Home > Sample essays > Complementary and Alternative Medicine for Management of Diabetes Mellitus: Tinospora Cordifolia as a CAM in Treatment of Diabetes

Essay: Complementary and Alternative Medicine for Management of Diabetes Mellitus: Tinospora Cordifolia as a CAM in Treatment of Diabetes

Essay details and download:

  • Subject area(s): Sample essays
  • Reading time: 15 minutes
  • Price: Free download
  • Published: 1 April 2019*
  • File format: Text
  • Words: 4,385 (approx)
  • Number of pages: 18 (approx)

Text preview of this essay:

This page of the essay has 4,385 words. Download the full version above.



1. INTRODUCTION

1.1. Diabetes mellitus

A metabolic disorder, commonly known as Diabetes mellitus (DM) is identified by hyperglycemia (Pontiroli, A.E. et al., 1994). Approximately 97% of diabetics suffer from type 2 diabetes mellitus commonly known as noninsulin-dependent (NIDDM), while the rest have type 1, insulin-dependent diabetes mellitus (IDDM) [Olokoba A.B. et al., 2012].

The number of people suffering from diabetes has increased significantly in 2014[Global report on Diabetes, WHO, 6th April 2016] and is projected to be the 7th leading cause of death by 2030 [Mathers and Loncar, 2006]. diabetes is  now considered as  one   of  the main health ssue to human in the 21st century [Zimmet et al., 2001], Considering the challenge, diabetes management has received wide research attention.

1.2. Complementary and alternative medicine for management of diabetes mellitus

Considering the challenge, diabetes management has received wide research attention. Hense, the use of CAM (complementary and alternative medicine) has augmented noticeably in recent decades [Frass et al., 2012] with an overall occasion of CAM use in diabetes (Ra et al., 2006).

1.3. Tinospora cordifolia as a CAM in treatment of diabetes.

Tinospora cordifolia (TC), is known as Guduchi / Giloy, a shrub belonging to the family Menispermaceae. The shrub is known as Amrita in Sanskrit. Ayurvedic system of medicine  use TC for treatment of diabetes mellitus [Sharma et al. 2015].

1.4. Herb-drug interactions

Natural products mainly herbs are regularly used along with conventional drugs, hoisting onset of herb-drug interaction. When the constituents of herb regulate absorption, distribution, metabolism and excretion of other co-administered drugs, then there will be onset of pharmacokinetic drug interaction. Alternatively, when the constituents alter the activity of receptors involved in the mode of action of the co-administered drug, then there will be onset of pharmacodynamic interaction. Pharmacokinetic interaction can occur mainly due to modulation of metabolic enzymes and various transports involved in the kinetics of the co-administered drug. The mechanism of herb-drug pharmacokinetic interaction are mainly due to the induction or inhibition of intestinal and hepatic metabolic enzymes particularly the CYP enzyme family, and similar effect on drug transporters particularly the P-glycoproteins in the intestines [D. Farkas, et. al.2008]

Figure 1. Graphical Representations of Drug-Herb Interactions

1.5. Metformin as drugs of choice in treatment of Diabetes.

Metformin Hydrocloride (CAS No.1115-70-4), chemically known as N,N dimethylimidodicarbonimidic diamide hydrochloride (Figure 3.), is the drug of choice for NIDDM belongs to the biguanide class. Mode of action of Metformin is by decreasing hepatic glucose production, decreasing intestinal absorption of glucose, and improving insulin sensitivity by increasing peripheral glucose uptake and utilization [https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021748s002lbl.pdf].

Figure 2. Chemical structures of Metformin (MET)

1.6. Glibenclamide (GLI) as drugs of choice in treatment of Diabetes.

Glibenclamide (CAS: 10238-21-8) is an oral sulfonylurea, chemically identified as 5-chloro-N-[2-[4-(cyclohexylcarbamoylsulfamoyl) phenyl] ethyl]-2-methoxybenzamide. It primarily lowers blood glucose by stimulating the release of insulin from pancreatic beta cells.

Figure 3. Chemical structure of Glibenclamide(GLI)

1.7. Mechanism of drug interaction for Metformin

Metformin do not unergo metabolism. The possible drug interaction can happen only through transporters OCT2 and hMATE transporters [Stage, T.B. et al. 2015].

Hence any herbal preparation containing   cationic constituents can alter the pharmacokinetic parameters of Metformin.

Figure 4. Graphical representation of drug transporters relevant to DDIs with Metformin

1.8. Mechanism of drug interaction for GLI

GLI primarily metabolized by CYP enzymes mainly through CYP2C9 and 3A4 to it’s hydrxylated metabolites. Drugs or herbes which can inhibit or induce these enzymes can mediate the drug-drug or drug-herb interaction with GLI.

1.9. Potential of Tinospora cordifolia for Herb-Drug interaction with Metformin and GLI

Tinospora cordifolia is reach in cationic photochemical like protoberberine alkaloids.  OCTs are involved in elimination path ways of protoberberine alkaloids including  jatrorrhizine and berberine which are constituents of TC.  Since both MET and constituents of TC are substrates for similar transporters, there is possibility of pharmacokinetic interactions.

CYP3A4 and 2D6 are inhibited by the hydro-alcoholic extract of TC. An active constituent of TC, Berberine, inhibits CYP 2C9 activity with IC50 of 500 µM. GLI is  metabolized to its cyclohexyl hydroxy methyl derivatives through by Cytochrome P450 enzymes (2C9, 3A4 and 2C19).

As TC alters the activity of metabolizing enzymes, it can influence the fate of coadministered GLI leading to an onset of herb-drug interaction.

   

Chapter 2

REVIEW OF LITERATURE

2. REVIEW OF LITERATURE

2.1. Complementary and Alternative Medicine (CAM) for Diabetes treatment

National center for Complementary and integrative health defines “Complementary and alternative medicine (CAM)” as term for medical products and practices that are not usually in standard medical care. Recent review documents describe the wide and frequent use of CAM, often without cunsultation with the patient's physician [Schimpff, S.C., 1997]. Most CAM are either a Natural product or a mind and body practices. Natural products are the major fraction among the total CAM in practice [https://nccih.nih.gov/sites/nccam.nih.gov/files/NHIS-10-Most-Common-Approaches-Adults-2012-01.gif] Countries like india where occurrence  of diabetes is at  a high, people rely on CAM including the use of herbal drugs [Kumar et al. 2006]. Many reviews have explained the craving of a large part of the world population on CAM for diabetes management. About 80% of the inhabitants of Africa and Asia rely on CAM primaryly for their healthcare [WHO, 2002; WHO, 2008 ]. The worldwide inclination towards CAMs for diabetes has  increased   significantly [Bell, R.A., et. al. 2006]. Te probability of use of CAM is 1.6 times more in case of diabetics than non-diabetics [Garrow, D., and  Egede, L.E., 2006].

2.2. General Awaireness regarding CAM

The perception that naturalproducts are safe led to the increased use of CAM. Around 80 % of the present day global population use CAM as a complement to the prescribed medicine [Mathew and Kuttan 1997; Noor et al., 1998; Malagi et al., 2014; Ekor, M., 2014.. It is a general misconception that herbal medicines are safe hence the patient do not consult their doctor regarding their concomitant use of herbal product and  prescribed drug [Obiageri O. O., 2012].  Mode of action of natural products is not yet known completely, it is beleved that they often act in a holistic manner. Their multiple constituents are the factors behind their net action. [La Clair JJ, 2010; Wink M., 2015]

2.3. Tinospora cordifolia as CAM for diabetes

TC celebrated its key position in Ayurvedic system of medicine for antidiabetic usages under a variety of formulation [Acharya, 2004; Chunekar et al., 2006; Sharma PV, 2006; Paradakara, 2010; Patel and Mishra, 2011, Rajalakshmi, et al., 2009]. Many modern herbal formulations for antidiabetic use v.i.z  Diasulin, Diabecon, and Diabeta are developedin india, which contain TC as a active ingradient [Modak et al., 2007]. Constituents like berberine, jatrorrhizine, mangnoflorine and palmatine, are the active constituent of TC which exert antidiabatic to the herb [Sharma R et al. 2015, Yin, J. et al. 2012].

2.4. Phytochemistry of Tinospora Cordifolia(TC)

A variety of chemical constituents such as alkaloids, aliphatic compounds, diterpenoid lactones, essential oils, glycosides, polysaccharides, and steroids, have been reported from various parts of TC.  Leaves of TC are loaded with protein (11.2%) and are quite rich in calcium and phosphorus [Zhao T., et. al. 1991].  Stem and root part of TC contain alkaloids like Aporphine, Berberine, Choline, Isocolumbin, Jatrorrhizine Magnoflorine, Palmetine, Tembetarine, Tinosporin,  and Tetrahydropalmatine [Upadhyay, A. et. al.., 2010; Rout, G.R., 2006; Gupta, R., and Sharma, V., 2011; Jagetia, G.C., Rao, S.K., 2006; Patel, M.B., Mishra, S., 2011]. Diterpenoid, Lactones like Columbin, Clerodane derivatives, Furanolactone, Jateorine,, Tinosporon and Tinosporides, are distributed in each and every parts of TC [Dhanasekaran, M., et. al 2009]. Stem extract contain Glycosides like 18-norclerodane glucoside (Tinosporaside), Cordifolioside A, B, C, D, E, Cordifolioside, Cordioside, Diterpene glucoside, Furanoid, Pregnane glycoside, Palmatosides, Syringin, Syringinapiosylglycoside Tinocordiside and Tinocordifolioside, , [Ly, P.T.T. et. al., 2007; Karpova, E.A., et. al., 1991; Kapil, A., Sharma, S., 1997]. Tinocordifolin a Sesquiterpenoid isolated in stem extract [Maurya, R., et. al., 1997]. Aliphatic compounds like Octacosanol, Heptacosanol Nonacosan-15-one dichloromethane are distributed all over the plant [Thippeswamy, et. al., 2008]. Many other compounds like 3,(a,4-di hydroxy-3methoxy-benzyl)-4-(4-hydroxy-3-methoxy-benzyl)tetrahydrofuran, Cordifol, Cordifelone, Giloin, Giloinin, Jatrorrhizine, Tinosporidine,  and Tinosporic acid are found in different parts of the plant [Jayaganthan, P., et. al., 2013]. Many alkaloids of TC are believed to have anti diabetic property. [Sharma R, et. al., 2015].

Table 1. Some chemical constituents of TC

Name Structure Monoisotopic Mass:

Molecular Formula:

Berberine,

336.123034 Da

C20H18NO4

Choline,  

104.10699 Da

C5H14NO

Tembetarine,

344.185635 Da

C20H26NO4

Name Structure Monoisotopic Mass

Molecular Formula

Magnoflorine,  

342.169985 Da

C20H24NO4

Columbin

358.141638 Da

C20H22O5

Palmetine

352.154335 Da

C21H22NO4

Aporphine,

235.1361 Da

C17H17N

Name Structure Monoisotopic Mass

Molecular Formula

Isocolumbin,

358.141638 Da

C20H22O6

Jatrorrhizine

338.138685 Da

C20H20NO4

Tetrahydropalmatine

355.178358 Da

C21H25NO4

Tinocordifolioside

412.209718 Da

C21H32O8

Name Structure Monoisotopic Mass

Molecular Formula

Tinosporaside

493.2068

C25H33O9

Tinocordside

396.214803 Da

C21H32O7

Syringin

312.120903 Da

C17H24O9

Name Structure Monoisotopic Mass

Molecular Formula

Cordioside

520.194462  Da

C26H32O11

Cordifoliside A

522.210112 Da

C26H34O11

Cordifoliside B

522.210112 Da

C26H34O11

Name Structure Monoisotopic Mass

Molecular Formula

Cordifoliside C

522.210112 Da

C26H34O11

Cordifoliside D

538.205027 Da

C26H34O12

Cordifoliside E

538.205027 Da

C26H34O12

Note: Most of the chemical components are cationic in nature

2.5. Herb-Drug Interaction potential of TC

Paucity of knowledge regarding usage of herbal drugs and prescription medicines concomitantly due to possible interaction further enhances safety concern for both patients and physicians. Herbs are an excellent source of potential drugs since about a third of existing allopathic drugs can be traced back to plants. As herbs are known to affect bodily functions, when used along with allopathic drugs there can be drug interactions which may affect the efficacy of allopathic drug.  [Obiageri O. O., 2012].

Broadly, three pathways account for herb-drug interaction. These include variation in metabolic system, modulation of the transporter proteins and agonistic/antagonistic effect of herbs with the co-administered drug. Pharmacokinetic of xenobiotics is controlled to a greater extent by the oxidative actions of cytochrome P450 (CYP) mono-oxygenase, whose activities are known to be affected by herbal drugs thereby resulting in alteration of metabolism of prescribed medicines [S.-F. Zhou, et. al. 2007].

CYPs play a major role in metabolism of drugs, resulting in either deactivation or bioactivation of drugs. This process accounts for nearly three fourths of drug metabolism.Further, constituents of herbs may induce CYP polymorphisms leading to alternationin drug metabolism and in turn altered pharmacokinetics. In addition, it may also result in undesirable drug interactions leading to possible toxicity [Wang, J.-F., Chou, K.-C., 2010].

Transporter proteins, such as P-glycoprotein, ATP-binding cassette transporter, etc., are responsible for the efflux of xenobiotics from a cell. However, their actions may be inhibited by natural products, resulting in herb-drug interaction [Eichhorn, T., Efferth, T., 2012].

Pharmacodynamics interactions between herbal products such as fenugreek and antidiabetic drugs have also been reported [Raghuram, 1994].

2.6. Antidiabetic Therapeutic use of T. Cordifolia

Extracts of TC are used as a home remedy for diabetes [Grover, Vats, and Rathi 2000]. Several reports have been published showing Hypoglycaemic effect of TC. [Stanely, Prince, and Menon 2000].TC is found as an active ingredient in majority of herbal formulations that are in use as antidiabetic medications, such as Diabeta ®, Diabecon ®, Diasulin ® [Venu Gopal, J. and Nilakash, S., 2013; Maninder Kaur, 2014]. The phytoconstituents of TC includingberberine, palmatine, jatrorrhizine and mangnoflorine have been reported as insulin mimetic and insulin secretary effect in vitro as well as in vivo [Yin, J. et. al. 2008; Patel and Mishra 2011; Jun Yin, J. et. al., 2012]. Patel MB and  Mishra S. investigated the isoquinoline alkaloid loaded fraction from stem, which largely contain palmatine, jatrorrhizine, and mangnoflorine acts like insulin mimetics and and insulin secretaryagent both in vitro (using rat pancreatic ß-cell line, RINm5F) and in vivo. [Patel, M.B., Mishra, S., 2011].Berberine, an active constituent of TC, significantly decrease spostprandial plasma glucose, glycosylated hemoglobin (HbA1c),total cholesterol, triglyceride and LDL-cholesterol. Berberine potentiates glucose disposal rate, and thus considered as an effective herbal therapy for NIDDM and dyslipidemia. [Zhang, Y., et. al., 2008].The root and stem of TC contain ß-sitostrol, cordioside, isocolumbin, palmatine, tinocordiside and tinosporinare known to elicit antidiabetic, antioxidant and antihyperlipidemic activities [Gupta, S.S., et. al., 1967]. The aqualcoholic and chloroform   extracts of the leaves of T.  Cordifolia at doses ranging from 50 to 400 mg/kg body weight exerted significant   hypoglycemic effect in rabbits [Wadood, N. et. al., 1992 ; Selvaraj, S., et. al., 2012; Puranik, N., et. al., 2010]. Transina (TR), an Ayurvedic compound formulation, containing T.cordifolia shows positive results for managing hyperglycemia [Bhattacharya, S.K. et. al., 1997].

Oral administration of  aqueous T.  cordifolia root  extract (TCE) to diabetic rats,  induced by alloxan  reduced blood glucose with lowering of alkaline phosphatase, hepatic glucose-6-phosphatase, serum acid phosphatase and lactate dehydrogenase.  Thus TCE is a potent hypoglycemic and   hypolipidaemic agent [Stanely, P. et. al., 2000].

Joladarashi et al demonstrated the aqua and alcoholic extracts of TC shows glucose uptake-stimulatory activity in tumor cells model of Ehrlich ascites [Joladarashi, D. et. al., 2014]. The leaf powder sample of TC showed hypoglycemic effect invitro [Ahmed, F. et. al., 2011]. Patel, M.B. and Mishra, S. reported the inhibition of  hydrlysing enzymes that regulates glucose level like fructose 1, 6-diphosphatase, and glucose 6-phosphatase by TCE in in vitro studies [Patel, M.B. and Mishra, S., 2011].  Isoquinoline alkaloids, namely, jatrorrhizine, magnoflorine and palmatine act as inhibitor of β-glucosidase enzyme thus supporting regulation of glucose level in an in-vitro study. [Patel, M.B., and Mishra, S.M., 2012].

 TC stem Extract containing glycosides, flavones, and phenolic compounds of plant extract demonstrate hypoglycemic effect in Streptozotocin induced diabetic Wistar rats [Naik, P.R., et al., 2012].

 Sangeetha, M. K. and colleagues   studied the effect of TC at dose rate of 100 and 200 mg/kg body weight in type 2 diabetes SD rats induced by administration of high-fat diet (HFD) and streptoztoocin. A 14 day experiment showed decresase in the blood glucose, improvement of insulin secretion and suppression of stress markers [Sangeetha, M.K., et. al., 2011].

Resistance to insulin, in high-fructose diet-induced rats, was suppressed by aqueous extract of TC stem, when treated at 400 mg/kg/day for 60 days. [Sreenivasa Reddy, S et. al., 2009].

400 mg/kg per day of aqueous extract of TC when treated for 15 weeks to experimental diabetic animal improve the condition in the moderate to severe diabetes [Grover, J.K., et. al., 2000]. Aqueous extract of root at 400 mg/kg for four months shows an antihyperglycemic effect on alloxan induced experimental diabetic rats [Stanely, P., et. al., 2000]. Hypoglycemic effect is observed after treatment of aqueous root extract  for two months to diabetic rats [Rathi, S.S., et. al., 2002].

Root extract extract of Tinospora cordifolia, when treated to alloxan induced diabetic rats for 42 days, reduced the glucose level in blood and urine. [Prince, P.S.M., and  Menon, V.P., 2003].

Extract of TC stem at 250 mg/kg body weight per day, improved the C-peptide levels and insulin in diabetic rats [Rajalakshmi, M., et. al., 2009].

Alcoholic crude extract of TC reduced glucose level in diabetic rats in an in-vivo experiment [Kar, A., et. al., 2003].

Plasma glucose level was reduced when TC whole plant extracts is treated orally for about two months at 200 mg/kg to  400 mg/kg/day to STZ induced diabetic rats. [Grover, J.K., et. al., 2001, 2002].

2.7. Clinical evidence of TC as Antidiabatic therapy

T. cordifolia leaf digest is found effective for decreasing Blood glucose clinically in type 2 diabetic subjects on the basis of glucose tolerance test[K.S., et. al., 2002].  Number of PG dissertation works are done on clinical efficacy of T. cordifolia in diabetic patients [Sharma, R., Amin, H., Galib, Prajapati, P.K., 2015.]. Clinical studies have been done on berberine a constituent of root extract of TC have showed its effects on hyperglycemia and dyslipidemia. [Zhang, Y., et al., 2008]. Another pilot clinical study was performed to determine the efficacy and safety of berberine in treating diabetes mellitus patients and the results signify the hypoglycemic effect of berberine [Yin, J. at. al, 2008]

When powered stem of Tinospora cordifoia at 50 mg/kg body weight orally is prescribed for 15 days significantly decreased total cholesterol, ß lipoproteins, triglycerides and fasting blood sugar levels in type 2 diabetic patients with [Kumar, V.,  and Mahdi, F. et. al., 2016].

2.8. Clinically desirable drug interactions of TC

TC is reported to have any harmful herb-drug interaction till date, however a lot of gaps need to be explored in this area. Pharmacokinetic and pharmacodynamic of Metformin is improved by concurrent administration of TC thus enhancing it’s antihyperglycemic and antihyperlipidemic activity [Patwardhan, B., 2012].

2.9. Toxicity and Safety concerns of TC

As per the available literature till date, TC is considered as safe herbal drug as no obvious toxicity data  is available. [Upadhyay, A., et al., 2010].   

2.10. Potential of Tinospora cordifolia for Herb-Drug interaction with Metformin and GLI

Plant alkaloid Berberine is reported to enhance the efficacy of Metformin [Prabhakar, P.K., and Doble, M., 2009]. Tinospora cordifolia is reach in cationic photochemical like protoberberine alkaloids. OCTs are involved in elimination path ways of protoberberine alkaloids including  jatrorrhizine berberine which are constituents of TC [Tan, Z., et al., 2013; Chen, C., et al. 2015].  Since both MET and constituents of TC are substrates for similar transporters, there is possibility of pharmacokinetic interactions. CYP3A4 and 2D6 can be inhibited to half of it’sactivity ata concentrationof 0.2 mg/mL of hydro-alcoholic extract of TC in in-vitro [Bahadur et al. 2016].

The IC50 of Berberine for inhibition of CYP 2C9 was found to be about 500 µM, which may contribute towards herb-drug potential of TC with other drugs [Chatterjee and Franklin. 2003].

Cytochrome P450 enzymes together with 2C9, 3A4 and 2C19 aremajorly responsible for metabolism of GLI to it’s oxidative biotransformation product “cyclohexyl hydroxy methyl derivatives”. cytosolic enzymes further metablize these cyclohexyl hydroxy methyl derivatives to carboxyl derivative [Zhou et al., 2009; Zharikova et al., 2007].

2.11. Authentication of TC

There are various methods for authentication of herbal extract. Among them, following three methods are commonly used.

1. Comparison of pharmacognostical parameters with the valid scientific literature

2. Chromatographic study against reference specimen

3. Chromatographic evaluation reference constituents

[https://www.tga.gov.au/publication/identification-herbal-materials-and-extracts]

Presence of protoberberine alkaloids as marker substances to check the quality of TC extract and different formulation by validated RP-LC-DAD method was reported. LC-MS (SIM) method was employed to identify the marker compounds (Jatrorrhizine, Palmatine and Berberine). [Patil, D., et. al. 2010]

Quality of the stem juice of TC under refrigerated storage was tested by UPLC-QTOFMS profile of the marker compounds. [Shirolkar, A., et.al. 2013.]

2.12. Chemistry and general description of Metformin

Metformin (CAS No.1115-70-4) is a biguanide, antidiabetic agents [https://www.drugs.com]. Metformin HCl, USP is a crystalline compound white to off white in coour. Molecular formula of MET.HCl is C4H11N5 • HCl with molecular weight of 165.62. MET.HCl is freely soluble in water and is insoluble in acetone, chloroform and ether. The pH of aqueous solution of Metformin HCl with pKa 12.4.,

2.13. Route of Administration of Metformin

Metformin is commonly administered as tablet dosageform. MET is administered  2 or 3 times a day with food [Campbell, I.W., et. al., 1987; Johnston, P., and Rough, T. 1983].

MET is administered as extended-release tablets with the evening meal in a dose regimen of once daily [Andrx Laboratories, 2005 May; Teva Pharmaceutical USA 2004 April].

2.14. Clinical dosage of metformin

Dose of MET starts with  500 mg twice daily with meals. Daily dosage  is in increased up to a maximum of 2 g daily.[Bristol-Myers Squibb Company, 2009 Jan].

2.15. Pharmacokinetics of MET

Bioavailability of MET is ranged from 50–60% with dosages of 0.5–1.5 g. [Vidon, N., et. al., 1988; Pentikäinen, P.J., et. al., 1979; Lucis, O.J., 1983; Tucker, G.T., et. al., 1981]. The extent of absorption of MET in extended-release tablets is increased by food.  [Andrx Laboratories, 2005 may].  

Metformin  is not bound to plasma proteins well hence rapidly distributed into peripheral body fluids and tissues [Wilcock, C., and Bailey, C.J., 1994; Scheen, A.J., 1996; Pentikäinen, P.J., et. al., 1979]

Metformin is not at all metabolized by metabic enzymes or GI tract and not excreted into bile.  No metabolites identified in humans. [Merck, 2011 April; Pentikäinen, P.J., et. al., 1979; Tucker, G.T., et. al., 1981; Sirtori, C.R., et. al., 1978]. Metformin is excreted unchanged through tubular excreation and feces.[ Somogyi, A., et.al., 1987]. Excretion of Metformin is regulated by human organic cation transporter 2 [hOCT2] for it’s uptake from blood and then eliminated into the lumen by apical organic cation antiporters [Muller, J., at. al. 2005].

Half life of Metformin is approximately 6.2 hours in clinic. [Caille, G., et. al., 1993; Arafat, T., et .al., 1994]

Organic cation transporters (OCTs), : multidrug and toxin extrusion transporters (MATEs)  and plasma membrane monoamine transporter (PMAT)  are the three different type of transporters involved in the transport of metformin [Staud, F et. al. 2013; Zhou, M et.al. 2007].

Drug interaction Potential of Metformin

A complete Review of Drug-Drug Interactions with Metformin by Stage et al 2015 compiled the DDI research with Metformin till date. The DDI of Metformin is mainly mediated through OCTs and PMATs. [Stage, T.B., et. al, 2015].

Drug interaction of Metformin with cataionic drug cimetidine was mediated through OCTs and hMATE1 on epithelial cells. Cimetidine had superior affinity for hMATEs than for hOCT2. [Graham, G.G., et. al., 2011].

2.16. Chemistry and general description of Glibenclamide (GLI)

GLI is an oral diabetes from Sulfonylurea group that helps control blood sugar levels with CAS registry number: 0010238-21-8, Chemical Formula : C23H28ClN3O5S, and molecular weight 494.0, Monoisotopic Mass 493.144 g/mol, and exact mass 493.144 g/mol

GLI is a solid with melting point at 169 – 170 ºC, Water Solubility of glimeperide is 2 mg/L [http://www.hmdb.ca/metabolites/HMDB0015151].

2.17. Route of Administration of Glibenclamide

GLI is always administered orally  after meals to reduce adverse GI effects. [https://www.accessdata.fda.gov/ drugsatfda_docs/ label/2009/017532s030lbl.pdf].

2.18. Dosage of Glibenclamide

The dose of GLI ranges from 1.25 mg/ day to 5 mg/day depending upon the age group and situation of the patient. [https://www.drugs.com/dosage/glyburide.html]

2.19. Pharmacokinetics of Glibenclamide

Absorption

GLI is absorbed within one hour; Cmax of GLI is attained at about four hours, and persists till twenty-four hours. GLI do not deposited in organs , as the AUC under the plasma concentration – time curve increases linearly with dose. The half-life of GLI is about 10 hours. [https://www.accessdata.fda.gov/drugsatfda_docs/label/ 2009/017532s030lbl.pdf]

Distribution

GLI is non ionic compared to other sulfonynl urea drugs. The extent of protein binding is less compared to the other  sulfonynl urea drugs. Hence GLI exert minimal drug interaction against the drogs that can displace the active sites of the plasma. [https://www.accessdata.fda.gov/drugsatfda_docs/label/ 2009/017532s030lbl.pdf]

Metabolism

GLI primarily metabolized by CYP enzymes mainly through CYP2C9 and 3A4 to it’s hydrxylated metabolites. The major metabolite of GLI, the 3-cis-hydroxy derivative and 4-trans-hydroxy derivative. are weekly active.

https://www.accessdata.fda.gov/drugsatfda_docs/label/ 2009/017532s030lbl.pdf]

Excretion

The metabolites of GLI are excreted in the form of it’s metabolites through urine and bile aboutb half in each route.

[https://www.accessdata.fda.gov/drugsatfda_docs/label/ 2009/017532s030lbl.pdf]

Drug interaction potential of GLI

The drug interaction of GLI is observed mainly due to modulation of metabolic enzyme.  Rifampin significantly reduce the availability of GLI by inducing the CYP enzymes such as CYP2C9 and 3A4 which are mainly responsible for metabolism of GLI. [https://www.accessdata.fda.gov/drugsatfda_docs/label/ 2009/017532s030lbl.pdf]

Many studies are reported on herb drug interaction potential with GLI. Extract of Pleurotus pulmonarius, demonstrates major increase in glucose thresheshold of GLI in oral glucose tolerance test. The possible mode of action is unknown. [Badole, S.L., et. al. 2008].

Gymnema sylvestre leaf extract show an synergistic effect on the hypoglycemic effects of GLI [Baskaran, K.,et. al., 1990; Shanmugasundaram, E.R., et. al., 1990].

Hypoglycemic effect of Aloevera juice synergise the effect of glibenclaide in a clinical trial [Yongchaiyudha, S., et. al., 1996]. Absorption of GLI  is reduced mainly by high fiber herbal drugs.[ Colalto, C., 2010] Efficacy of GLI is increased by chloroform/benzene extract of Karela in NIDDM subjects.[Tongia, A., et al., 2004.]. In one of the study in a STZ-induced diabetes in rat model, ginger extract enhanced the effect of GLI[Al-Omaria, I.L., et. al. 2012]. Lipid peroxidation (LPO) induced by ferrous sulphate, hydrogen peroxide and carbon tetrachloride in liver were performed. Fenugreek seed extract enhances the inhibition of the hepatic LPO by GLI in a combination treatment. [Neha, S., Anandet.  al., 2015.]. Cassia fistula increase the activity of GLI by inhibition of  activities of CYP2C9 [ Appiah-Opong, R., et al., 2008].

 

Chapter 3

RATIONALE OF THE STUDY

3. RATIONALE OF THE STUDY

Diabetes is now considered as one   of the main health issue to human in the 21st century (Zimmet et al., 2001). Difficulties in its management and complications in chronic conditions have attracted alternative and complimentary approaches for its effective management. Thus, this has received wide research attention.

CAM is popular in diabetes and many herbs/foods are concomitantly taken with antidiabetic drugs for maximizing the efficacy. The perception that everything green is good for health has advanced the use of CAM in India as well as the world. Herbs are often advocated to act in a holistic manner. Their multiple components are the factors behind their polypharmacology. Accordingly their influences on pharmacokinetics of either their co-component or co-administered drugs may contribute to significant drug interaction.

TC is well known for its antidiabetic action mainly due to insulin mimicking and insulin releasing effects. This is largely attributed to its constituents including palmatine, jatrorrhizine, mangnoflorine and berberine. Nevertheless contribution from other components cannot be ruled out. Since it is widely used as a complimentary medicine in diabetes, it has potential to interfere in the pharmacokinetics of co-administered drugs owing to its   chemically diverse multiple components.

Metformin and Glibenclamide are the drugs of choice for treatment of Diabetes mellitus. Metformin is not metabolized and eliminated unchanged by renal tubules.Hence it should be less prone to metabolic enzyme mediated drug interaction. Nonetheless, its interaction with TC can be expected due to the fact that its uptake and excretion are mediated by saturable transportation system. OCTsand PMATs are largely responsible for its uptake and excretion Metformin. Since TC also contains many cationic components, competitive saturation can lead to significant drug interaction with Metformin following co-admonistration. Unlike Metformin, Glibenclamide is extensively metabolized through CYP enzymes mainly via CYP2C9 and CYP3A4. Since TC constituents including Berberine are known to inhibit these enzymes, their co-administration may have significant impact on the metabolism of GLI which may lead to HDI.

Taking the above into consideration we took up this research with following objectives

• Determine the pharmacokinetic interaction of TC with MET

• Influence of TC on metabolism of GLI

• Determination of the pharmacokinetic interaction of TC with GLI

...(download the rest of the essay above)

About this essay:

If you use part of this page in your own work, you need to provide a citation, as follows:

Essay Sauce, Complementary and Alternative Medicine for Management of Diabetes Mellitus: Tinospora Cordifolia as a CAM in Treatment of Diabetes. Available from:<https://www.essaysauce.com/sample-essays/2018-9-10-1536564658/> [Accessed 29-03-24].

These Sample essays have been submitted to us by students in order to help you with your studies.

* This essay may have been previously published on Essay.uk.com at an earlier date.