical macromolecular complexes of lipids (cholesterol and phospholipid especially) with specific proteins called apoproteins or apolipoprotein (Champe et al, 2008; Pellery and Goldan, 2011). Lipoprotein are globular micelle-like particles that consist of nonpolar core of triacylglycerol and cholesteryl esters surrounded by an amphiphilic coating of protein, phospholipid and cholesterol (Voet and Voet, 2011). Macheboeut (1929) and Adair (1943) were the first people to work on lipoproteins. Plasma proteins are soluble in aqueous and weak salt solvents because of their protein components (Diribe et al, 1999).
1.1.2.2 GENERAL FUNCTIONS OF BLOOD LIPOPROTEINS
Blood lipoproteins have many functions including:
1.1.2.3 TYPES OF BLOOD LIPIDS
Lipoproteins have been classified into five broad categories on the basis of their functional and physical properties (Voet and Voet, 2011). Classification depends on density (by ultra-centrifugation) or on the electrophoretic mobility (Vasudevan et al, 2011) or on composition, size,density and site of origin (Champe et al, 2008). These lipoproteins are chylomicrons, very low density lipoprotein, low density lipoprotein, high density lipoprotein and intermediate density lipoprotein (Voet and Voet, 2011; Vasudevan et al, 2011). Other blood lipids not included in classification of lipoprotein include free fatty acid, triglyceride and cholesterol.
1.1.2.4 CHYLOMICRON
Contains apolipoprotein B-48 (Vasudevan et al, 2011). They are rich in triacylglycerols and transport of lipids of dietary origin (Gurr and Harwood, 1991). Chylomicron are delipidated in the intestinal mucosal and secreted into the lacteals of lymphatic system (Vasudevan et al, 2011).
Large lipids especially those whose carbon chain number exceeds 14 carbons are too large to diffuse across capillary wall and are thus carried by chylomicrons. The later can not travel in blood either for its size, hence are secreted in lacteal (lymphatic capillaries) and travel through thoracic duct to enter systemic blood circulation at the left subclavian vein.
1.1.2.5 VERY LOW DENSITY LIPOPROTEIN (VLDL)
VLDL is also called pre-beta lipoproteins. They are rich in triacylglycerol but transport lipids of endogenous origin (Gurr and Harwood, 1991). VLDL has more protein, phospholipids and cholesterol than the chylomicrons. They are charged and migrate before the β-globulins. For this reason are called the pre-β globulins (Diribe et al, 1999). They are synthesized in the liver from glycerol and fatty acid and incorporated into VLDL along with hepatic cholesterol, apo-B-100, C-II and E. ApoB-100 is the major lipoprotein present in VLDL when it is secreted. Apo-E and C-II are obtained from HDL in plasma (Vasudevan et al, 2011).
1.1.2.6 INTERMEDIATE DENSITY LIPOPROTEIN (IDL)
Also broad bitter lipoproteins are major carriers of plasma cholesterol in man (Gurr and Harwood, 1991). Lipoprotein can be converted from one form to another. VLDL can give rise to an intermediate IDL by the loss of triacylglycerol (TAG) and Apo-C and subsequently from LDL (Deribe et al, 1999). IDL is richer in protein and poorer in cholesterol content than LDL (Deribe et al, 1999).
The lipoprotein lipase (LPL) found on the surface of endothelial cell lining removes the F.As of triacylglycerol in chylomicron and VLDL. The apo CII in the chylomicrons in the presence of Phospholipids activate LPL. The free fatty acids enter the cells, whereas the glycerol backbone of triglyceride is returned to the liver and kidney (via blood) where it is converted to DHAP, a glycolytic intermediate. During the process of fatty acid removal from chylomicrons, substantial portion of PL, Apo A and Apo C are transferred to HDL preventing further degradation VLDL or chylomicron by lipoprotein lipase.
1.1.2.7 LOW DENSITY LIPOPROTEIN (LDL)
Also called βeta lipoprotein because they migrate with beta globulin . Its main apoprotein is B-100. LDL particles contain much less triglycerol than their VLDL predecessors, and have a high concentration of cholesterol and cholesteryl ester. LDL transport cholesterol from liver to peripheral tissues. The only apoprotein present in LDL is apo-B-100. Most of the LDL particles are derived from VLDL, but a small part is directly released from the liver. The half-life of LDL in the blood is about 2 days (Vasudevan et al, 2011).
1.1.2.8 HIGH DENSITY LIPOPROTEIN
HDL is formed from lipoprotein by the loss of ApoB in LDL (Diribe et al, 1999) .The major apoprotein in HDL are Apo-A1, with some Apo-A2, Apo-C and ApoE (Vasudevan et al, 2011). HDL serves as a transport reservoir of ApoC and ApoE which can be transferred to VLDL and chylomicrons and back (Vasudevan et al, 2011). Transport phospholipid and cholesterol from peripheral tissues to the liver (Diribe et al, 1999). In HDL-facilited lipid transport the excess cholesterol is taken to the liver for reprocessing (Gurr and Harwood, 1991). The intestinal cells synthesize component of HDL and release into blood. The nascent HDL in plasma is discoid in shape (Vasudevan et al, 2011).
1.1.2.9 FREE FATTY ACID
Or non-esterified fatty acid (NEFA) are complexed with albumin. Free fatty acids are not generally included in the classification of lipoprotein because they loosely bound to protein (Vasudevan et al, 2011). Free fatty acid help in the transport of lipid e.g. cholesterol (Diribe et al, 1999).
1.1.2.10 BIOCHEMICAL BASIS OF LIPOPROTEIN IMPLICATION IN PATHOLOGIES
Abnormal plasma concentrations of the different blood lipoproteins is implicated is many pathologies including atherosclerosis and coronary heart disease. In human the lipoprotein transport system is less perfect than in other animal and as a result human experience a gradual deposition of lipid – especially cholesterol in tissues (Champe et al, 2008). This is a potentially life-threatening occurrence when lipid deposition contributes to plaque formation, causing the narrowing of blood vessels (atherosclerosis) (Champe et al, 2008). Polyanionic interaction like lipoprotein acid mucopolysaccharide complex have been implicated in human disease such as atherosclerosis and diabetes mellitus (Diribe et al, 1999). Since mucopolysaccharide are part of human connective tissues, they get involved in a number of reactions. The lipid acid mucopolysaccharide complex increase with increase in calcium concentration of the tissue (Diribe et al, 1999).
1.1.2 .11 IMPLICATION OF ABNORMAL LIPID PROFILE
High density lipoprotein (HDL) is believed to transport cholesterol away from tissues e.g. heart to the liver where it is removed from the body. It is thus known as “good cholesterol” good cholesterol of are made of little cholesterol and mostly protein. The LDL is on the other side known as “bad cholesterol” for its atherogenicity – it carries cholesterol away from the livers and deposits it in the arteries, which increases the risk of heart attack, stroke and other cardiovascular diseases.
Lipid profile therefore is important in ascertaining the body levels of the different lips, this may be necessary in knowing the risk of someone developing cardiovascular disease or for some other purpose e.g. to determine how effect an administered drug.
One can conclude on the implication of lipid profile by saying that it
1.1.2.12 FACTORS AFFECTING LIPID PROFILE
Include among others:
1.3 KAKA BITTERS
Kaka bitters is an uncommon Indian polyherbal medicine consisting of over 13 medicinal plants. According the manufacturer’s information it is a powerful blend of some premium quality herbs. We formulate for the removal of harmful toxins in the body, thereby supporting the immune system and body’s activity to resist disease.
COMPOSITION: Each 5ml Kaka bitters contains 40g of Piper retrofractum, 10g of Butea monosperma, 50g of Swertia chirata, 50g of Nardostachys jatamansi, 16g of Myristic fragrance, 50g of Bacopa monnieri, 50g of Embelia ribes, 20g of Apium graveolens, 50g of Holarrhena antidysenterica, 30g of Cassia angustiofolia, 75g of Azardirachata indica, 33g opf Aloe barbadensis and 15g of Cassia cinnamomum.
1.3.1 SWERTIA CHIRATA
SCIENTIFIC CLASSIFICATION
Kingdom: Plantae
Unranked: angiosperm-eudicots_asterids
Order: gentianales
Family: gantianaceae
Ganus: swertia
Species: chirata
The name Swertia chirata iss the botanical name of kiratatikta, as suggested by the name the plant ioriginalle came from kirata. The plant is known for if multifactorial medical value in the Dexi and is a bitter -herb. since centuries it has been used in Ayurveda as a tonic bitter, febufuge and anti-helminthic.
Description; the herb grows wild in the temperate Himalays from Kasmir to Bhutan and Khasi range, between 1200-3000 meter altitude. It is also cultivated in Kashmir, Meghalaya, khasi will and Madhya pradesin. The plant has an erect, about 2-3 it long stem, the middle portion is round, while the upper is four anglead, with a prominent current line at each angle. The stems are orange brown or purplish in colour. The roof is simple, tapering and stout, short, almost km long and usually half an inch thick, floering in swertia chivata is in the form of numerous small, axillary, opposite, lax ymes arranged as short branches and the whole inflorescence is 2ft long flowers are small stalked, green-yellow, finged with purple colour with the flowered-tube twice long as the sepal-up and divided near the base into four ovate-lance like segments (Alam et al, 2011). Chirata is also an annual herb growing 0.5-1.5 meter in height.
PROPERTIES
The chirata plant extract is bitter in taste, as earlier suggested. Also it is pungent in the post digestive effect and has cold potency. It possess mil and light laxative attributes, it is believed to be medicinal in fever, asthma, cough, intestinal worm skin disease, edema and burning sensation of the body. The plant is also used in diuretic as well as for treatment of some type of mental disorders (Saha and Das, 2010).. Reportedly it possesses anti-inflammatory, antipyretic, antiviral activities. Fraction of S. chirata also shows significant hypopolycanic activity on Swiss albino mice (Alam et al 2011). In recent times it is use in pharmaceutical industry for preparation of drugs for prevention and treatment of chronic human disorder like for recent diabetes, cardiac problem and cancer (Saha and Das, 2010). But in direct relation to lipid profile it promotes secretin of bile thereby activates the bile.
Chemical composituent: it has been documented that Swertia chirata contain flavonoids, xanthones, terpenoids, iridoid and secoindoid plycoside (Alam et al, 2011).
1.3.2 PIPER PETROFRACTUM
Fig 1: Piper retrofractum (Wikipedia, the free encyclopedia, 2013).
Botanical Classification
Kingdom: plantae
Subkingdom: tracheobionta (vascular plants0
Superdivision: spermatophyte (seed plant)
Division: magnoliophyta (flower plant)
Class: magnoliosida (dicotyledons)
Order: piperales
Family: piperaceae
Gender: piper
Species: p.retrofractum
Fig 2. Piper retrofractum fruit (Tropicalplantbook.com , 2013).
p. retrofractum commonly known in English as Javanese pepper, javaness long pepper baliness long is a short flowering perennial vine cultivated for its fruit hich is usually dried and used as a spice and seasoning. pretrofractum is grown in Indonesia and spread over warm climate countries.
DESRIPTION
Piper retrofractum is stout climber often times confused with piper longum, the common long pepper. It stem grow sometimes length reaching by up to 12m in length. It leaves are large, stacked, Oblong-ovate or elliptic–chanceolate shaped but are short petioled, green in colour measuring between 6 to 7.5 cm in length and 3.2 to 8.5cm wise, chartaceous. The base is sublateral. Teval, pointed or slightly cordate with tips acute. It is penni nerved, lateral nerve 7-11 on each side of he midrib ascending. The inflorescence in pediculate flower spike that come from the main stem mode, opposed to the leaves. Its floweres are greenish yellow and arranged in spiral along the spine. The fruit of java long pepper is a small drupe, hich is arranged in flower spike forming a compact fruiting, welded reminiscent of black catkins, thye fruit is more or less united partly or wholly imbedded in and concresent with rachis. Short stigmas the drupe fruit when dry are between 2 and 3 (sometime up to 5) cm long. These are three stigmas. The seeds are sub-globose to obovoid-globose 2 to 2.5 mm (Globinmed).
PROPERTIES OF P. RETROFRACTUM
The P. retrofratum secies is a more spicy than piper nigrum. It has been altributed with siituable properties including antianorexia, anti-henorrhoid, anti-stomachache, digestif and flatulence-correctinf properties (Botonanial, 2013). Its other proper his care and dropenic and antihelmintic, expectorant stimulant and serve as tonic to stomach, it is alexiteric (especially the root).
Uses
Traditionally to treat stomach distension or flatulence, diarrhea (using the decoction of the ripe fruit), toothache (using a pondered ripe fruit).Flatulence, dyspepsia, colic and gastralpia and stomactitis. In its native home Indonesia it is used to treat neurasthemia, rheumatism and bronchits. Its fruit is considered a tonic and is given to women after delivery to help in revive whle at the same time lean the uterus (Globinmed, 2011). It is reportedly also useful in cold, ough, asthma, fever, pile and in hemorrhoidal infections.
PHYTOHEMICAL CONSTITUTEUNTS
Stem bark of the plant has been reported to contain lignin, and alkaloids, such as piper a mine; 2,4-decadiemoic acid piperidine, and alkamides suh as piperine, sylvatine, piplatine and piperlonguminone and also p-sitosterol. The plant stem contains piperine, B-sitoterol and piplartine. Several free amino acids and monosaccharide (like glucose) also reportedly contained in the plant. Three amides-N-isobutyltrideca-13(3,4-methylenedioxyphenyi)2,4,12-trienamidell), fillfiline (N. isobutyldecosa trans-2, trans-4, Cis trienamide) and N-isobytyleicosa-trans-2, trans-4, cis-8-trienamide (II) have been isolated from fruits (Uddin, 2013).
1.3.3 BUTEA MONOSPERMA
Fig 3.Butea monosperma (Sahu and Pady, 2013).
Fig 4.Fruit and flower of Butea monosperma (Pal and Bose, 2011).
Scientific Classification
kingdom : plantae
subkingdomi: Traheobionta – vascular plants
super-division: Spermatophyta – seed plant
Division: magnoliophyta – flowering plants
Class: magnoliopsida – Dicotyledons
Subclass: Rosidae
Order: Fabales:
Family: Fabacea – Pea family
Genus: Butea
Species: B. Monosperma
B. Monosperma commonly known as flame of forest’ in English and ‘Palesh’ in Hindi is distributed in the aid and semiarid regions in greater part of India (Sharma and Garg, 2009).
DESCRIPTION
Butea monosperma is an erect medium sized dry season – deciduous tree, growing 12-15m fall with crooked the leaves are pinnate, with an 8-16cm petiole and three leaflets large and stipulate, each leaflet 10-20cm long (pal and Bose, 2011). It flowers are large, in a rigid racemes 15cm long, 3 flowered together forms the tumid nodes of the dark olive-green velvety rachis. Pedicles about twice as long as the calyx, densely brown-velvety: bracts and bracteoles small, deciduous. Calyz 13mm long, dark Olive-green, densely velvety outside, clothed with silky hair within teeth short, the 2 upper connate, the 3 lower equal, deltoid.Corolla 3.8-5cm long, clothed outside with silky, silver hairs, orange or salmon coloured: standard 2.5cm broad: keel semicircular, beaked, veinerd..pod stalked 12.5m by 2.5-5cm, thickened at the sutures reticulately veined orgenteocanescent: stalked 2m long (Sharma and Deshoval, 2011).
PHYTOCHEMICAL CONSTITUENTS
This plant contain among others, alkaloid, carbohydrates, flavanoids, glycoside, protein, saponin, starch, sterols and tannins (Sahu and padly, 2013).
PROPERTIES (ACTIVITY)
B. Monosperma possess antibacterial activity Isahu and padly, 2013), hypolipidemic anti-diabetic and hypoglycemic activities (Naeem and Khan, 2008), it possess astringent bitter, alterative, aphrodisiac, anti-asthmatic properties (Mishra et al, 2012). Other properties of B. Monosperma include diuretic activity (Sindhia and Bairwa, 2010), anticonvulsant, and anti oxidative (Sharma and Garg, 2009) and also anti microbial, anthelmintic, anti-inflammatory, antifertility (anti conceptive and anti-implantation), anti tumor, antidiarrheal and anti fungal activities (Talubmook and Buddhakala, 2013).
MEDICINAL/TRADITIONAL USES
B. monosperma is an ethno medicinal plant whih is used by aborigine in many and other infections diseases. It is used in part of India against diarrhea.
Treatment of eye-related disease e.g. blindness; also war, tumor, useful as an appetizer, laxative, anthelmintic aphrodisiac in bone fracture, disease of anus, dysentery, piles, hydrocele, stomatitis, cough, pterygium, skin disease, abdominal troubles, etc. (Mishra et at, 2012).
Traditionally B. monosperma flowers are astringent to bowel, incure “Kapha”, leprosy, strangury, gout, skin diseases, thirst, sensation; flower Juice is useful in eye diseases. Flower is bitter, aphrodisiac, expectatorant, tonic, emmenagogue, diuretic, good in biliousness, inflammation and gonorrhea. The dye is useful in enlargement of spleen. Flowers are depurative, as a poultice they are used to disperse swelling and to menstrual flow. They are given to pregnant women in case diarrhea. It is also useful to prevent pus from urinogenital tracts of male and also cures leucorrhoea, the fruits and seeds are digestible, aperients, cure ‘Vata’ and ‘Kapha’. The seeds are also as powerful rubefacient and they have been successfully used in curing a form of herpes, known as Dhobies’s itch. Leaves are also carminative, cures boil and pile. It also used to check irregular bleeding during menstruation. The gum is applied for cracks on foot sole, cures dysentery. Among host other traditional uses of the different part of the plant. Poonful of root of powder mixed with water is drunk as an antidote for snake bites (Sharma and Deshwal, 2011).
1.3.4 NARDOSTACHYS JATAMANSI
Fig 1.5Nardostachys jatamansi,
(Wikipedia, the free encyclopedia, 2013).
Scientific classification
Kingdom: plantae
Ivision: Magnoliopjyta
Class: Magnoliopsida
Order: disacales
Family: valeriance
Genus: Nardostachys
Species: N. jatamnasi
N. jatamansi also called Indian Spike nard, nard, nardin muskroot, Jatamanshi, balchar is a flowering plant of the valerian family that flows in the Alpine Himalayas of Nepal, China, Punjab to Sikkim and India. It is used in manufactures of an intensely aromatic amber-coloured essential oil.
Description
N. jatamansi, a perennial herb height ranging from 10 to 60cm, it also grow to heights of about 1M and has stout and long woody root stocks. The leave is long, sessile and oblong-ovate leaves of length 15 to 20cm in length.
The plant has a slight pink or blue in dense cymes, belt shaped flower, its flowers are rosy and one, two or five in number. The underground stems, rhizomes contain the intensely aromatic amber-coloured essential oil. The rhizome is thick. Fragrant and covered with brown fibers. The plant bears 1/3-inch long fruits that are oval in shape and have sharp apex. The plant is found in the altitude 3000-5000 meters
Uses: Apart of its medicinal use, Nard oil used as a perfume, an incense, a sedative etc.
Property: reportedly N. jatamansi Rossesses antidepressant activity,anti convulsant, anti arrhythmic, antioxidant and lipid peroxidation activities (Ahemad et al, 2012). It also promotes appetite and digestion.
Phytochemical constituents: volatile essential oil, resin sugar, starch, bitter extractive matter, gum, jata mansone, jatamansic acid, jatamansone semicarbazone, lupeol, malliene, calarene, farpenic coumarin-jatamansin, oroselol, dietheniod bicyclic ketonenardo stachone, sesquiter pene ketone-jatamansone.
Side effect of large doses of N. jatamansi when consumed causes vomiting and diarrhea with abdominal pain, nausea, colic and urinary problem. Normal doses may harmful in pregnancy and lactatean.
Uses: Nard oil obtained from the rhizome normally is used as perfume, an incente, a sedative e.t.c. extract from N. jatamansi is well-known brain from tonic and imparts a sense of calm and peace of mind. It is in the same vein tonic for liver and heart. It also reduces buring sensation, inflammation, and pain and improves skin texture, also in Ayurveda, roots and rhizomes of Nardostachys jatamansi are used to treat hysteria, epilepsy and convulsions. The decoction of the drug is also used in neurological disorders, inosmia and disorder of cardiovascular sysem (Ahemad et al, 2012). It is also known to reduce hyper activity, restlessness and aggressiveness in hyperactive children, it is also used as uterus cleanser and also used in menstrual ailments like dysmenorrheal and inflammation of the uterus. It also relieves symptoms like vertigo, seizure e.t.c. in fever and also an adjunct in treatment of sexual debility and improtence. The other usefulness is in relieveing the phlegin in cough and asthma, proves useful in hepatitis and treatment of enlargement of the liver. Then in regularizing digestion in the body, regularizing respiratory track and suppressing general body weakness and also useful in urine realted problem and aslso maintaining the circulatory system.
1.3.5 MYRISTICA FRAGRANCE
Fig 1.6a.M.fragrans fruit()Fig.1.6b. Mace (red) within nutmeg fruit (Wikipedia).
Fig 1.6c.Nutmeg seeds showing "veins"(wikipedia).
Scientific classification
Kingdom: plantae
Sub-kingdom: Tracheobionta – vascular plants
Super division: spermato plyta – seed plant
Division: magnoliophyta – flowering plant
Class: magnoliopsida – Dicotydons
Subclass: magnoliidea
Order: magnoliales
Family: myristicaceae –nut meg family
Gamis: myristica Gronov
Species: Myristica fragrans
The M. fragrans popularly called nutmeg is a dioeious (or occasionally monoeious) evergreen aromatic perennial plant. A native of the Banda islands in the Moluccas (or spice Island) of Indonesia. It is also grown in Tamil Nadu, Kerala, Assani and other states in India, also in penang Island in Malaysia and the carribean, espevailly in Grenada.
DESCRIPTION
M. Fragrains, a tree usually growing to around 5 to 13 meters high, occasionally 20 meters has it bark containing watery pink or red sap. The pointed dark green leaves (5-15cm x 2 to 7cm) are arranged alternately along the branches and are borne on leaf stem about km long. The upper leaf surfaces are shinny. Flowers are usually single sexed occasionally male and female flowers are found on the same tree. Female flowers arise in group of 1 to 3; males in groups of 1 to 10. The flowers are pale yellow, waxy, fleshy and bell-shaped. Male flowers are pale yellow, waxy, fleshy and bell-shaped. Male flowers are 5 to 7mm long; female flowers are up to km long. The fruits are fleshy, drooping, yellow smooth 6-9cm long with a longitudinal ridge. When ripe, the succulent yellow fruit coat splits into 2 valves revealing a purplish-brown, shiny seed (nutmegs i.e the kernel) surrounded by a red aril (Mace. The seeds (nutmegs) are broadly avoid (2 to 3 cm long). Firm, fleshy, whitish and transverseed by red-brown veins. When flesh, the aril (Mace) is bright scarlet becoming more horny, brittle and a yellows brown colour when dried. The tree soes not flower until around 9 years old, when it fruits; it can continue to do so for a further 75 years. The three bears 2 to 3 crops a year. The seed (nutmegs) needs 3 to 6 weeks to dry before they are ready for use (Lumpur, 1997).
M. Fragrains posses hypolipidemic activity (Kostry and Vijayalakshmi, 2001), antidiabetic, andti-aggregator and hypogypoglycemic effects (somani and singhai, 2008), antfugal, hepatoprotective and antioxidant properties including anti-inlfammatory, antidysentric, analgestic and hypotensive activities and (Kareem et al, 2009) reportedly insulin-like biology activity. M. Fragrams also is known to be an aromatic stimulant, carminative and antimicrobial agent. Also nutmeg prevents hypercholterolemia and atherosclerosis, its ethamolic extract significantly produce hypolipidemia (Somani and sigghai, 2008). Amenapogue and abortifacient, aperlif and antrol of flafulenece (lumpur, 1997).
PHYTOCHEMICAL CONSTITUENTS
Flavonvids, saponin and cardiac glycoside. Oher onstituent include camphene, pinene, limonene d-bormeol, 1-terpineol, geraniol, safrol and myristic & elemicin. It has been sngyested that myristicin (C5H12O3, molecular weight 122.21) and elemicin (C12 H16 O3) molecular weight 208.26) may not be an active ingredients but they may be metabolized in the body to 3-methoxy-4,5-methylenedioxy amphetamine (MMDA) and elemiine, an ether analogous to myristicin, 3,4,5 trimethoxy amphetamine (TMA) (Lampur, 1997).
USES
Culinary use: both Nutmeg and mace in drunks and spice/seasons/flavor, perfumery as well as pharmaceutical industries uses hudely the essential oil obtained by steam distillation of ground nutmeg.
Medicine: In traditional medicine nutmeg oil were used for disorders related to the nervous and disgestive systems. The plant is used as anti-diarrhoea agent for patients with medullary carcinoma of the thyroid. The effectiveness of the treatment may be due is the inhibition of prostagladin synthesis in the mucosa and sub mucosa of the colon. M. fragrans is also used in treatment of diarrhea, mouth sores and insomnia (Somani and singhai, 2008).
SIDE EFFECT OF M. FRAGRANS
The use of M. fragrans especially it abuse (large doses) may result into psychosis, fathy livers and hepatic necrosis, renal toxicity,teratogen and possibly death. Nutmeg has a pattern of intoxication that resembles anti cholinergic-likesymptom. e.g. profuse sweating, flushed face, delirium, dry throat, e.t.c. (lumpur, 1997). This is been attributed to the myristicin (a monoamine oxidase inhibitor) and elemicin. Other symptoms associated with misuse of M. fragransexcited and confused state of headaches, nausea and dizziness, dry mouth, bloodshot eyes and memory disturbance. Nutmeg reportedly also can induce Mallucinogemic effects e.g. visual distortions and paranoid ideation. Fatal muristicin prisoning in humans are however rare.
1.4 JUSTIFICATION
1.4.1 SIGNIFICANCE OF THE STUDY
The medicinal uses of each of the components of Kaka bitters are well documented. Also Kaka bitters just other bitters is believed to possess myriad of therapeutic effects, but as at the time of this study, there is yet no record in the available literatures validating the scientific uses of Kaka bitters. Biochemical and pharmacological investigations are required to elucidate the precise action mechanism(s) of the medicinal effect found in this prong of medicinal plants (Naeem and Khan, 2008). The present study was carried out to ascertain the hyperlipidemic effect of Kaka bitters. The result obtained will be required to predict the safety of exposure and determine efficacy of the use of the polyherbal medicine
1.4.2 THE OBJECTIVE OF STUDY
This study seek to
CHAPTER ONE
1.0 INTRODUCTION
Bitters as well as other medicinal plants have been the companions of man since time immemorial (Adaramoye, 2008). They occupy a central and integral place in modern herbal therapeutic medicine because of their efficacy and lesser toxicity compared synthetic drug. Many herbal remedies including bitters have been believed or known to be effective in management of dyslipidemia.
Dyslipidemia is a leading cause of coronary heart disease (CHD) and other related cardio- vascular disorders (CVDs). It is known that the occurrence of CHD is positively correlated with high total cholesterol and even more strongly with low density lipoprotein cholesterol. In contrast LDL Cholesterol, high level of HDL cholesterol has been associated with a decreased risk for heart disease (Clark et al, 2012). Efforts therefore have extensively been directed towards to reduce the risk of CVDs through the regulation of cholesterol (Adaramoye, 2008).
Kaka bitters like most other bitters is claimed to be an effective therapy for the management of abnormal blood lipid metabolism. However, there is a dearth of scientific data to support the folkloric use of this bitters in the treatment of abnormal lipid-related diseases (Adaramoye, 2008).
The present study therefore, was designed to provide scientific proof of the use of Kaka bitters in the management of dyslipidemia.
1.1 LITURATURE REVIEW
1.1.1 BITTERS – An Overview
1.1.1.1 HISTORY OF BITTERS
BIBLICAL VIEW
Mentions of herbal bitters with therapeutic effects were made in the Christian Holy Bible bitters. The Psalmist, king David talked about the “herb for the service of man… which strengthened man’s heart” (Psalm 104: 14, 15 KJV). Apostle Paul mentioned “wine (liquor) for thy stomach’s sake (i.e. aperitif, digestif, carminative, etc.) and thine own infirmities (who knows, may be antimicrobial, anti-genotoxic, astringent, diuretic or laxative involving infirmities) 1 Timothy 5:23. The name “bitters” to mean these drinks was used in different bible passages including James 3:11.
CONTEMPORARY VIEW
It is in literature that the Angostura bitters was first compounded by a German physician, Dr. Johann Gottieb Benjamin Siegert in Venezuela in 1824 as a cure for sea sickness and had been discovered long before this. The bitter was reported to have effects of settling mild case of nausea, and also an apertif, digestive and carminative properties. The origin of herbal bitters has been tracked down to more than 5,000 years ago, possibly due to the opening of trade route with China (Oyewo et al, 2013b).
1.1.1.2 GENERAL MEDICINAL PROPERTIES OF BITTERS
Bitters generally are known to have
1.1.1.3 CHEMISTRY OF BITTERS
Bitters are many from different herbal extract, many of these plants are from the plant family, Asteraceae, which often sesquiterpene lactones. The primary active ingredients in most bitters include saponin, tannin, flavonoid, etc. That of blessed thistle is a bitter tasting sesquiterpene lactone called cnicin (Alam et al, 2011). The bitter principles in artichoke, burdock and milk thistle for instance are flavonolignans. Other glycosides such as those from bitter-fasting flavonoid glycosides such as those from bitter orange peel including neohesperidin and naringin (Kareem et al, 2009).
1.1.1.4 MECHANISM OF ACTION OF BITTERS
Bitter generally use bitter taste to elicit their effects. They act on the tongue receptor where their effects are carried to the various area of the brain and further their signal they create are been interpreted and messages are appropriately sent out for their effect, for instance bitters elicit their effects as aperitifs by acting on the hypothalamus and increasing peristalsis.
There are fine distinct tastes that can be registered by the taste buds, viz: sally, sweet, bitter, sour, and umani or “savory”.
The bitter taste from bitters (a long sweet and umani taste) unlike salty and sweet bud taste which are sense by the taste bud through ion channels triggered by electronically charged particles, ions or certain food, are sensed by the taste bud through G-protein coupled receptors, a more sophisticated mechanism that is not well understand as that of ion channels. The compounds in bitters trigger certain molecules that close potassium ion channels, creating an action potential. Three cranial nerves are responsible for carrying the action potential initiated in taste buds to brain, where taste is ultimately registered. The facial nerve carries signals from the front two-thirds of the tongue and the vagus from the soft platelet and epiglottis.
1.1.2 BLOOD LIPIDS
1.1.2.1 INTRODUCTION
Plasma lipid consist of triacylglycerol (16%), phospholipids (30%), cholesterol (14%), and cholesteryl esters (36%) and much smaller fraction of unesterified long-chain fatty acid (4%) (Murray et al, 2003). This later fraction the free fatty acid is metabolically the most active in plasma lipid (Murray et al, 2003). Blood lipids such as triglycerides, phospholipids, and cholesterol possess oil nature and are not soluble (or sparing soluble) in blood. They are found noncovalently to protein to form lipoprotein (Voet and Voet, 2011). Lipoproteins are spherical macromolecular complexes of lipids (cholesterol and phospholipid especially) with specific proteins called apoproteins or apolipoprotein (Champe et al, 2008; Pellery and Goldan, 2011). Lipoprotein are globular micelle-like particles that consist of nonpolar core of triacylglycerol and cholesteryl esters surrounded by an amphiphilic coating of protein, phospholipid and cholesterol (Voet and Voet, 2011). Macheboeut (1929) and Adair (1943) were the first people to work on lipoproteins. Plasma proteins are soluble in aqueous and weak salt solvents because of their protein components (Diribe et al, 1999).
1.1.2.2 GENERAL FUNCTIONS OF BLOOD LIPOPROTEINS
Blood lipoproteins have many functions including:
1.1.2.3 TYPES OF BLOOD LIPIDS
Lipoproteins have been classified into five broad categories on the basis of their functional and physical properties (Voet and Voet, 2011). Classification depends on density (by ultra-centrifugation) or on the electrophoretic mobility (Vasudevan et al, 2011) or on composition, size,density and site of origin (Champe et al, 2008). These lipoproteins are chylomicrons, very low density lipoprotein, low density lipoprotein, high density lipoprotein and intermediate density lipoprotein (Voet and Voet, 2011; Vasudevan et al, 2011). Other blood lipids not included in classification of lipoprotein include free fatty acid, triglyceride and cholesterol.
1.1.2.4 CHYLOMICRON
Contains apolipoprotein B-48 (Vasudevan et al, 2011). They are rich in triacylglycerols and transport of lipids of dietary origin (Gurr and Harwood, 1991). Chylomicron are delipidated in the intestinal mucosal and secreted into the lacteals of lymphatic system (Vasudevan et al, 2011).
Large lipids especially those whose carbon chain number exceeds 14 carbons are too large to diffuse across capillary wall and are thus carried by chylomicrons. The later can not travel in blood either for its size, hence are secreted in lacteal (lymphatic capillaries) and travel through thoracic duct to enter systemic blood circulation at the left subclavian vein.
1.1.2.5 VERY LOW DENSITY LIPOPROTEIN (VLDL)
VLDL is also called pre-beta lipoproteins. They are rich in triacylglycerol but transport lipids of endogenous origin (Gurr and Harwood, 1991). VLDL has more protein, phospholipids and cholesterol than the chylomicrons. They are charged and migrate before the β-globulins. For this reason are called the pre-β globulins (Diribe et al, 1999). They are synthesized in the liver from glycerol and fatty acid and incorporated into VLDL along with hepatic cholesterol, apo-B-100, C-II and E. ApoB-100 is the major lipoprotein present in VLDL when it is secreted. Apo-E and C-II are obtained from HDL in plasma (Vasudevan et al, 2011).
1.1.2.6 INTERMEDIATE DENSITY LIPOPROTEIN (IDL)
Also broad bitter lipoproteins are major carriers of plasma cholesterol in man (Gurr and Harwood, 1991). Lipoprotein can be converted from one form to another. VLDL can give rise to an intermediate IDL by the loss of triacylglycerol (TAG) and Apo-C and subsequently from LDL (Deribe et al, 1999). IDL is richer in protein and poorer in cholesterol content than LDL (Deribe et al, 1999).
The lipoprotein lipase (LPL) found on the surface of endothelial cell lining removes the F.As of triacylglycerol in chylomicron and VLDL. The apo CII in the chylomicrons in the presence of Phospholipids activate LPL. The free fatty acids enter the cells, whereas the glycerol backbone of triglyceride is returned to the liver and kidney (via blood) where it is converted to DHAP, a glycolytic intermediate. During the process of fatty acid removal from chylomicrons, substantial portion of PL, Apo A and Apo C are transferred to HDL preventing further degradation VLDL or chylomicron by lipoprotein lipase.
1.1.2.7 LOW DENSITY LIPOPROTEIN (LDL)
Also called βeta lipoprotein because they migrate with beta globulin . Its main apoprotein is B-100. LDL particles contain much less triglycerol than their VLDL predecessors, and have a high concentration of cholesterol and cholesteryl ester. LDL transport cholesterol from liver to peripheral tissues. The only apoprotein present in LDL is apo-B-100. Most of the LDL particles are derived from VLDL, but a small part is directly released from the liver. The half-life of LDL in the blood is about 2 days (Vasudevan et al, 2011).
1.1.2.8 HIGH DENSITY LIPOPROTEIN
HDL is formed from lipoprotein by the loss of ApoB in LDL (Diribe et al, 1999) .The major apoprotein in HDL are Apo-A1, with some Apo-A2, Apo-C and ApoE (Vasudevan et al, 2011). HDL serves as a transport reservoir of ApoC and ApoE which can be transferred to VLDL and chylomicrons and back (Vasudevan et al, 2011). Transport phospholipid and cholesterol from peripheral tissues to the liver (Diribe et al, 1999). In HDL-facilited lipid transport the excess cholesterol is taken to the liver for reprocessing (Gurr and Harwood, 1991). The intestinal cells synthesize component of HDL and release into blood. The nascent HDL in plasma is discoid in shape (Vasudevan et al, 2011).
1.1.2.9 FREE FATTY ACID
Or non-esterified fatty acid (NEFA) are complexed with albumin. Free fatty acids are not generally included in the classification of lipoprotein because they loosely bound to protein (Vasudevan et al, 2011). Free fatty acid help in the transport of lipid e.g. cholesterol (Diribe et al, 1999).
1.1.2.10 BIOCHEMICAL BASIS OF LIPOPROTEIN IMPLICATION IN PATHOLOGIES
Abnormal plasma concentrations of the different blood lipoproteins is implicated is many pathologies including atherosclerosis and coronary heart disease. In human the lipoprotein transport system is less perfect than in other animal and as a result human experience a gradual deposition of lipid – especially cholesterol in tissues (Champe et al, 2008). This is a potentially life-threatening occurrence when lipid deposition contributes to plaque formation, causing the narrowing of blood vessels (atherosclerosis) (Champe et al, 2008). Polyanionic interaction like lipoprotein acid mucopolysaccharide complex have been implicated in human disease such as atherosclerosis and diabetes mellitus (Diribe et al, 1999). Since mucopolysaccharide are part of human connective tissues, they get involved in a number of reactions. The lipid acid mucopolysaccharide complex increase with increase in calcium concentration of the tissue (Diribe et al, 1999).
1.1.2 .11 IMPLICATION OF ABNORMAL LIPID PROFILE
High density lipoprotein (HDL) is believed to transport cholesterol away from tissues e.g. heart to the liver where it is removed from the body. It is thus known as “good cholesterol” good cholesterol of are made of little cholesterol and mostly protein. The LDL is on the other side known as “bad cholesterol” for its atherogenicity – it carries cholesterol away from the livers and deposits it in the arteries, which increases the risk of heart attack, stroke and other cardiovascular diseases.
Lipid profile therefore is important in ascertaining the body levels of the different lips, this may be necessary in knowing the risk of someone developing cardiovascular disease or for some other purpose e.g. to determine how effect an administered drug.
One can conclude on the implication of lipid profile by saying that it
1.1.2.12 FACTORS AFFECTING LIPID PROFILE
Include among others:
1.3 KAKA BITTERS
Kaka bitters is an uncommon Indian polyherbal medicine consisting of over 13 medicinal plants. According the manufacturer’s information it is a powerful blend of some premium quality herbs. We formulate for the removal of harmful toxins in the body, thereby supporting the immune system and body’s activity to resist disease.
COMPOSITION: Each 5ml Kaka bitters contains 40g of Piper retrofractum, 10g of Butea monosperma, 50g of Swertia chirata, 50g of Nardostachys jatamansi, 16g of Myristic fragrance, 50g of Bacopa monnieri, 50g of Embelia ribes, 20g of Apium graveolens, 50g of Holarrhena antidysenterica, 30g of Cassia angustiofolia, 75g of Azardirachata indica, 33g opf Aloe barbadensis and 15g of Cassia cinnamomum.
1.3.1 SWERTIA CHIRATA
SCIENTIFIC CLASSIFICATION
Kingdom: Plantae
Unranked: angiosperm-eudicots_asterids
Order: gentianales
Family: gantianaceae
Ganus: &n
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