study of pharmacodynamic interaction between diclofenac and rumacct®, a polyherbal formulation in...

7/29/2019 STUDY OF PHARMACODYNAMIC INTERACTION BETWEEN DICLOFENAC AND RUMACCT, A POLYHERBAL FORMULAT

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Publication Ref No.: IJPRD/2009/PUB/ARTI/VOV-1/ISSUE-9/NOV/001 ISSN 0974 9446

International Journal of Pharma Research and Development Online

www.ijprd.com1

STUDY OF PHARMACODYNAMIC INTERACTION BETWEEN DICLOFENAC AND

RUMACCT, A POLYHERBAL FORMULATION IN ALBINO RATS

Pankaj S. Kothavade1*, Balasaheb D. Siraskar1,

Mahesh D. Burande2 Avinash D. Deshpande1

1Pad. Dr. D. Y. Patil Institute of Pharmaceutical sciences and research,

Pimpri, Pune-411018., Maharashtra, India.2Institute of Pharmaceutical Education and Research,

Pune, Maharashtra, India.

E-mail- [email protected]

ABSTRACT

Non-steroidal anti-inflammatory (NSAIDs) are most commonly used in management of acute and

chronic pain and inflammation. Combined use of Diclofenac and rumacct a polyherbal formulation to assess

anti-inflammatory action with reduced gastric injury caused due to NSAIDs (Diclofenac). The data wereinterpreted using isobolographic analysis. Carrageenan induced rat paw edema (acute) and cotton pellets

induced granuloma (chronic) inflammatory test in albino rats were employed to study interaction of

diclofenac and rumacct, and anti-ulcerogenic effect evaluated to reduce gastric injury induced by NSAIDs.

In carrageenan induced rat paw method, diclofenac (10 mg/kg) and rumacct (125 and 250 mg/kg) showed

significant inhibition of increased rat paw edema. Combination of diclofenac and rumacct (10 + 250, 5 +

125 and 2.5 + 125) mg/kg showed significant (p


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INTRODUCTION

Inflammation involves complex array of enzyme activation, mediator release, and extravasations of

fluid, cell migration, tissue breakdown and repair1. The potential advantage of using combination therapy is

that anti-inflammatory effect can be maximized while the incidence of adverse side effects can be

minimized2, therefore combination of medication that offer synergism should allow a reduction in required

dosage and decreased incident of adverse effect3.

Rumacct tablets (Mfg. Lic. No.- KD-AYU-200) manufactured by Nirmal Ayur Life Pharma,

Mumbai consist of active ingredients ofVanda roxburghii, Vitex negundo, Curcuma longa, shudha shilajit,

stryachnos nux-vomica, Boerhaavia diffusa, maharasnadi quath and Balsamodendron mukul etc. all ofthese plants have been reported for anti-inflammatory activity4-10, while two plant viz. Curcuma longa and

Shudha shilajithave antiulcer activity7,11

.

The anti-inflammatory action of NSAIDs is primarily due to inhibition of prostaglandinsbiosynthesis through inhibition of cyclooxygenase enzymes: COX-1 (constitutive) and COX-2 (inducible in

inflammatory process)12

. However absolute separation between physiologic and pathological role of COX-1and COX-2 is becoming less tenable and indeed their activity overlap to a considerable degree13.

Co-administration of two or more drugs may results in additive, subadditive or supra-additive

(synergistic) interaction14. The present study have been carried out to observe pharmacodynamic interaction

between Diclofenac and rumacct tablets to assess beneficial interaction, further nature of interaction wasanalyzed by Isobologram15.

MATERIAL AND METHOD

AnimalWistar albino Rats of either sex weighing about 180-220 g were purchased from National

Toxicology Center, Pune. Animals were housed in a group of 3-4 per cage under standard laboratory

conditions, temperature and humidity was maintained at 22 3oC and 55 10% respectively. A 12 hr light

and dark cycle was maintained. All experimental procedures were carried out in strict accordance with the

guidelines prescribed by the Committee for the Purpose of Control and Supervision on Experimentation on

Animals (CPCSEA) (Reg. no. 198/99/CPCSEA) and were approved by the Institutional Animal EthicsCommittee.

Drugs and Chemicals

Diclofenac (Novartis India Ltd.), Omeprazole (Dr. Reddy laboratory, India), Indomethacin (Cadila

Healthcare Ltd., India), Ketamine (Neon Laboratory Ltd., India), Carrageenan (S. D. Fine Chemical Ltd,Boisar, India) and Rumacct tablets a polyherbal formulation (Nirmal Ayur Life Pharma, Mumbai, India).

Dose selection and Preparation of the suspension of RumacctTabletsThe absolute dose of rumacct tablets (RT) for rats was calculated from the human dose. The human

dose (absolute) of rumacct tablets is 705 mg/70 kg, 2 tablets twice a day. Hence 50 mg/200 g absolute dose

of Rumacct for wistar rat were used in the present study which was calculated using the formula16

-

Absolute dose in rats = Absolute dose in man factor (0.018).

Hence, 125, 250 and 500 mg/kg dose of Rumacct tablets for rats were used. suspension of theRumacct was prepared by using 2% gum acacia.


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Study designThe anti-inflammatory effects produced by rumacct tablets (a Polyherbal formulation) and

Diclofenac individually and in different combinations were studied according to isobologram17. ED50 valueswere determined for rumacct and NSAIDS. The isobologram was constructed by connecting the ED50 of the

NSAIDs plotted on abscissa with the ED50 of the rumacct tablets on the ordinate to obtain the additive line,

to analyze of possible synergistic or additive interaction see. Fig 1.

Isobolgram

0, 25010, 250

10, 0

5, 1252.5, 125

0

50

100

150

200

250

300

0 2 4 6 8 10 12

Diclofenac (mg/kg)

Rumacct(mg/kg)

Figure 1: Isobologram showing diclofenac and rumacct interaction. The oblique line between x-axis and y-axis is the

theoretical additive line. The point in the middle of this line is the theoretical additive point. A point below theadditive line indicates synergistic and above the additive line indicates subadditive interactions.

Selection of Doses of combination1. Diclofenac (2.5 mg/kg) and Rumacct tablets (125 mg/kg)

2. Diclofenac (5 mg/kg) and Rumacct tablets (125 mg/kg)

3. Diclofenac (10 mg/kg) and Rumacct tablets (250 mg/kg)

Anti-inflammatory activity

Carrageenan induced rat paw edema18

Wistar albino rats were used, which were divided into 8 groups, fasted overnight and allowed freeaccess to water. Left paw was marked with ink at the level of lateral malleolus; basal paw volume was

measured by volume displacement method using plethysmometer (UGO Basile 7140) by immersing the paw

till the level oflateral malleolus. The animals were administered with 2% gum acacia (vehical) (10 ml/kg,p.o.), diclofenac (10 mg/kg, p.o.), rumacct formulation at the doses of 125, 250 and 500 mg/kg (p.o.) and

combination of indomethacin and rumacct tablets (10 + 250, 5 + 125 and 2.5 + 125) mg/kg p.o. to respective

groups.One hour after dosing, the rats were challenged by a subcutaneous injection of 0.1ml of 1% solution

of carrageenan into the sub-plantar side of the left hind paw. The paw volume was measured at 1, 2, 3, 4 & 5

hours after challenge. The difference of average values between treated animals and control group was


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calculated for each time interval and evaluated statistically. The percent Inhibition was calculated using the

following formula% Inhibition = 1 Vt / Vc 100

Where, Vc = Mean edema volume in control group,Vt = Mean edema volume in test group.

Cotton pellets induced granuloma19

The animals used in this method were Wistar rats divided into 7 groups, fasted overnight and

allowed free access to water, The effects of rumacct tablets and diclofenac on proliferative phase of

inflammation were examined. The animals were administered with 2% gum acacia (10 ml/kg, p.o.),

Diclofenac (10 mg/kg, p.o.), Rumacct at the doses of 125, 250 mg/kg (p.o.) and Combination of diclofenac

and rumacct formulation (10 + 250, 5 + 125, 2.5 + 125) mg/kg to respective groups.One hour after the first dosing, the animals were anesthetized with ketamine (25 mg/kg) and 30 mg

of the sterile cotton pellet was inserted one in each axilla and groin of rats by making small subcutaneous

incision. The incisions were sutured by sterile catgut. The animals were sacrificed by excess anesthesia(ether) on the 8

thday and cotton pellets were removed surgically. Pellets were separated from extraneous

tissue and dried at 60oC to its constant weight. The net dry weight, i.e. after subtracting the initial weight of

the cotton pellet was determined. The average weights of the cotton pellet of the control group as well as of

the test groups were calculated. The percent change of the granuloma weight relatively with vehicle control

was determined and statistically evaluated. The percentage inhibition of the increase in the weight of the

cotton pellet was calculated.% Inhibition = 1- Wd / Wc 100

Wd = Weight of granuloma of the drug treated group

Wc = Weight of granuloma of the control group.

Measurement of gastrointestinal side effect

Anti-ulcerogenic effect20, 21

- Female Wistar rats (180-220 g) were fasted 24 h before the experiments withfree access to water ad. libitum. Indomethacin (10 mg/kg p.o.) was given for seven days to produce 100%

gastric ulcer. Omeprazole (4 mg/kg), vehicle (2% gum acacia 10 ml/kg), diclofenac (10 mg/kg p.o.),

rumacct tablets (250 mg/kg) and combination of diclofenac and rumacct tablets (10 + 250, 5 + 125, and 2.5+ 125) mg/kg were administered orally for seven days. On 8 th day, animals were sacrificed and stomach

isolated along with its gastric content was subjected to analyze for volume, pH, free acidity and total acidity.

pH was measured using indichrom pH strips with pH range 2.0 4.5 and 5.0 8.5 with difference

range 0.5. Free acidity and total acidity were estimated by titrating 1 ml of the centrifuge sample with 0.01

N NaOH using Topfers indicator and phenolphthalein indicator, respectively. Acidity was expressed inclinical units, i.e. the amount of 0.01 N NaOH base required to titrate 100 ml of gastric secretion. For

measurement of ulcer index, the stomach was cut open along the greater curvature and the inner surface

was examined for ulceration, according to the following scale: 0 = normal gray colored stomach, 0.5 =

pink to red coloration of stomach, 1 = spot ulcer, 1.5 = hemorrhagic streak, 2 = number of ulcers, 5, 4 = ulcers with bleeding. Ulcer index was calculated by adding the total number of

ulcers plus the severity of ulcer.


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Statistical analysis

The results were expressed as mean S.E.M. The results were analyzed statistically by one way

ANOVA, followed by Dunnetts multiple comparison test. Values p< 0.05, p< 0.01 were consideredsignificant.

RESULTS

ANTI-INFLAMMATORY ACTIVITY

Carrageenan induced rat paw edema

In the present study, the animals treated with rumacct (250 and 500 mg/kg, p.o.) showed significant

inhibition in carrageenan induced paw edema (p


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leukotrienes and prostaglandins produced by tissue macrophages22

. Carrageenan induced inflammation is

useful in detecting orally active anti-inflammatory agents23

. Indomethacin showed edema inhibition in bothphases while rumacct showed edema inhibition mainly in late phase (3-5 h), hence combinations showed

maximum inhibition in both phases. In present study, all three combinations of indomethacin and rumaccti.e. 2.5 + 125 mg/kg, 5 + 125 mg/kg and 10 + 250 mg/kg showed significant inhibition of rat paw edema.

Hence, synergistic interaction observed at dose of 2.5 mg/kg diclofenac and 125 mg/kg rumacct.

Cotton pellets induced granuloma is another widely used method for evaluation of transudative and

proliferative component of chronic inflammation24

. The wet weight of cotton pellets correlates with

transuda; the dry wet of cotton pellets correlates with amount of granulomatous tissue25

. Monocyte

infiltration and fibroblast proliferation rather occur in chronic inflammation than neutrophils infiltration and

exudation26

. The ability of rumacct may be in reducing the fibroblast, synthesis of collagen andmucopolysaccharides which are natural proliferative events of granuloma formation. Our study showed that,

diclofenac (2.5 mg/kg) along with rumacct (125 mg/kg) had significant inhibition of granuloma formation,

from isobologram this combination showed supra-additive (synergistic) interaction.

The use of NSAIDs for the relief of pain and inflammation, but increases risk of gastrointestinal sideeffects ranging from dyspepsia to symptomatic and complicated ulcer27. Vasoactive agents (Prostaglandins,

nitric oxide, calcitonin, gene related proteins) play a role in mucosal defensive processes28. Indomethacin

(10 mg/kg) induced 100% ulceration by inhibiting COX enzyme, which leads to inhibition of prostaglandins

and formation of free radical (reactive oxygen species)29. Gastric injury (%) showed better combinationfrom these three combination, at therapeutic dose combination i.e. 10 mg/kg diclofenac and 250 mg/kg

rumacct (41.50%), at additive combination i.e. 5 mg/kg diclofenac and 125 mg/kg rumacct (17.25%) and

synergistic combination i.e. 2.5 mg/kg diclofenac and 125 mg/kg rumacct (8.81%) while only diclofenac

(10mg/kg) showed gastric injury (72.37%). Analysis of gastric content showed decreased in volume, free

acidity and total acidity output while increased in pH in combinations with diclofenac and rumacct, hencethese parameters show anti-ulcerogenic effect. In consideration of gastric injury synergistic and additive

interaction had negligible ulcerogenic effect compared to only diclofenac (10 mg/kg).

It is now clear that two isoenzymes of prostaglandin endoperoxidase synthase (COX) called COX-1

and COX-2 both isoenzymes catalyses conversion of arachidonate to PGH2. Ideal anti-inflammatory drugs

should have an inhibitory action on prostaglandin synthesis mediated by COX-2, but not by COX-130

. Thesehypotheses suggest that, rumacct may inhibit COX-2 rather than COX-1. Rumacct contain Vitex negundo

has inhibitory action on prostaglandins biosynthesis; it contains mainly flavonoids which are known to

inhibit enzyme prostaglandin syntheses, more specifically endoperoxidase5. Balsamodendron mukul

contains myrrhanol-A and myrrhanone-A responsible for potent anti-inflammatory effect31. Boerhaavia

diffusa suppress lymphocyte proliferation and inhibition of nitric oxide and TNF- production32. Strachnosnuxvomica contains brucin and brucin N-oxide responsible for inhibition of prostaglandins synthesis, so

reduce the content of PGE2 and decreased content of 6-keto PGF1in blood plasma. Brucin and brucin N-

oxide responsible for inhibition of release of 5-HT in inflammatory tissue, probably due to stimulation of

MAO activity8. Curcuma longa contains curcumin responsible to reduces pro-inflammatory leukotriene

synthesis via inhibition of LOX enzyme33

. and it act against gastric ulcer by blocking H2 histamine

receptors11

. Shilajitproved as anti-inflammatory as well as antiulcerogenic indicating an increased mucus

barrier7. However, other pharmacodynamic and pharmacokinetic interactions need to evaluate for detail

mechanism of action.


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CONCLUSION

From the isoblographic analysis, synergistic and additive interaction occurs diclofenac (NSAIDs)and rumacct a polyherbal formulation when administered orally against inflammation and reduced adverse

(gastric) side effect. Herbal with the synthetic drug interactions is of paramount importance, as theseinteractions may lead to alteration in therapeutic response as well as lower incidence of adverse effects.

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Inflammation Research, 44 (1995) 1.

2. Picard P, Bazin JE, Conio N, Ruiz F, Schoeffeler P, Ketorolac potentiates morphine in postoperativepatient control analgesia, Pain, 267 (1997) 331.

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4. Prasad DN, Achari G, A study of anti-arthritic action of Vanda roxburghii in albino rats, J Ind medAsso, 46 (1996) 234.

5. Telang R S, Chattergee S, Varshneya C, Studies on analgesic and anti-inflammatory activities ofvitex negundo linn, Indian J Pharmacol, 31(1999) 363.

6. Arora RB, Kapoor V, Basu N, Jain AP, Anti-inflammatory studies on curcuma longa, Indian J Medres, 59 (1971) 1289.

7. Goel RK, Banerjee RS, Acharya SB, Antiulcerogenic and anti-inflammatory studies with shilajit, JEthnopharmacol, 29 (1990): 95.

8. Yin W, Wang TS, Yin FZ, Cai BC, Analgesic and anti-inflammatory properties of brucine andbrucine N-oxide extracted from seeds of Strychnos nux-vomica, J Ethnopharmacol, 88 (2003) 205.

9. Hiruma-Lima CA, Gracioso JS, Bighetti EJ, Robineou L, Souza Brito AR, The juice of fresh leavesof Boerhaavia diffusa L. (Nyctaginaceae) markedly reduces pain in mice, J Ethnopharmacol,

71(2000) 267.10.Gujral ML, Sareen K, Tangari KK, Amma MK, Antiarthritic and anti-inflammatory activity of gum

guggul (Balsamodendron mukul Hook), Indian J Physiol Pharmacol, 4 (1960) 267.

11.Kim DC, Kim SH, Choi BH, Baek NI, Kim D, Kim MJ, Kim KT, Curcuma longa extract protectsagainst gastric ulcers by blocking H2 histamine receptors, Biol Pharm Bull, 28 (2005) 2220.

12.Mitchell JA, Warner TD, Cyclooxygenase 2: pharmacology, physiology, biochemistry and relevanceto NSAID therapy, Br J Pharmacol, 128 (2004) 1121.

13.Wallace JL, Selective COX-2 inhibitors: is the water becoming muddy?, Trends Pharmacol Sci, 20(1999) 4.

14.Garcia-Hernandez L, Deciga-Campos M, Guevara-Lopez U, Lopez-Munoz FJ, Co-administration ofrofecoxib and tramadol results in additive or sub-additive interaction during arthritic nociception in

rat, Pharmacol Biochem Behav, 87 (2007) 331.15.Tallarida RJ, An Overview of Drug Combination Analysis with Isobolograms, J Pharmacol Exp

Ther, 319 (2006) 1.

16.Ghosh MN, Some common evaluation techniques. Fundamentals of Experimental Pharmacology,(2

ndedn). (1984) 146.

17.Tallarida RJ, Porreca F, Cowan A, Statistical analysis of drug-drug and site-site interaction withisobologram, Life Sci, 45 (1989) 947.

18.Winter CA, Risley EA, Nuss GW, Carrageenan induced edema in hind paw of the rat as assay foranti-inflammatory drugs, Proc Soc Exp Bio Med, 111 (1962), 544.


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19.Winter CA, Porter CC, Effect of alteration in side chain upon anti-inflammatory and liver glycogenactivities of hydrocortisone esters, J Am Pharma Asso, 46 (1957), 515.

20.Muruganandan S, Shrinivas K, Chandra S, Tandon SK, Lal J, Raviprakash V, Anti-inflammatoryactivity of Syzgium cumini bark, Fitoterapia, 72 (2001) 369.

21.Bhave AL, Bhatt JD, Hemacathi KG, Antiulcer effect of amlodipine and its interaction with H 2blocker and proton pump inhibitor in pylorus ligated rats. Indian J Pharmacol, 38 (2006) 403.

22.Brito ARMS., Antonio MA, Oral anti-inflammatory and antiulcerogenic activities of ahydroalcoholic extract and partitioned fractions of Turnera ulmifolia (Turneraceae), J

Ethnopharmacol, 61 (1998), 215.

23.Di-Rosa M, Firoud JP, Willoughby DA, Studies of the acute inflammatory response induced in ratsin different sites by carrageenan and turpentine, J Patho, 104 (1971) 15-59.

24.Gupta M, Mazumder UK, Gomathi P, Selven VT, Anti-inflammatory evaluation of Plumeriaacuminate, BMC compl alt med, 6 (2006) 36.

25.Olajide OA, Awe SO, Makinde JM, Ekhler AI, Olusola A, Morebise O, Okpako D T, Studies on theantiinflammatory, antipyretic and analgesic properties of the Alstonia boonei stem bark, JEthnopharmacol, 71 (2000) 179.

26.Hosseinzadeh H, Ramezani M, Salmani G, Antinociceptive, antiinflammatory and acute toxicityeffects of Zataria Multiflora Boiss extracts in mice and rats, J Ethnopharmacol, 73 (2000) 379.

27.Hawkey CJ, Laine L, Simon T, Quan H, Shingo S, Evans J, Incidence of gastrodeodenal ulcers inpatients with rheumatoid arthritis after 12 weeks of rofecoxib, naproxen, or placebo: a multicentre,

randomized, double blind study, Gut 52 (2003) 820.28.Ehrlich K, Sicking C, Respondek M, Peskar BM, Interaction of cyclooxygenase isoenzymes, nitric

oxide, and afferent neurons in gastric mucosal defense in rats, J Pharmacol Exp Ther, 308 (2004)

277.

29.Olaley SB, Farombi EO, Attenuation of Indomethacin and HCl/ethanol induced oxidative gastricmucosa damage in rats by Kolaviron, a natural bioflavonoid of Garcia kola seed, Phytother Res 20(2006) 14.

30.Smith WL, Meade EA, De Witt DL, Pharmacology of prostaglandin endoperoxide synthaseisozymes-1 and -2. Ann New York Acad Sci, 714 (1994) 136.

31.Kimura I, Yoshikawa M, Kobayashi S, Sugihara Y, Suzuki M, Oominami H, Murakami T, MatsudaH, Doiphode V V, New triterpenes, myrrhanol A and myrrhanone A, from guggul-gum resins, and

their potent anti-inflammatory effect on adjuvant-induced air-pouch granuloma of mice, Bio MedChem Lett, 11 (2001) 985.

32.Pandey R, Maurya R, Singh G, Sathiamoorthy B, Naik S, Immunosuppressive properties offlavonoids isolated from Boerhaavia diffusa Linn, Int Immunopharmacol 5 (2005) 541.

33.Kohali K, Ali J, Ansari MJ, Rehaman Z, Curcumin a natural anti-inflammatory agent, Indian JPharmacol, 37 (2005) 141.


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FIGURES AND TABLES :

Fig. 2 Slides of rat Stomach of indomethacin (10mg/kg), rumacct (250mg/kg), diclofenac(10mg/kg) and various

combination of rumacct and diclofenac treatments.Indomethacin 10 Diclofenac 10

Omeprazole 4 RT 250

Diclo 10 + RT 250 Diclo 5 + RT 125

Diclo 2.5 + RT 125


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Tables:

Table 1: Effect of different combinations of Diclofenac and Rumacct tablets on carrageenan induced

paw edema.Edema volume (ml) Mean SEM

Groups1

sthr 2

ndhr 3

rdhr 4

thhr 5

thhr

Control 1.02

0.102

1.24

0.264

1.85

0.264

1.68

0.196

1.63

0.25

Standard 0.63 0.164**

0.51 0.163**

0.47 0.084**

0.40 0.068**

0.36 0.071**

RT 125 0.88

0.079

0.98

0.108

1.45

0.099

1.28

0.128

1.14

0.087*

RT 250 0.89

0.050

1.02

0.066

0.98

0.023*

0.80

0.123**

0.69

0.138**

RT 500 0.82 0.087

0.93 0.017*

0.96 0.102**

0.73 0.184**

0.64 0.153**

Diclo 10 +

RT 250

0.48

0.071**

0.63

0.063**

0.51

0.063**

0.36

0.088**

0.34

0.061**

Diclo 5 +

RT 125

0.57

0.096**

0.58

0.112**

0.51

0.107**

0.31

0.05**

0.25

0.07**

Diclo 2.5 +

RT 125

0.68

0.0.84**

0.66

0.061**

0.65

0.116**

0.58

0.066**

0.52

0.032**

Each value is the mean SEM of six rats.**p


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Diclofenac 38.23 58.87 74.59 76.19 77.91

RT 125 13.72 19.67 21.62 23.80 30.06

RT 250 11.60 27.74 47.02 52.38 57.66RT 500 19.60 25.00 48.10 58.28 60.73

Diclo 10 + RT 250 35.29 52.41 76.75 78.57 79.75

Diclo 5 + RT 125 44.11 53.22 72.43 81.54 84.66

Diclo 2.5 + RT 125 33.33 46.77 64.86 65.47 68.09

Table 3: Effect of Rumacct polyherbal formulation and different combination of Diclofenac and Rumacct

tablets on cotton pellets induced granuloma.

Groups Wet weight

(mg)

%

inhibition

Dry weight

(mg)

%

inhibitionControl 322.33 6.95 - 154.66 11.13 -

Standard 162.38 2.98** 49.63 72.50 4.31** 53.12

RT 125 277.43 3.98* 13.96 127.66 11.80* 17.45

RT 250 230.83 4.64** 28.38 101.83 12.43** 34.15

Diclo 10 + RT 250 139.16 4.67** 56.82 58.66 5.61** 62.07

Diclo 5 + RT 125 172.45 3.95** 46.49 68.50 7.19** 55.70

Diclo 2.5 + RT 125 199.83 3.92** 38.00 81.66 5.53** 47.20

Each value is the mean SEM of six rats.

**p


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RT 2500.81

0.09**3.60

0.18**30.00

2.58**90.00

4.47**0.45

0.22**4/6 5.83

Diclo 10 + RT

250

1.60

0.20**

2.75

0.21**

53.33

3.33**

136.66

4.94**

3.20

0.23**

0/6 41.50

Diclo 5 + RT

125

1.13

0.12**

3.81

0.27**

36.66

6.14**

108.33

4.77**

1.33

0.32**

2/6 17.25

Diclo 2.5 + RT

125

1.08

0.11**

3.61

0.21**

32.50

4.42**

103.33

4.94**

0.68

0.27**

3/6 8.81

Each value is the mean SEM of six rats.#p

study of pharmacodynamic interaction between diclofenac and rumacct®, a polyherbal formulation in...

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