Thursday, December 6, 2007

A Scientific Approach Towards The Pharmacology Of "Guggulu"



Guggulu is the one of the most used and potent drug of Ayurveda , which literally means that ‘It protects body from those diseases which may otherwise decrease the strength of body’.

Whole Ayurvedic science is based upon three dosas namely Vata, Pitta and Kapha in which Vata is the main causative factor of most of diseases. Total eighty specific diseases (Nanatmak Vyadhis) are caused by only Vata which are more than the specific diseases totally caused by Pitta and Kapha ( Ch. Su.20 ) and Guggulu, alone or in combination, is most potent and important drug to fight against Vata disorders. Charak and Vagbhatta also prescribed Guggulu as a most important drug for Vata vaydhi and medoroga (obesity)

“Guggulurmedoanilharanam” (A. S. Su. 13)

“Medoanile gugguluh” (A. H. Ut. 40)

Bhavprakash described total five varieties of Guggulu i.e. Mahishaksha, Mahanila, Kumuda, Padma and Hiranya. According to him only Hiranya guggulu is beneficial for human being. Now a days two types of guggulu are available i.e. ‘Kana Guggulu’ with translucent small particles and granular form and ‘Bhainsa Guggulu or Mahishaksha guggulu’ with greenish tinge like buffalo’s eye.

The Guggulu of commerce is the pale yellow or brown aromatic gum resin. The gum oleo-resin is located in ‘gum oleo-resin ducts in the parenchymatous bark as pale-yellowish milky juice . The gum oleo-resin consists of irregular roundish masses of varying sizes about 0.5 cm to 2 cm. It is opaque and slightly sticky to touch. This resin melts in the intense summer and solidifies in winter. Gugglu gum is graded into three categories on the basis of shape, colour and purity –

Grade 1– Contains translucent guggulu free from bark, sand and adulterants

Grade 2 - Guggulu mixed with bark and sand, dull coloured.

Grade 3- Guggulu of inferior quality, mixed with lot of extranematters

Adulteration

Gum Boswellia serrata (Shallaki) and Hymenodictyon excelsum are used as common adulterants in the gum resin of guggulu. Other common adulterants are Albizia lebbeck (shirish), Butea monosperma (Palash), Moringa olifera (Sehzan), Acacia nilotica (Babbul) and Acacia catechu ( Khair) etc.

So the resin must be tested for quality before use. The variety which bursts in to flame when put in to fire, melts and evaporate on heating, dissolves easily in hot water, is best for use.

The water soluble extractives, alcohol soluble extractives, ash value, acid insoluble ash, weight loss on drying of guggulu gum are as followings –

1) Water soluble extractives - < 48.42%
2) Alcohol soluble extractives - < 39.49%
3) Ash value - < 5.57%
4) Acid insoluble ash - < 3.35%
5) Loss on drying - <>

Essential oil can also be obtained by steam distillation. The yield is 0.5% V/W.

Chemical constituents

Guggulu resin is produced more abundantly and is stronger during winter and summer. The primary chemical constituents of Guggulu include Phytosterol, Guggulipid and Guggulsterols. Guggulu gum is mixture of 61% resin, 29.3% gum, 6.1% water 0.6% volatile oil and 3.2% foreign matter. Chemical compounds whose are isolated from guggulu gum by many scientists are followings -

1) Oleo-fraction -

(I) Myrcene

(II) Dimyrcene

(III) Polymyrcene Compound

2) Gum fraction A7-

(I) α–arbinose

(II) D-galactose

(III) L-flucose

4) Gum fraction B -

(I) 6-D (4-D-methyl-β-D-glucopyranosyluronic acid)

(II) D-galacto pyranose

5) Resin fraction -

(I) Guggul sterol- I
C27 H44O4
(II) Guggul sterol-II;
C27H46O3
(III) Guggul sterol-III;
C27H44O3
(IV) Guggul sterol –IV;
Cholestane-50-ol-3, 6- dione
(V) Guggul sterol-V;
Cholestance-3β, 50 c-diol-6-β- aceltate
(VI) Guggul sterol-Z
(VII) Guggul sterol-E
(VIII) Nonadecan-1,2,3,4-tetrol
(IX) Diterpene alcohol
C20H34O
(X) Octadecan-1,2,3,4-tetrol

Many pharmacological studies have been done on a standardize ethyl acetate extract of guggulu. This extract has been named “Guggulipid” and has been standardized to contain 4 gm of Z and E-guggulsterons per 100 gm

Pharmacological Action

In Ayurveda there is no mention of concept Cholesterol but our classical texts prescribed Guggulu for the treatment of Medoroga and this very closely resembles with the symptoms of High cholesterol.

Ketone fraction that is extracted from the resin contains the most potent cholesterol lowering compounds. This is composed of C21 or C27 steroids with major component being Z-guggulsterones and E-guggulsterones and commonly known as Guggulsterons. These compounds have been known to provide Lipid Lowering Agent. To find out Hypolipidaemic effect of guggulu, a study was conducted in AIIMS, New Delhi. The study was to evaluate the effect of Petroleum ether fraction of Guggulu (Fraction ‘A’) on

1) Serum Lipid

2) Tissue lipid

3) Body weight

4) To decide its effect on Cholesterol metabolism

In this study the effectiveness of Fraction ‘A’ of guggulu was compared with Clofibrate, an established hypolipidaemic agent. Conclusion confirmed that fraction ‘A’ of Guggulu increases the rate of excretion of cholesterol from body same as Clofibrate and it is more potent than Clofibrate because fraction ‘A’ increased fecal excretion of sterol by 59% while Clofibrate increased it only 49.3%.

Thus it is proved that Fraction ‘A’ of guggulu is a potent hypolipidaemic agent and can be administered safely and continuously over a prolonged period. There is no tolerance to the drug with major side effects. This study brings out that hypolipidaemic effect of guggulu is possibly due to-

1) Increase in rate of removal/excretion of Cholesterol via Gut

2) Decrease in the input or synthesis of Cholesterol.

3) Mobilization of cholesterol from tissues.

Several studies were published in Indian Journal of medicine , Indian pharmacopoeia and in Journal Of Association Of Physicians in India about the hypolipidaemic activity of Guggulu extract but these studies only showed Lipid lowering activity of guggulu extract but not able to find out the exact action of guggulu extract. In U.S.A. (University of Texas and Bayer college) it is confirmed that Guggulu extract blocks the activity of Farnesoid X Receptor (FXR) which is found in liver and responsible for regulating cholesterol and affecting bile salts.

Word Cholesterol is made up of Greek word Cole (Bile), Stereos (Solid) and the suffix ‘–ol’ from an alcohol. There are two sources of cholesterol in our body –

1) Food Cholesterol

2) Cholesterol synthesized from active acetates in the body.

The term bad cholesterol is used for LDL (low density lipoprotein) which is harmful for our body and good cholesterol for HDL (High density lipoprotein) which is beneficial for our body. One of the aims of the treatment of atherosclerotic disorder is to lower plasma or body cholesterol.

Bile acids are principal oxidative product of hepatic cholesterol metabolism. They are exclusively synthesized by the liver and secreted via the bile duct in to intestine to facilitate the absorption of dietary fat and insoluble vitamin. Nearly 95% of the bile acids secreted in to the intestine, are reabsorbed by terminal ileum and returned to the liver through the portal system where they are again utilized. Nonetheless, the bile acids and biliary cholesterol that are not reabsorbed represent the major route of removal of cholesterol in the body. The two major bile acids Cholic and Chenodeoxycholic acid are produced from 7α-hydroxycholesterol, which is formed from cholesterol by the action of cholesterol 7α-hydroxylase (CYP7A1), the rate limiting enzyme in bile acid synthesis. Bile acid synthesis is under feedback regulation with cholic and chenodeoxycholic acids inhibiting the activity of cholesterol 7α-hydroxylase (CYP7A1). The Farnesoid X Receptor (FXR) has recently been identified as a bile acid activated nuclear receptor and is considered as an orphan. It controls bile acid synthesis, conjugation as well as lipid metabolism.

The major pathway of bile acid synthesis can be controlled by controlling the activity of cholesterol 7α-hydroxylase. Bile acid activates the nuclear receptor Farnesoid X Receptor in the liver which indirectly results in the suppression of CYP7A1 transcription by orphan nuclear receptor small heterodimer partner (SHP) partenered to the liver receptor homolog-1 (LRH-1). Besides CYP7A1, many of the genes modulating the dynamics of entero-hepatic circulation of bile acids are also FXR regulated indicating the importance of controlling their activity in response to bile acid concentrations. Guggulsterones blocks the activity of Farnesoid X Receptor so the feedback inhibition of cholesterol 7α-hydroxylase (CYP7A1) activity is released, leading to increase in the bile acid synthesis. This increased diversion of cholesterol in to bile acid synthesis causes an apparent decrease in the pool of intracellular cholesterol.

This way Guggulu decreases Cholesterol level and is used in the treatment of atherosclerosis. Cholesterol level may be less likely to develop erectile dysfunction or impotency due to atherosclerosis which may impede blood flow to and from the penis. So Guggulu can also be used for the treatment of Impotency.

Guggulu reduces the stickiness of platelets and this helps in the lowering of coronary artery diseases. A direct anti-inflammatory action has also been shown by guggulsterones. Researches on the animals show that guggulu can enhance Thyroid function and can increase Basic metabolic rate (BMR) by increasing the level of triiodothyroxin (T3). So it can be used in the treatment of Obesity or Medoroga. But little is known about the action of guggulu on human thyroid.

Properties and Uses -

Properties of guggulu gum are viscous, light, penetrating, and drying. It is hot in potency (Virya) and post-digestive effect (Vipak), Vata and Kapha pacifying, and Pitta aggravating. Its actions are antiseptic, carminative, diaphoretic, diuretic, expectorant, uterotonic, alternative, stomachic, and sedative. It can be used alone or in combination for Obesity, Gout, Sciatica, Hemiplegia, Dyspepsia, Cough, Dysmenorrhoea, Amenorrhoea and Urinary calculus etc. The Guggulu gum is used as an anti-inflammatory, anthelminic, antiseptic, and as a nervine tonic.

Guggulu gum Side Effects -

Guggulu gum is generally well tolerated. The common side effects are Diarrhea, Anorexia, Abdominal discomfort and skin rashes. So the guggulu should be used with caution in the persons with liver diseases, in cases of inflammatory bowel disease and diarrhea.

Guggulu Drug Interactions

Guggulsterones may increase the potency of anti-inflammatory drugs due to its anti-inflammation property, drugs used to lower blood pressure, muscle relaxants (Valium), lithium, and diuretics. It may reduce the effects of anti-arrhythmic (such as digoxin) and anti-diabetic drugs.

Dose -

Daily recommendations for guggulu are typically based on the amount of guggulsterones in the extract and condition of the patient and disease. Most extracts contain 5-10% guggulsterones. So the dose can vary from 25 mg to 75 mg TDS.

References

1)Cultivation Of Guggulu – C.C.R.A.S. ; New Delhi

2)Essential Medical Pharmacology- KD Tripathi

3)Basic and Clinical Pharmacology – Lange

4) The Pharmacological basis Of Therapeutics-Goodman and Gillman

5) Clinical Pharmacology – Melmon and Morrelli

6) Clinical trials with guggulipid. A new hypolipidaemic agent. J Assoc Physicians India 1989 May; 37(5):323-8 Nityanand S, Srivastava JS, Asthana OP.

7) The farnesoid X receptor: a novel drug target, Authors: Thierry Claudel; Ekkehard Sturm; Folkert Kuipers; Bart Staels

8) The farnesoid X-activated receptor mediates bile acid activation of phospholipid transfer protein gene expression.
Urizar NL, Dowhan DH, Moore DD; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas USA

9) Medicinal Plants Of India

10) Ayurvedokta Oushadhamala – Dr. J.L.N. Shastry

11) Guggulsterone is an FXR antagonist in coactivator association assays but acts to enhance transcription of bile salt export pump. Cui J, Huang L, Zhao A, Lew JL, Yu J, Sahoo S, Meinke PT, Royo I, Pelaez F, Wright SD.

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