Comparative Evaluation of the Clinical efficacy of 3% Satranidazole and 1% Ornidazole (Ornigreat^TM) gel through local drug delivery system in the treatment of Chronic periodontitis

 

Gautami. S. Penmetsa^*, Bhavana. P, Arunbhupati. P, Meghana. K, Kausalya. P, Venkatalakshmi. M

Department of Periodontics, Vishnu Dental College, Bhimavaram-534202, West Godavari District,

Andhra Pradesh, India

 

ABSTRACT:

Aim: To compare the efficacy of subgingivally delivered 1% Ornidazole (Ornigreat^TMgel) and 3% Satranidazole gel in the treatment of chronic periodontitis. Materials and methods: The effect of satranidazole gel and Ornigreat^TM gel in the reduction of periodontal disease was evaluated in a randomised, split-mouth study. Sixteen chronic periodontitis patients having pocket depths ranging from 4-6 mm bilaterally atleast in one site were included in the study. The patients were subjected to non-surgical periodontal therapy (NSPT) and were evaluated for plaque index (PI), gingival index (GI), bleeding index (BI), Probing pocket depth (PD) and clinical attachment level (CAL) both at baseline and after 4 weeks. Results: A significant improvement in bleeding index, probing pocket depth and CAL was demonstrated in both the test and control groups from baseline to 4weeks. However, on comparing Satranidazole gel group and Ornigreat^TM group, the results showed no significant difference in the above-mentioned parameters after NSPT. Conclusion: Further clinical trials are needed to be carried out to evaluate the efficacy of satranidazole in longterm.

 

 

 

INTRODUCTION:

Chronic periodontitis (CP) is an inflammatory disease of the supporting tissues of the tooth caused by specific microorganisms in a susceptible host, with the gram-negative anaerobic bacteria being the most commonly associated in the initiation of periodontitis.¹

 

The goal of periodontal therapy being the transformation of diseased periodontium into a healthy one, non-surgical periodontal therapy is the main therapeutic approach in the treatment of periodontal diseases which has been used as the “gold standard” for mechanical therapy.²

 

Mechanical therapy may however, fail to reduce or eliminate the anaerobic infection at the base of the pocket, with in the gingival tissues or in furcations. Potential periodontal pathogens present in thick deposits of polymicrobial communities on affected root surface, interact with other members of the biofilm community, thereby modifying their biochemical and physiological properties.¹⁵

 

Some of the periodontal pathogens travel into lacunar defects in the cementum, which further extend into radicular dentin. These can act as bacterial reservoirs from which recolonization of mechanically treated root surfaces can occur. The bacterial reservoirs not eliminated by conventional periodontal therapy can be further suppressed with the use of chemotherapeutic agents.³

 

Hence the introduction of antimicrobial therapy in general and localized antimicrobial therapy in particular has evoked growing interest because of the site‑specific nature of periodontal infections, with the rationale behind its usage being attributed to the fact that higher the concentration of anti‑microbial agent sub-gingivally the lower would be the side‑effects attributed to systemic antibiotic use.⁴

 

Various locally delivered chemotherapeutic agents available are the tetracycline fibers, metronidazole gel ornidazole gel, minocycline ointment and minocycline microspheres, chlorhexidine chip, doxycycline hyclate, etc.⁵

 

Although, several antimicrobial agents like tetracycline¹⁴, metronidazole, clarithromycin and azithromycin have been tested for local drug delivery use in periodontal therapy, Satranidazole (SZ) is another antibiotic that belongs to the 5-nitroimidazole group which differs from other 5-nitroimidazoles such as metronidazole, ornidazole, and tinidazole, in that the 2C of the imidazole ring is connected via a nitrogen to a substituted imidazolidinone moiety. The properties of longer half-life and higher blood levels that have been demonstrated in the Pharmacokinetic studies of Satranidazole in humans, resulted in necessitating less frequent dosing of SZ as compared to metronidazole. These properties combined with its greater potency are believed to contribute to its therapeutic efficacy.

 

Though comparision has been made regarding the efficacy of satranidazole and metronidazole, there is no literature available comparing the efficacy of satranidazole and ornidazole in the treatment of chronic periodontitis.

 

Hence, this study is undertaken to compare the efficacy of sub-gingivally delivered satranidazole gel and Ornidazole gel (Ornigreat^TM) in the treatment of chronic periodontitis.

 

MATERIALS AND METHODS:

Source of the Data:

This was a randomised, split-mouth study wherein patients were selected from the outpatient section of the Department of Periodontology, Vishnu Dental College and Hospital, Bhimavaram, Andhra Pradesh, India.16 patients (7 males and 9 females) who were diagnosed with CP were enrolled in this study. Written informed consent was obtained from subjects and ethical clearance (VDC/IEC/fac/2018/10) for the study was received from the Institutional Ethical Committee, Vishnu dental college.

 

Selection Criteria:

Patients with ages ranging from 25-65yrs having atleast 20 teeth diagnosed with mild to moderate Chronic Periodontitis (PD 4mm to 6mm and clinical attachment level (1 to 4mm) and with no periodontal or antibiotic therapy in the past 6 months were included. Patients on systemic antimicrobial therapy, patients with aggressive periodontitis and uncontrolled systemic diseases were excluded.

 

Ornidazole gel:

Ornigreat^TM gel which is a commercially available product (Mankind) with 1% concentration of ornidazole was used as a LDD agent in our study.

 

Formulation of Satranidazole in Situ Gel:

The Satranidazole gel was developed at the Vishnu College of Pharmacy, Bhimavaram, Andhra pradesh, India, after intensive in vitro investigations for optimization and stability.50 ml of McIlvaine buffer at pH 6.6 was used to dissolve twenty weighed carbopol 934P. The above composition was used to dissolve the SZ drug and this mixture was finally added to solution of CB 934P with stirring. To this solution, sodium carboxymethyl cellulose (SCMC) which is a gelling agent was added slowly under continuous magnetic stirring at 100 rpm. McIlvaine buffer pH of 6.6 was further added to this mixture to make it up a volume of 100ml. Thus, the SZ in situ gel was prepared with a concentration of 3% which was kept for 24hrs at room temperature for complete polymer dissolution. This whole process followed the guidelines given by Bansal et al.⁶

 

Administration of LDD:

The prepared Satranidazole gel or ornigreat^TM gel were delivered into the periodontal pocket at the control or test site, respectively by using a blunt cannula for standardisation. Both the gels were viscous in nature wherein the viscosity of these gels decreased after the delivery and swelled up thereby resulting in occluding of periodontal pocket. Periodontal pack was placed and patients were instructed to avoid brushing or using any interdental aids near the treated areas or chewing hard or sticky foods for 1 week after the gel placement.

 

Experimental design:

Patients who met the inclusion criteria were selected and were randomly divided into any of the two groups according to split mouth design by flip of a coin. Of the selected 32 sites, 16 were test sites and 16 were control sites. Group I comprised 16 sites in which local delivery of ornidazole (Ornigreat^TM gel) was done and Group II comprised 16 sites in which the local delivery of Satranidazole gel was done.

 

Measurement parameters:

Periodontal examination was carried out at baseline and at 4 weeks after non-surgical periodontal therapy by the assessment of plaque index (Loe and Sillness)⁸, gingival index (Silness and Loe)⁹, bleeding index (Muhlemann H.R and Sons)¹⁰, probing depth and clinical attachment level.

 

STATISTICAL ANALYSIS:

After completion of the clinical trial, data obtained at baseline and at 4 week revaluation were computed and subjected to statistical analysis. Site based analysis was performed using parameter tests for the comparison between Ornigreat^TM and Satranidazole groups for outcome variables under study. For each treatment group, the mean values for the probing pocket depth, gingival index, plaque index, bleeding index, clinical attachment level were calculated at the baseline and after 4 weeks. Paired t-test for difference with in the group and ANOVA for difference between the groups were performed.

 

RESULTS:

Out of 16 patients, 15 patients completed the study, there being one dropout. No patients showed any adverse reaction or reported any discomfort. There was improvement in the BI and Probing depth measurements at the end of 4 weeks in both the groups which was statistically significant. Taking CAL into consideration though improvement was there in both the groups it was not statistically significant in ornidazole group whereas statistically significant difference was found in Satranidazole group. On comparing Ornigreat^TM group and Satranidazole group, results showed no significant difference between the groups in any of the parameters except CAL after NSPT.

 

Plaque index:

At baseline, plaque index values (Table 1) for the ORNIGREAT^TM group and Satranidazole group were 0.952±0.4 and 0.954±0.4 respectively. There was no significant difference between both the groups at the baseline (p = 0.989).

 

After 4 weeks, in Ornigreat^TM group there was a decrease in plaque index values from 0.9520±0.39728 to 0.7587±0.29006 (p=0.136) which is not statistically significant. In the Satranidazole group, there was a decrease in the plaque values from 0.9540±0.39316 to 0.7687±0.27207 (p=0.143) which is also not statistically significant. However on intergroup comparison, the difference was not statistically significant (p= 0.923).

 

Gingival index:

The GI values for the Ornigreat^TM group and Satranidazole group at baseline were 0.77±0.3 and 0.8±0.3 respectively. There was not any significant difference between both the groups at the baseline (p = 0.764).

 

 

After 4 weeks, in Ornigreat^TM group there was a decrease in gingival index values from 0.77±0.3 to 0.61±0.28 which are not statistically significant (p=0.112). In the Satranidazole group, there was a statistically significant decrease in the plaque values from 0.8±0.3to 0.6±0.28 (p=0.042). In an intergroup comparison though the Satranidazole group group showed slightly better results than the Ornigreat^TM group but the difference was not statistically significant (p= 0.990).

 

Table 1: Plaque index values at the baseline and after 4 weeks

 

Table 2: Gingival index values at the baseline and after 4 weeks

 

Bleeding index:

At baseline, BI values for the Ornigreat^TM group and Satranidazole group were 1.2±0.55 and 1.16±0.56 respectively. There was no significant difference between both the groups at the baseline (p = 0.889).

 

After 4 weeks, in Ornigreat^TM group there was no statistically significant decrease in BI index values from 1.2±0.55 to 0.7±0.3(p =0.06). In the Satranidazole group, there was a statistically significant decrease in the BI values from 1.16±0.56 to 0.8±0.43 (p=0.060). In an intergroup comparison though the Satranidazole group showed slightly better results than the Ornigreat^TM group the difference was not statistically significant (p= 0.692).

 

Table 3: Bleeding index values at the baseline and after 4 weeks

 

Probing depth:

At baseline, probing depth values for the Ornigreat^TM  group and Satranidazole group were 5.1±0.5 and 5.1±0.6 respectively. There was no significant difference between both the groups at the baseline (p = 0.344).

 

After 4 weeks, in Ornigreat^TM group there was a statistically significant decrease in probing depth values from 5.1±0.5 to 4±0.85 respectively (p < 0.001). In the Satranidazole group, there was also a statistically significant decrease in the probing depth values from 5.1±0.6 to 4±1.2 (p<0.001). In an intergroup comparison between ORNIGREAT^TM group and Satranidazole group the difference was not statistically significant (p= 1.000).

 

Table 4: Probing depth values at the baseline and after 4 weeks

 

Clinical attachment level:

At baseline, CAL values for the Ornigreat^TM group and Satranidazole group were 3.4±0.7 and 4±0.7 respectively. There is no significant difference between both the groups at the baseline (p = 0.054).

 

After 4 weeks, in Ornigreat^TM group there was no statistically significant decrease in CAL index values from 3.46±0.7 to 3.42±0.7 respectively (p = 0.768). In the Satranidazole group, there was statistically significant decrease in the CAL values from 4±0.7 to 3.6±0.5 (p < 0.001). In an intergroup comparison though the Satranidazole group showed slightly better results than the Ornigreat^TM group, however the difference was not statistically significant (p= 0.378).

 

Table 5: Clinical attachment level values at the baseline and after 4 weeks

 

DISCUSSION:

Periodontal diseases are a heterogenous group of diseases wherein destruction of the periodontium is a result of interaction between microorganisms and specific host defense mechanism. In an attempt to combat these periodontal diseases and attain periodontal health various modalities of treatment have been advocated in the literature. Along with the conventional scaling and root planning, various antimicrobial agents have been advocated both systemically and locally to prevent periodontal disease progression. One such method is the concept of local drug delivery which was introduced by Dr. Max Goodson in 1979 utilizing the principle of controlled local delivery of therapeutic agents in the treatment of periodontitis.

 

This local route of drug delivery can attain 100-fold higher concentrations of an antimicrobial agent in subgingival sites compared with a systemic drug regimen thereby reducing the total patient dose by over 400 fold avoiding development of drug-resistance at non oral body sites. It also has various advantages of reducing the superinfections, adverse reactions and drug resistance compared to that of systemic administration which are likely to cause side effects.

 

Various local drug delivery systems like Fibers, films, microspheres, gels and nano particulate system do exist wherein gels have high water content and large pore size resulting in relatively rapid drug release. Amongst these Ornidazole gel is the most recent established one. Even though it belongs to the nitroimidazole family, unlike metronidazole it requires a very low minimum inhibitory concentration in inhibiting the growth of periodontal pathogens as compared to that of metronidazole.¹³ Although the antimicrobial activity of ornidazole has been proposed to be due to the reduction of nitro group to a more reactive amine thus attacking the microbial DNA, a combination of ornidazole and chlorhexidine on the other hand shows a prolonged antiplaque action, substantivity and the ability to adsorb and desorb there by providing in effect a timed release of the antimicrobial agent.¹⁴

 

On the other hand Satranidazole which is also a 5-nitroimidazole derivative used in intestinal infections like cecal amoebiasis. Satranidazole has exhibited a longer half-life (t1/2 14h) and higher blood levels when compared to other nitroimidazole antibiotic like metronidazole (t1/2 8.7h)¹. Satranidazole has also demonstrated more activity against aerobic, microaerophilic, and anaerobic bacteria than metronidazole.⁶

 

Although studies in the literature do exist evaluating the individual roles of ornidazole and Satranidazole, no study has compared the effects of local drug delivery of ornidazole and Satranidazole in the treatment of chronic periodontitis. Hence in our study, periodontal parameters of both Ornigreat^TM, which is commercial tradename of Ornidazole and Satranidazole gel local drug delivery groups at baseline and 4 weeks were evaluated.

 

In the present study when plaque index scores were evaluated after scaling and rootplaning at baseline there was no statistically significant difference in the mean plaque scores between the two groups. These results correlate with the study done by Sato et al¹¹ on the effect of subgingival debridement on periodontal parameters, which stated that scaling is effective in reducing plaque scores. In a study done by Patel B 2014¹² in which ornidazole gel was used as an adjunct to scaling, there was no significant difference in the mean plaque scores between the two sites. A study was conducted by Bansal et al⁶ to compare and evaluate the efficacy of locally delivered satranidazole and metronidazole in the treatment of periodontitis. The authors concluded that treatment with Satranidazole gel showed marked reduction in probing depth, plaque index, gingival index, calculus criteria and bleeding index than marketed metronidazole gel.⁶

 

When the gingival scores were taken into consideration, there was no significant difference in the gingival scores between the two sites. However additional benefits were elicited when antimicrobial gel was used as an adjunctive therapy on scaling and rootplaning as depicted in a study done by Pradeep AR 2012¹³. In this study systemically administered ornidazole was used as an adjunct to scaling in treatment of periodontitis and a statistically significant difference in plaque index, gingival index was noted. In another study done by NagasreeM et al², SRP along with Ornidazole had shown better efficacy in terms of all clinical parameters and microbial analysis when compared to that of those who were treated with SRP alone. In a study done by Awasthi et al⁷, the efficacy of systemically administered Ornidazole and Satranidazole were compared and Ornidazole was found to be better than Satranidazole in treatment of chronic periodontitis.

 

In another investigation, combination of Satranidazole plus Ofloxacin was compared with Ornidazole plus Ofloxacin through systemic administration in a open label, randomised study to assess efficacy and tolerability of the drugs. The fixed dose combination of Satranidazole plus Ofloxacin have shown better efficacy as compared to Ornidazole plus Ofloxacin in patients with periodontal infections. This combination improved Gingival Index, Periodontal Index, Mobility Index and VAS Score compared to fixed dose combination of Ornidazole plus Ofloxacin.¹⁶

 

As there are studies with the combination of synergistic drugs, the estimation of drugs such as in combinations of ornidazole plus Ofloxacin or satranidazole plus ofloxacin can be done by RP-HLC method^17,18,19 or different spectrophotometric methods.^20,21,22,23

 

The results of our study showed a significant improvement in the bleeding index and pocket depth measurements of both the groups at the end of 4 weeks but no statistically significant improvement was noticed between the groups. Taking CAL into consideration, there is significant improvement from baseline to 4 weeks in Satranidazole group. However on comparing other parameters like gingival index, plaque index, Ornigreat^TM and Satranidazole groups results showed no significant difference from baseline to 4 weeks and even between the two groups after NSPT.

 

Satranidazole gel that was administered into the periodontal pockets in our study showed similar improvements in clinical parameters with that of Ornigreat^TM gel without any adverse reactions and was well tolerated by the patients. Taking this into consideration Satranidazole can be considered as an equally effective substitute for Ornigreat^TM.

 

CONCLUSION:

Within the limitations of the study, it can be concluded that the local application of 1% ornidazole (Ornigreat^TM) gel and 3% Satranidazole gel as an adjunct to Non surgical periodontal therapy reduces the periodontal inflammation. As the results of both control and test groups, Ornigreat^TM and Satranidazole gel are comparable, local application of Satranidazole gel can be an effective substitute for ornigreat^TM. However, further clinical trials are needed to be carried out to evaluate the efficacy of satranidazole in long term.

 

ETHICS:

Procedure follows were in accordance with the ethical standards of clinical trials registry (CTRI/2019/06/ 019522) and conducted with approval by the Institutional ethical committee.

 

CONFLICT OF INTREST:

No conflict of interest.

 

REFERENCES:

1.      Priyanka N, Kalra N, Saquib S, Kudyar N, Nikhil Malgaonkar N, Jain H. Clinical and microbiological efficacy of 3% satranidazole gel as a local drug delivery system in the treatment of chronic periodontitis: A randomized, controlled clinical trial. Contemp Clin Dent.2015; 6(3): 364–370.

2.      NagasreeM, Madhuri P B, Musalaiah S V V S, Kumar A, Indeevar P. Efficacy of ornidazole gel as an adjunct to scaling and root planing in chronic Periodontitis patients: a clinical and microbiological study. Journal of Biomedical and Pharmaceutical Research. 2016; 5(6).

3.      Adriaens PA, De Boever JA, Loesche WJ. Bacterial invasion in root cementum and radicular dentin of periodontally diseased teeth in humans. A reservoir of periodontopathic bacteria. J Periodontol 1988; 59:222‑30.

4.      Tonetti MS, Pini‑Prato G, Cortellini P. Principles and clinical applications of periodontal controlled drug delivery with tetracycline fibers. Int J Periodontics Restorative Dent 1994; 14:421‑35.

5.      Greenstein G, Polson A. The role of local drug delivery in the management of periodontal diseases: A comprehensive review. J Periodontol 1998; 69:507-20.

6.      Bansal K, Rawat MK, Jain A, Rajput A, Chaturvedi TP, Singh S. Development of satranidazole mucoadhesive gel for the treatment of periodontitis. AAPS PharmSciTech. 2009; 10(3):716-23.

7.      Awasthi BB, Singh S. Comparative evaluation of satranidazole and ornidazole effectiveness in the treatment of chronic periodontal diseases along with mechanical debridement. Int J Res Med Sci2018; 6:1579-87.

8.      Silness, J. and Löe, H.: Periodontal disease in pregnancy. II. Correlation between oral hygiene and perio-dontal condition. Actaodont. Scand., 22:112-135, 1964.

9.      Löe, H. and Silness, J.: Periodontal disease in pregnancy. I. Prevalence and severity. Actaodont. Scand., 21:533-551, 1963.

10.   Mühlemann HR, Son S. Gingival sulcus bleeding--a leading symptom in initial gingivitis. Helv Odontol Acta. 1971; 15: 107-113.

11.   Sato K, Yoneyama T, Okamto H, Dahlen G, Lindhe J. The effect of subgingival debridement on periodontal parameters and the subgingivalmicobiota. J Clin Periodontol. 1993 May:20(5):359-65

12.   Patel B, Shah S, Kumar S. Evaluation of Ornidazole Gel as an Adjunct to the Phase I Therapy. Adv Hum Biol. 2014; 4(3):21-25.

13.   Wust J. Susceptibility of anaerobic bacteria to metronidazole, ornidazole, and tinidazole and routine susceptibility testing by standardized methods. Antimicrob Agents Chemother. 1977; 11(4):631-7.

14.   Jiji John, Pamela Emmadi, N. Ambalavanan, Esha Verma. Comparative Evaluation of Adjunctive Use of Locally Delivered Tetracycline Fiber (Actisite) With Scaling and Root Planning in the Treatment of Chronic Periodontitisa Clinical Study. Research J. Pharm. and Tech. 6(1): Jan. 2013; Page 90-95.

15.   Gayathri. M, Dr. Gheena. S, Gopinath. Comparison of the aerobic microbes in supragingival plaque of chronic and aggressive periodontitis patients. Research J. Pharm. and Tech 2016; 9(9):1363-1366.

16.   Mundade Y, Srivastava A, Somani R, Kulkarni K. A comparative study for efficacy and tolerability of satranidazole plus ofloxacin versus ornidazole plus ofloxacin in periodontal infections. 2013.

17.   T Venkatachalam, S Narendiran, P Kalai Selvi, P Dheen Kumar. RP-HPLC Method for Simultaneous Determination of Ofloxacin and Satranidazole in Tablet Dosage Form. Asian J. Research Chem. 2(4): Oct.-Dec. 2009 page 469-471.

18.   RS Jadhav, PN Kendre, MH Kolhe, S N Lateef, SM Shelke, RK Godge. RP- HPLC Method for Simultaneous Estimation of Ofloxacin and Ornidazole from Bulk and Tablets. Research J. Science and Tech. 2009; 1(1):43-46.

19.   M. Seetha Devi, G. Raveendra Babu, NVL Sirisha MulukuriA. new stability indicating RP-HPLC method for the simultaneous estimation of Diloxanide and Ornidazole in bulk and Pharmaceutical Dosage forms. Research J. Science and Tech.

20.   Wankhede SB, Prakash A, Chitlange SS. Simultaneous Spectrophotometric Estimation of Ofloxacin and Satranidazole inTablet Dosage Form. Asian J. Research Chem. 1(1): July-Sept. 2008; Page 9-11.

21.   Bhusari KP, Chaple DR. Simultaneous Spectrophotometric Estimation of Ofloxacin and Ornidazole in Tablet Dosage Form. Asian J. Research Chem. 2(1): Jan.-March, 2009; Page 60-62.

22.   SS Merukar, PS Mhaskar, SR Bavaskar, KB Burade, PN Dhabale. Simultaneous Spectrophotometric Estimation of Levofloxacin Hemihydrate and Ornidazole in Pharmaceutical Tablet Dosage Form. Asian J. Research Chem. 2(3): July-Sept., 2009, page 336-339.

23.   Wankhede SB, Prakash A, Chitlange SS. Spectrophotometric Estimation of Satranidazole in Tablet Dosage Form. Research J. Pharm. and Tech. 1(4): Oct.-Dec. 2008; Page 441-443.

 

 

 

Received on 23.09.2019           Modified on 19.11.2019

Accepted on 10.01.2020         © RJPT All right reserved