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Hempedu Bumi (Andrographis paniculata)
· Literature review summary
Some important chemical compounds were been isolated from this plant. The aerial part contains several diterpenoids and diterpene glycosides. Its main constituent, andrographolide, a diterpene lactone, is mainly responsible for its bitter taste. Besides, diterpene lactones, flavone derivatives such as oroxylin and wogonin were also isolated from the leaves. From its rhizomes, several kinds of flavonoids and their glycosides (andrographidine A-F) are found (Chan KL 2001).
Diterpene andrographolide, was found to induce significant stimulation of antibody production and delayed type hypersensitivity (DTH) response to sheep red blood cells (SRBC) in mice (Puri et al 1993; J-Nat-Prod.; 56(7): 995-9). It has been suggested that substance(s) other than andrographolide present in the crude extract may also be contributing towards immuno-stimulation (Puri et al 1993). The extracts also showed potent cell differentiation activity in mouse myeloid leukaemia (M1) cells (Matsuda et al 1994; Chem-Pharm-Bull-Tokyo., 42(6): 1216-25).
Besides the diterpene andrographolide compound, andrographiside and neoandrographolide have been shown to have protective effects on hepatotoxicity induced in mice by carbon tetrachloride or tert-butylhydroperoxide (tBHP) (Kapil-A et al 1993; Biochem-Pharmacol., 46(1): 182-5).
A. paniculata is also traditionally known to have antifertility effect. Studies done by giving andrographolide (an active substance of A.paniculata) im (intramuscular) to male rats (Jonarthanan S, 1990) and A. paniculata dried leaves powder orally to male albino rats (Akbarsha et.al, 1990) and female mice (Zoha et.al, 1989) showed that A. paniculata has antifertility effect in male as well and female subjects. However the possible mode of action of the herb as contraceptive is yet to be determined.
On the other hand, Burgos et.al in 1997 failed to demonstrate any testicular toxicity caused by A. paniculata dried extract in male Spraque Dawley rats. In that study the animals were treated with dried ethanolic extract of A. paniculata. Panossian et.al (1999) reported that powder extract of A. paniculata leaves (Kan Jang tablet: Andrographolide 4.6% and deoxo-andrographolide 2.3%) doesn’t cause significant reduction of progesterone concentration in pregnant rats and suggest that at therapeutic dose, A. paniculata extract cannot induce progesterone-mediated termination of pregnancy. Based on the above studies it is obvious that A.paniculata may have antifertility effect depending on the type and quality of preparation used. It is therefore of important to properly evaluate the male and female reproductive toxicity effects of the A. paniculata extracted. The teratogenicity effect of the herb so far hasn’t been evaluated and it is of our interest to study the possible teratogenicity effect of the similar extract.
Owing to the extensive knowledge of this herb for treatment of various serious ailments, it is deemed necessary to study in detail the broader benefits of this herb to humans. Since it has been known that the biological activities shown by the herb is mainly due to andrographolide and it derivatives, it is vital to prolong the shelf-life of these compounds. This is carried out by determining standardised and consistent raw material with optimum bioacive compound together with its metabolite obtained, dry and store at optimum conditions to reduces the rate of andrographolide degradation.
Malays believe this A. paniculata can treat Diabetes mellitus. Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Several pathogenic processes are involved in the development of diabetes. These range from autoimmune destruction of the b -cells of the pancreas with consequent insulin deficiency, to abnormalities that result in resistance to insulin action. Often, impairment of insulin secretion and defects in insulin action frequently coexist in the same patient, and it is often unclear which abnormality, if either alone, is the primary cause of the hyperglycemia. In Type 1 diabetes, there is total destruction of pancreatic b -cells and patient is dependent on exogenous insulin. Type 2 diabetes is more prevalent, and the cause is a combination of resistance to insulin action and an inadequate compensatory insulin secretory response. As a result, a poorly controlled Type 2 patient will require a lot more insulin to lower the glucose level in the blood. The mechanism is still not clearly identified.
There are many types of therapeutic approach used to treat Type 2 diabetes. While sulfonylureas stimulate b -cells to secrete more insulin and hence lower blood glucose concentration, metformin therapy improves insulin sensitivity. On the other, the newer antidiabetic agents, the thiazolidinedione derivatives, have been shown to cause increase glucose utilization in both muscle and liver cells in vitro, and reduce insulin resistance by modifying the glucose transporter (GLUT) system, especially GLUT1 and GLUT4, in both muscles and liver.
A. paniculata has been in a number of studies to exert antihyperglcaemic and hepatoprotective effects (6,7). Aqueous extract of Andrographis paniculata when administered orally (2 g/kg) did not lower the blood glucose levels in fasted rats but significantly inhibit the increase in blood glucose during oral glucose tolerance test. Whereas, glibenclamide (10 mg/kg) reduced the blood glucose levels in both experiments (Asmawi and Ahmad, 1987). It is known that orall glucose tolerance test is a more sensitive method to detect diabetes mellitus (Herfindal and Hirschman, 1984) The not so active hypoglycaemic activity of the extract was thought due to insufficient amount of the active ingredient had been extracted from the plant. Thus, it was decided to extract the plant with less polar solvent, methanol and then to extract the methanol extract obtained serially with chloroform, butanol and water. In doing so, we hope that the active antidiabetic compound(s) would be concentrated in one of the fractions. It was found that the methanol extract, butanol and water fractions (1 gm/kg) did not lower the blood glucose level in normoglycaemic rats nor inhibit the increase in blood glucose level during glucose tolerance test. However, the chloroform fraction of the plant extract (1 g/kg) significantly reduced both the blood glucose level of normoglycaemic rats and during glucose tolerance test. These results suggested that the antidiabetic component of the Andrographis paniculata were present in the chloroform fraction of the extract that is relatively less polar fractions as compared to the water and butanol fractions (Ahmad and Asmawi, 1990). It can be concluded that the conventional usage of Andrographis paniculata in the form of an aqueous decoction is relatively less effective as an antidiabetic agent. The best antidiabetic activity from this plant can only be obtained if the extract is prepared to include the active compound(s) in the chloroform fraction. This can be prepared in the form of standardised extract. Although by doing activity guided isolation, the active antidiabetic compound(s) can be isolated and identified, the compound isolated can not be commercially developed into modern antidiabetic drug because it would make it to costly to produce. Therefore, the production of standardised Andrographis paniculata extract as an antidiabetic drugs commercially more viable.
The increased use of herbal medicines has resulted in increased concern about both the efficacy and safety of these products. Indeed, there have been a number of reports of toxic effects from traditional and herbal medicines - the WHO database currently lists 8985 adverse drug reaction reports in which herbal preparations are suspected of being implicated. The increasing use of herbal medicines means that there is a potential for more drug interactions, particularly between the herbal products and conventional ‘Western’ medicines where the former is often used by individuals with chronic health conditions. There have been a number of interactions reported to date where the toxicity and interaction studies are mostly conducted on herbal plants/products found in the developed countries. For example, Echinacea could cause hepatotoxicity and therefore should not be used with other known hepatotoxic drugs such as anabolic steroids, amiodarone, methotrexate and ketoconazole.
Literature survey indicated that there are very few toxicity and herb-drug interaction studies done on local medicinal plants. Few studies on herb-drug interaction of local medicinal plants and herbal products have been reported by the author and its group (Hussinet al, 1998; Taher and Hussin, 1998; Hussin, Baie and Asmawi, 1999; Hussin et al, 1999). Due to its promising and high commercial potential, we have chosen Hempedu Bumi to further develop their scientific uses through scientific herb-drug interaction studies of the standardized extract of this plant. It is our hope that through this project, we will be able to formulate new pharmaceutically formulated product of Hempedu Bumi which is efficacious and safe for consumer consumption.
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Development and Clinical Studies of Hempedu Bumi (Andrographis paniculata) as a Commercial Preparation for the Treatment of Diabetes
Project Team 1 : Sourcing and propagation of Hempedu Bumi raw materials ( MARDI, UPM)
Project 1: Evaluation, screening and mass production of Andrographis paniculata accession with high bioactive metabolites for anti diabetic activity
Principle Investigator: Norlia bt Yunus (Group Leader)
Project 2: Genetic and elite planting material of A.paniculata for development of variety for antidiabetic effectsPrinciple Investigator: Prof. Madya Dr. Mohd. Said Saad
Project 3: Suitable Drying and Storage Conditions to Maintain the Stability of Andrographolide and its Derivatives in A.paniculata.Principle Investigator: Dr. Johnson Stanslas
Project Team 2 : Extraction, isolation and characterization of chemical or bioactive constituents foruse as markers in the standardization of extracts and formulations(USM)
Project 1: Standardization of hempedu bumi (Andrographis paniculata) for antidibetic.
Principle Investigator: Assoc. Prof. Dr. Norhayati Ismail (Group Leader)
Project 2: Extraction, isolation, characterization and analysis of the chemical constituents from Andrographis paniculata for use as markers in the standardization of extracts and manufacture of its commercial formulation for clinic trialPrinciple Investigator : Prof Chan Kit Lam
Project Team 3 : Pharmacological and Clinical evaluation on adiabetic activity (USM,IMR)Project 1: Mechanism of actions of the standardized Andrographis paniculata extract as hypoglycaemic agent in normal rats (USM Penang).
Principle Investigator : Assoc Prof Dr Mariam Ahmad (Group Leader)
Project 2: Long-term effect of Andrographis paniculata extract in steptozotocin-induced diabetic rats (USM Kubang Kerian)Principle Investigator : Dr Siti Amrah Sulaiman
Project 3: Effect of andrographis paniculata on RIN-5F pancreatic cells and 3T3-L1 adipocytes (IMR)Principle Investigator : Dr Wan Nazaimoon Wan Mohamud
Project 4: Clinical Study On The Efficacy and Safety of Andrographis paniculata (hempedu bumi) extract in patients with type 2 diabetes mellitusPrinciple Investigator : Profesor Mafauzy Mohamed
Project Team 4 : Toxicological Studies of Hempedu Bumi (Andrographis paniculata) (IMR, USM)Project 1: General Toxicological evaluation of identified extracts of Andrographis paniculata
Principle Investigator : AP (Dr) Munavvar Zubaid (Group Leader)
Project 2: Mutagenecity study of Hempedu Bumi (Andrographis paniculata)Principle Investigator : Dr. Zakiah Ismail
Research Assistant: Mohd Idham Mohd Fahmi
Project 3: Reproductive ToxicologyPrinciple Investigator : Dr Siti Amrah Sulaiman
