Keywords

Gymnema sylvestre, Pharmacokinetics, pharmacodynamics, Diabetes, Gliclazide.

Introduction

Many medicinal herbal and pharmaceutical drugs are therapeutic at one dose and toxic at another dose. Interactions between herbal and pharmaceutical drugs can increase or decrease the pharmacological or toxicological effects of either component, herbal drugs are traditionally used to decrease glucose concentrations in diabetic patients [1] could theoretically precipitate hypoglycaemia if taken in combination with conventional drugs.

Experimental studies have shown that herb-drug interactions have both a pharmacokinetic and pharmacodynamic basis, most of that are attributed to the induction or inhibition of hepatic and intestinal microsomal enzymes (primarily cytochrome P450) drug transporters [2]. Gliclazide is an oral antihyperglycemic agent used for the treatment of non-insulin- dependent diabetes mellitus (NIDDM). It belongs to the sulfonylurea class that act by stimulating β cells of the pancreas to release insulin [3].Gliclazide binds to the β cell sulfonyl urea receptor (SUR1). This binding subsequently blocks the ATP sensitive k + channels. The binding to closing of the ion channels and leads to a resulting decrease in k + ion efflux leads to depolarization of the β cells. This opens voltage gated calcium channels in the β islet, that leads to exocytosis of insulin containing secretorty granules [4].Oral absorption of gliclazide is similar in patients and healthy volunteers, there is inter subject variation in time to reach peak plasma concentrations (tmax). Tmax and cmax are increased after repeated gliclazide administration. Steady state concentration is achieved after 2 days administration of 40 to 120 mg of gliclazide. Gliclazide has low volume of distribution (13 to 24L) in both patients and healthy volunteers because of its high protein binding affinity (85 to 97%) . The elimination half-life (t1/2) is about 8.1 to 20.5 hr in healthy volunteers and patients after administration of 40 to 120 mg orally. Moreover, its plasma clearance is 0.78 L/h (13 ml/min). It is extensively metabolized to 7 metabolites and excreted in urine therefore renal insufficiency has no influence in pharmacokinetic of gliclazide [5].The most notable effects are hypoglycaemia; gastrointestinal disturbances such as indigestion, epigastric pain and chest pain; dermatological reactions such as rash and transient itching; and biochemical abnormalities such as elevated serum creatinine, alkaline phosphatase, AST,and raised serum bilirubin. Cerebral vasodilation, mild disulfiram-like reactions and lassitude have been reported [6]. Gymnema sylvestre is used in different systems of medicine as a remedy for the treatment of diabetes, rheumatism, and cough. [7]. The major phytoconstituents of Gymnema sylvestre are gymnemic acids, gudmarin and saponins. Gymnemic acid (C43H68O14) is a pentacyclic triterpenoid and is the main active phytoconstituents of Gymnema sylvestre, exhibiting potent anti-diabetic activity [8]. Gymnemic acid show different physiological activities as lower blood glucose and levels of insulin in the diabetic subjects and inhibit intestinal glucose absorption [9].Recent times have witnessed increased incidence of diabetes across the globe, along with increased popularity of herbal products in the international market [10].

Rural people are still dependent on indigenous knowledge for health care that are being influenced by culture and socioeconomic aspects, providing a cheaper and accessible alternative to the high cost pharmaceutical remedies. In spite of the overwhelming influence and our dependence on modern medicine and tremendous advances in synthetic drugs, many people still rely on herbs the reason is that, if the herbs are used properly they don’t have any side effects. Hence, the study need to be subjected to pharmacological studies in order to discover their effect on the patients who are taking the treatment with synthetic drugs.

Materials and Methods

Drugs And Chemicals

Albino rats of either sex weighing between 180 and 250 g obtained from National institute of Nutrition India. These animals were maintained proper conditions in animal house of Vaageswari College of pharmacy {IAEC number VCP/2012/10/6/16}. streptozotocin (Neocare Naturals Pvt. Ltd, Hyderabad, India).Gymnema sylvestre collected from Mahadevepur forests India and Plant is authenticated by Dr.E.Narasimha Murthy, Department of Botany, Satavahana University, Karimnagar, Andhra Pradesh. {Specimen Accession Number ENM-100127}.

Extraction Procedure Of Gymnema Sylvestre

500gm of leaves of Gymnema sylvestre were taken, a small amount of dust present as dust was removed by shifting through a sieve of mesh number 30.initial identification was done by chewing few leaves for a minute. the mouth rinsed clean with water few grains of sugar were placed in mouth and disappearance of sugars sweetness was felt.1gm powdered material was shaken vigorously with water and examined for more than 30 minutes for froth test confirmed presence of saponin glycosides that is gymnemicacid.500gm of powdered dry leaf powder was packed soxhlet thimble and extracted continuously with 80% of ethanol until the material was completely exhausted. The final product was dark green amorphous powder after evaporation of solvent [11] .

Pretreatment

Albino rats of both gender weight between 180 and 250 g obtained from National institute of Nutrition, Hyderabad, India. These animals were maintained under standard conditions in animal house of Vaageswari College of pharmacy [IAEC number VCP/2012/10/6/16]. Each were kept in elevated wire cages and were provided with high fat food (carbohydrates: proteins: fat in 42:18:40 ratios) and water ad libitum for a period of 14 days [12].

Induction Of Diabetes In Rats By Using 60mg/Kg Of Streptozocin [13]

After 2 weeks of feeding with high fat food the rats were fasted for a period of 18 hours before induction of diabetes, and were injected intra-peritonially with a single dose of Streptozocin 60 mg/kg (Sigma–Aldrich, St. Louis, MO, USA), freshly dissolved in normal saline solution. After the administration, the rats had free access to food (normal pellet diet) and water ad libitum. Diabetes in rats was identified by moderate polydipsia and marked polyuria. After 3 days i.e. 72hrs of injection, the fasting blood glucose levels were determined by following glucose oxidase/peroxidase GOD/POD method using a commercial glucose estimation kit with UV-Visible Spectrophotometer at 505nm. The rats showing fasting blood glucose more than 150 mg/dL were considered diabetic rats and selected for the grouping in experimentation.

Study Design

The hyperglycemic rats are divided in to 6 groups 6 animals in each

Group I: Diabetic Control group (0.5% Na.CMC suspension)

Group II: Gymnema sylvestre (100 mg/kg)

Group III: Gymnema sylvestre (500 mg/kg)

Group IV: Gliclazide (40 mg/kg)

GroupV: Combination of Gliclazide (20mg/kg) + Gymnema sylvestre (500 mg/kg).

Group VI: Combination of Gliclazide (40 mg/kg) + Gymnema sylvestre (500 mg/kg). [14]

Pharmacokinetic Study in Diabetic Rats

Single Dose Study (Acute Study)

The diabetic rats were divided into 6 different treatment groups same as mentioned in study design and Daily treatment was carried for 21 days(3 weeks).Blood samples were collected from different groups on 0,7,14,21st day immediately after treatment. Blood samples were collected in to micro-centrifugal tubes containing sodium citrate from retro-orbital sinus under, mild ether anaesthesia. The blood samples were subjected to centrifugation at 3000 rpm for 10 min and plasma was stored at -200 C for analysis and determination of pharmacokinetic parameters as absorption rate constant, elimination rate constant, t1/2, V/F, CL/F, Tmax, Cmax, AUC 0-t, AUC 0 – ∞ .

Multiple Dose Study (Chronic Study)

The diabetic rats were divided into 6 different treatment groups same as mentioned in study design and Daily treatment was carried for 21 days(3 weeks).Blood samples were collected from different groups on 0,7,14,21st day immediately after treatment. Blood samples were collected in to micro-centrifugal tubes containing sodium citrate from retro-orbital sinus under, mild ether anaesthesia. The blood samples were subjected to centrifugation at 3000 rpm for 10 min and plasma was stored at -200 C for analysis and determination of pharmacokinetic parameters as absorption rate constant, elimination rate constant, t1/2, V/F, CL/F, Tmax, Cmax, AUC 0-t, AUC 0 – ∞ .

Pharmacodynamic Study in Diabetic Rats

Single Dose Study (Acute Study)

Adults albino rats weighing 180-250g with fasting serum glucose >150 mg/dl are considered as diabetic. The treatment was given as mentioned in study design. Different biochemical parameters as serum glucose, cholesterol, urea concentrations are measured at different time intervals of 0, 1, 2, 4, 8, 12 and 24hr by using semi auto analyzer. These values are considered as acute study values.

Multiple Dose Study (Chronic Study)

The diabetic rats were divided into 6 different treatment groups same as mentioned in study design and Daily treatment was carried for 21 days (3 weeks).Different biochemical parameters as glucose, cholesterol, urea concentrations of the overnight fasted rats were determined on 0,7,14,21st day using semi auto analyzer.[15]

Statistical Analysis

All data are expressed as Mean+Sd. For comparison amongst different groups, One-way analysis of variance (ANOVA) followed by Dunnet test was performed. P value fewer than 5% (P <0.05) was considered to be statistically significant.Pharmacokinetic data was calculated by using pk solver software and statistical analysis was done by INSTANT graph pad software.

Histopathological Studies

After the last blood glucose estimation, the rats were sacrificed and pancreas were excised and subjected to histopathological studies to determine the inflammatory and necrotic changes. The tissues were stained using H&E stain and observed under 100 × magnifications. [16].

Results & Discussion

Table 1

Blood glucose levels mg/dl (0th,1st ,2nd,4th,8th, 12th and 24th Hour) after oral administration of Gymnema sylvestre, Gliclazide and combination of Gliclazide and Gymnema sylvestre in diabetic rats (n=6).

TREATMENT/Hours BLOOD GLUCOSE LEVELS (mg/dL)
DIABETIC CONTROL G S (DOSE) GLICLAZIDE(DOSE) GLICLAZIDE + G S (DOSE)
vehicle 100mg/kg 500mg/kg 40mg/kg 20mg/kg +500mg/kg 40mg/kg +500mg/kg
0th Hour BLOOD GLUCOSE LEVELS 402.2±11.6 411.2±10.4* 390.8±6.5* 386.11±8.13* 381.08±6.15* 378.24±6.73*
1st Hour BLOOD GLUCOSE LEVELS 463.6±9.8 409.6±1.20* 387.19±9.3* 380.09±9.05* 371.81±4.28* 356.93±5.66*
2nd HourBLOOD GLUCOSE LEVELS 464.1±9.3 349.2±12.9* 379.11±8.6* 375.13±4.51* 365.15±6.19* 344.08±9.03*
4th HourBLOOD GLUCOSE LEVELS 429.6±7.9 337.4±13.4* 365.26±4.8* 346.88±9.08* 340.86±5.68* 331.99±6.16*
8th HourBLOOD GLUCOSE LEVELS 440.1±8.4 298.2±4.5* 274.91±8.7* 261.81±1.35* 249.81±11.2* 240.18±8.28*
12th HourBLOOD GLUCOSE LEVELS 414.7±9.2 314.6±8.5* 294.7±5.5* 258.36±8.11* 245.81±8.24* 236.91±9.16*
24th HourBLOOD GLUCOSE LEVELS 415.8±11.2 323.4±9.6* 301.6±3.4* 264.18±10.16* 251.05±10.61* 241.18±8.11*

Values are given as mean± Standard deviation. *Statistical significance p < 0.05 (compared with the control group) G S -Gymnema sylvetsre n – number of animals used.

Table 2

Blood cholesterol levels mg/dl (0th,1st ,2nd,4th,8th, 12th and 24th Hour) after oral administration of Gymnema sylvestre, Gliclazide and combination of Gliclazide and Gymnema sylvestre in diabetic rats (n=6).

BLOOD CHOLESTEROL LEVELS (mg/dL)
TREATMENT/Hours DIABETIC CONTROL G S (DOSE) GLICLAZIDE(DOSE) GLICLAZIDE + G S (DOSE)
vehicle 100mg/kg 500mg/kg 40mg/kg 20mg/kg +500mg/kg 40mg/kg +500mg/kg
0th HourBLOOD CHOLESTEROL LEVELS 199.3±12.5 208.2±9.4* 203.5±12.1* 200.81±10.35* 195.94±10.62* 190.16±4.92*
1st HourBLOOD CHOLESTEROL LEVELS 194.2±10.4 200.2±8.4* 195.5±14.2* 183.11±8.04* 179.18±9.16* 176.11±6.45*
2nd HourBLOOD CHOLESTEROL LEVELS 201.1±6.8 184.6±4.4* 181.6±7.4* 175.05±7.11* 169.15±8.16* 165.99±5.72*
4th HourBLOOD CHOLESTEROL LEVELS 204.9±12.5 175.2±7.8* 170.2±7.5* 154.24±9.16* 151.18±8.11* 149.03±6.91*
8th HourBLOOD CHOLESTEROL LEVELS 203.8±8.6 148.1±5.5* 145.9±8.4* 140.66±10.15* 136.15±5.18* 129.66±8.19*
12th HourBLOOD CHOLESTEROL LEVELS 210.6±9.5 154.9±6.3* 150.4±6.5* 138.48±11.81* 131.61±8.15* 126.48±11.94*
24th HourBLOOD CHOLESTEROL LEVELS 211.5±7.9 178.7±8.2* 169.6±2.4* 144.88±2.08* 134.84±9.06* 130.11±6.08*

Values are given as mean± Standard deviation. *Statistical significance p < 0.05 (compared with the control group) n – number of animals used G S – Gymnema sylvetsre

Table 3

Blood urea levels mg/dl (0th,1st ,2nd,4th,8th, 12th and 24th Hour) after oral administration of Gymnema sylvestre, Gliclazide and combination of Gliclazide and Gymnema sylvestre in diabetic rats (n=6)

BLOOD UREA LEVELS (mg/dL)
TREATMENT/Hours DIABETIC CONTROL G S (DOSE) GLICLAZIDE(DOSE) GLICLAZIDE + G S (DOSE)
vehicle 100mg/kg 500mg/kg 40mg/kg 20mg/kg +500mg/kg 40mg/kg +500mg/kg
0th HourBLOOD.UREA LEVELS 63.72±7.5 64.8±5.5* 74.36±4.1* 71.52±5.9* 65.88±6.6* 63.78±4.2*
1st HourBLOOD UREALEVELS 63.18±2.6 64.72±7.8* 67.5±5.1* 70.38±5.5* 61.02±6.5* 60.48±2.6*
2nd HourBLOOD UREALEVELS 66.34±9.2 62.02±5.2* 65.24±7.1* 65.18±6.2* 58.78±6.32* 57.7±8.1*
4th HourBLOOD UREALEVELS 66.96±5.6 59.4±6.2* 57.24±5.4* 54.66±5.2* 56.16±6.35* 55.08±5.5*
8th HourBLOOD.UREALEVELS 68.04±4.5 50.76±6.4* 48.6±5.8* 51.23±71* 45.36±5.4* 43.2±4.4*
12th HourBLOOD UREALEVELS 69.12±4.4 54±6.6* 52.38±7.4* 53.26±5.2* 47.52±5.4* 45.36±7.4*
24th HourBLOOD UREALEVELS 68.24±9.0 61.56±5.2* 59.4±7.5* 56.36±5.1* 55.23±5.4* 52.35±4.4*

Values are given as mean± Standard deviation. *Statistical significance p < 0.05 (compared with the control group) G S – Gymnema sylvetsre n – number of animals used.

Table 4

Blood glucose levels mg/dL (0th,7th, 14th and 21st day) after oral administration of Gymnema sylvestre, Gliclazide and combination of Gliclazide and Gymnema sylvestre in diabetic rats (n=6)

BLOOD GLUCOSE LEVELS (mg/dL)
TREATMENT/DAYS DIABETIC CONTROL G S (DOSE) GLICLAZIDE(DOSE) GLICLAZIDE+ G S (DOSE)
vehicle 100mg/kg 500mg/kg 40mg/kg 20mg/kg +500mg/kg 40mg/kg +500mg/kg
0ty dayBLOOD GLUCOSE LEVELS 410.2±4.5 419.2±2.2* 395.4±1.2* 390.4±3.1* 386.9±2.3* 370.8±1.3*
7th dayBLOOD GLUCOSE LEVELS 394.2±.2.4 238.1±2.4* 231.±3.1* 217.6±5.2* 211.5±1.34* 202.5±3.3*
14th dayBLOOD GLUCOSE LEVELS 385.8±3.4 180.5±1.5* 150.6±3.4* 120.5±2.6* 111.5±2.4* 106.8±2.4*
21st dayBLOOD GLUCOSE LEVELS 391.7±3.4 130.6±2.4* 121.5±2.5* 101.6±1.6* 98.8±1.4* 91.4±.3.4*

Values are given as mean± Standard deviation. *Statistical significance p < 0.05 (compared with the control group) G S – Gymnema sylvetsre n – number of animals used.

Table 5

Blood cholesterol levels mg/dl (0th,7th, 14th and 21st day) after oral administration of Gymnema sylvestre, Gliclazide and combination of Gliclazide and Gymnema sylvestre in diabetic rats (n=6).

BLOOD CHOLESTEROL LEVELS (mg/dL)
TREATMENT/DAYS DIABETIC CONTROL G S (DOSE) GLICLAZIDE(DOSE) GLICLAZIDE+ G S (DOSE)
vehicle 100mg/kg 500mg/kg 40mg/kg 20mg/kg +500mg/kg 40mg/kg +500mg/kg
0ty dayBLOOD CHOLESTEROL LEVELS 193.7±11.5 188.3±9.5* 182.5±12.2* 186.5±6.3* 181.8±8.4* 175.6±9.2*
7th dayBLOOD CHOLESTEROL LEVELS 194.8±10.6 105.4±9.6* 102.4±8.4* 103.2±8.1* 94.6±6.6* 90.5±8.6*
14th dayBLOOD CHOLESTEROL LEVELS 186.2±9.5 86.5±9.23* 84.4±7.8* 77.5±8.24* 72.28±5.8* 69.6±10.8*
21st dayBLOOD CHOLESTEROL LEVELS 191.2±7.8 73.6±10.4* 70.±9.2* 69.2±8.4* 55.1±7.8* 51.2±6.4*

Values are given as mean± Standard deviation. *Statistical significance p < 0.05 (compared with the control group) G S – Gymnema sylvetsre n – number of animals used.

Table 6

Blood urea levels mg/dl (0th,7th, 14th and 21st day) after oral administration of Gymnema sylvestre, Gliclazide and combination of Gliclazide and Gymnema sylvestre in diabetic rats (n=6).

BLOOD UREA LEVELS (mg/dL)
TREATMENT/DAYS DIABETIC CONTROL G S (DOSE) GLICLAZIDE(DOSE) GLICLAZIDE+ G S (DOSE)
vehicle 100mg/kg 500mg/kg 40mg/kg 20mg/kg +500mg/kg 40mg/kg +500mg/kg
0th dayBLOOD.UREA LEVELS 71.2±4.83 68.13±8.24* 69.6±6.51* 78.32±4.32* 74.25±4.33* 70.45±3.91*
7th dayBLOOD.UREA LEVELS 77.64±9.21 42.25±2.42* 38.12±4.01* 36.24±4.31* 33.21±4.21* 30.23±6.81*
14th dayBLOOD.UREA LEVELS 79.25±7.33 32±8.51* 32.05±6.03* 27.32±5.44* 25.14±9.14* 22.43±8.24*
21st dayBLOOD.UREA LEVELS 70.08±6.25 32.47±9.23* 30.12±8.54* 26.35±10.08* 23.75±9.94* 20.19±8.64*

Values are given as mean± Standard deviation. *Statistical significance p < 0.05 (compared with the control group) G S – Gymnema sylvetsre n – number of animals used.

Table 7

Effect of Gymnema sylvestre on Pharmacokinetic parameters of Single dose administration of Gliclazide in diabetic rats(n=6)

Pharmacokinetic parameter Units for Pharmacokinetic parameters 40mg/kg of GLICLAZIDE GLICLAZIDE + Gymnema sylvestre (DOSE)
20mg/kg+500mg/kg 40mg/kg+500mg/kg
ka h-1 0.91±0.04 0.52±0.11* 0.54±0.31*
ke h-1 0.21±0.01 0.24±0.05* 0.25±0.08*
t1/2 h 9.19±0.11 9.14±0.83* 9.62±0.14*
V/F (mg/kg)/(μg/ml) 22.25±0.82 28.32±3.14* 34.93±16.26*
CL/F (mg/kg)/(μg/ml)/h 4.59±0.25 6.41±0.31* 8.64±0.61*
Tmax h 2.04±0.08 2.48±0.19* 2.63±0.46*
Cmax μg/ml 1.44±0.02 0.86±0.08* 0.98±0.08*
AUC 0-t μg/ml*h 9.61±0.29 6.88±0.38* 8.98±0.11*
AUC 0 – ∞ μg/ml*h 10.64±0.48 7.45±0.36* 9.68±0.35*

Values are given as mean± Standard deviation. *Statistical significance p < 0.05 (compared with the control group) G S – Gymnema sylvetsre n – number of animals use

Table 8

Effect of Gymnema sylvestre on Pharmacokinetic parameters of Multiple dose administration of Gliclazide in diabetic rats (n=6)

Pharmacokinetic parameter Units for Pharmacokinetic parameters 40mg/kg of GLICLAZIDE GLICLAZIDE + Gymnema sylvestre (DOSE)
20mg/kg+500mg/kg 40mg/kg+500mg/kg
ka h-1 4.31±0.11 3.51±0.44* 3.92±0.25*
ke h-1 0.46±0.08 0.55±0.09* 0.64±0.03*
t1/2 h 10.4±0.31 9.33±0.61* 9.41±0.88*
V/F (mg/kg)/(μg/ml) 48.18±0.55 35.66±7.81* 55.06±11.43*
CL/F (mg/kg)/(μg/ml)/h 9.02±0.36 8.51±0.99* 10.75±0.83*
Tmax h 3.91±0.06 2.91±0.74* 4.81±0.59*
Cmax μg/ml 3.68±0.09 0.86±0.08* 0.98±0.08*
AUC 0-t μg/ml*h 19.83±0.41 11.52±0.26* 14.63±0.33*
AUC 0 – ∞ μg/ml*h 26.99±0.56 19.81±0.11* 21.53±0.51*

Values are given as mean± Standard deviation. *Statistical significance p < 0.05 (compared with the control group) G S – Gymnema sylvetsre n – number of animals used.

Table 9

Volume of islet cells in pancreas in different groups after multiple dose administration of gliclazide. (n=6).

GROUP Volume of islets (mm3/mm3) / Volume of pancreas (mm3/mm3)
Diabetic Control 0.082 ± 0.004
G S (100 mg/kg, p.o.) 0.195 ± 0.052*
G S (500 mg/kg, p.o.) 0.244 ± 0.007*
Gliclazide (40 mg/kg, p.o.) 0.137 ± 0.009
Gliclazide (20 mg/kg, p.o.) +G S (500 mg/kg, p.o.) 0.241 ± 0.036*
Gliclazide (40 mg/kg, p.o.) +G S (500 mg/kg, p.o.) 0.285 ± 0.043*

Volume of islet cells in pancreas in different groups after multiple dose administration of gliclazide. (n=6).

The histopathological studies reveal that the combination of gliclazide (40 mg/kg) and Gymnema sylvestre not only increased the volume of islets and also recovered partially destroyed beta cells.

Pharmacodynamic Study

The combination of high dose of gliclazide (40 mg/kg) with 500mg/kg Gymnema sylvestre showed maximum hypoglycaemic action, decrease in serum cholesterol, urea levels. The influence produced by combination of gliclazide (20 mg/kg) with Gymnema sylvestre was greater than the hypoglycaemic action produced by Gymnema sylvestre (500 mg/kg) alone, but less than gliclazide (40 mg/kg).

Pharmacokinetic Study

The pharmacokinetic study shows that, 27% decreased in AUC( 0 – ∞) in 500mg/kg of Gymnema sylvestre and 20mg/kg of gliclazide. 47% decrease AUC( 0 – ∞) in 500mg/kg of Gymnema sylvestre and 40mg/kg of gliclazide. C max was decreased by 34% in 500mg/kg of Gymnema sylvestre and 20mg/kg of gliclazide., 53% in 500mg/kg of Gymnema sylvestre and 40mg/kg of gliclazide that was attributed by significant decrease in absorption rate constant Ka by about 37% in Lower dose of 500mg/kg of Gymnema sylvestre and 20mg/kg of gliclazide, 41% in 500mg/kg of Gymnema sylvestre and 40mg/kg of gliclazide. Significantly increase in clearance 38 % in 500mg/kg of Gymnema sylvestre and 20mg/kg of gliclazide. 88% in 500mg/kg of Gymnema sylvestre and 40mg/kg of gliclazide compared to 40mg/kg Gliclazide group.

Conclusion

The interaction of modern medicine with herbs is a developing area with research activities being carried out in different parts of the world. The interaction of herbs with various classes of drugs have been reported and some drugs such as terfenadine and astemizole from the market due to such interactions.

The interaction appears to be pharmacokinetic interaction at absorption, elimination. Gymnema sylvestre inhibits the absorption of oral hypoglycemics that results in a significant decrease in the bioavailability of the later and combination group with a lower dose of oral hypoglycemics produced increment to the volume of islets in pancreas compare to individual treatment. Since the interaction was seen in rats it is likely to occur in humans leading to decreased activity of oral hypoglycemic that can need dose adjustments. Hence care must be taken when the combination is prescribed for clinical benefit in diabetic patients. The present study warrants next plan to find out the relevance of the interaction in human beings.

Acknowledgement

I take this privilege and pleasure to acknowledge the contributions of many individuals who have been inspirational and supportive throughout my work undertaken and endowed with the precious knowledge to see success in my endeavour.