3Mixstatin ,Tri-Antibiotic Mix & Simvastatin in the Treatment of Primary Molars

A Comparative Clinical and Radiographic Study of 3Mixstatin vs Tri-Antibiotic Mix and Simvastatin in the Treatment of Primary Molars With Inflammatory Root Resorption A Randomized Clinical Trial

The aim of this study is to determine whether the success rate of pulp therapy undergone on primary molars with signs and symptoms of odontogenic infection that may render them indicated for extraction will improve with the use of the Simvastatin alone, the Tri-Antibiotic Mix alone or when in combination together 3Mixstatin as a component in the root filling material.

Study Overview

• Status: Unknown
• Conditions: Tooth, Deciduous
• Intervention / Treatment: Procedure: Pulpectomy for primary molars + triple antibiotic mix; Procedure: Pulpectomy for primary molars + 3mixstatin; Procedure: Pulpectomy for primary molars + simvastatin

Detailed Description

A clinical situation will often present itself where primary teeth under radiographic examination show inter-radicular or periapical root resorption, perforation of coronal third of roots and/or loss of bone support as a result of infective or inflammatory conditions. Pathologic root resorption is the most common cause of premature tooth loss in primary dentition. The reason for that may be the high content of undifferentiated mesenchymal cells, which may give rise to odontoclastic cells in response to either the caries process or the pulp-capping materials, resulting in the exaggerated inflammatory response and consequently internal resorption in primary teeth. It would make sense to utilize the rich supply of undifferentiated mesenchymal cells towards regeneration of remaining dental tissues.

Antibiotic Mix as an intracanal medicament

In recent years, the Cariology Research Unit of Niigata University School of Dentistry has developed the concept of lesion sterilization and tissue repair (LSTR) therapy that employed a mixture of antibacterial drugs for disinfection. Repair of damaged tissues can be expected if lesions are disinfected. This procedure uses a mixture of three antibacterial drugs (3Mix MP) as a root canal medicament to eliminate the remaining bacteria in endodontic lesions. The medicament consists of metronidazole, ciprofloxacin and minocycline - with macrogol (M) as the ointment base and propylene glycol (P) as the carrier Alone, none of these drugs resulted in complete elimination of the bacteria. However, in combination, these drugs were able to consistently sterilize all samples.

Although a local antibiotic medication in endodontics offers many advantages, this mode has some drawbacks, including development of bacterial resistant strains. That is a major concern and may lead to the transfer of resistance genes from antibiotic-resistant to antibiotic-susceptible microorganisms. Other drawbacks include allergic reactions inhibition of angiogenesis , and tooth staining or discoloration particularly with Minocycline. More importantly is that although the concept of Lesion sterilization and tissue repair (LSTR) therapy is that it provides an efficient and predictable disinfection, through 3 Mix on a local level and providing the suitable environment for tissues to heal, it does not in itself have any anti-inflammatory nor regenerative potential. Statins may provide these two benefit.

Choice of comparator Statins are structural analogs of HMG-CoA (3hydroxy-3-methylglutaryl-coenzyme A). These drugs are the first-line for hyperlipidemia and it has been recognized to be a safe and low-priced drug as a result of its worldwide longtime usage. Moreover, statins have multiple functions including anti-inflammation, induction of angiogenesis and improvement of the vascular endothelial cell function. Another interesting and important function of statin is its effect on bone formation. It has been reported that several statins such as simvastatin and lovastatin have anabolic effects on bone metabolism at in vitro and in vivo studies. They promote mineralization in non-mineralizing osteoblasts through induction of BMP-2 and osteocalcin. Local application of simvastatin gel has shown to stimulate the regeneration of alveolar bone defects Statins have an anti-inflammatory effect. They act by decreasing the production of interleukin-6 and interleukin-8 and may also improve the function of odontoblasts, thus dentin formation.

3 Mixstatin as an intracanal medicament

Often, different chemicals or drugs are combination in a cocktail in an attempt to elicit variety of effects with a single application.

Aminabadi et al combined the above-mentioned techniques by adding simvastatin powder to the tri-antibiotic mix (3Mix) and proposed the term "3Mixtatin", (an acronym of 3Mix and simvastatin) with the aims of suppressing bacteria, preventing pulp inflammation, and inducing hard tissue formation. His study population involved poor prognosis primary molars with advanced root resorption and/or pulpal floor perforation.

When compared with MTA, radio graphic and clinical healing occurred more successfully following 3Mixtatin treatment within a 24-month study period 96.8% success rate both clinically and radiographically. 3Mixstatin, a previously unstudied combination was applied, lead to preservation of the primary teeth that were otherwise indicated for extraction according to current guidelines. It may lead to a paradigm shift in the treatment of primary teeth in the future.

• Study Type: Interventional
• Enrollment (Anticipated): 45
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Dina y El Kharadly, Msc; Phone Number: +201222189574; Email: d.elkharadly@gmail.com
• Study Contact Backup: Name: Rania N Abdalla, DDs; Phone Number: 00201005037367; Email: nasrania05@yahoo.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 5 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Patients:

1. Young cooperative patients with no history of systemic disease that may contraindicate pulp therapy
2. Age range 4-6 years.
3. Patient has at least one restorable primary molar that exhibits signs and symptoms of odontogenic infection with inflammatory root resorption and require pulpectomy,
4. Patient's parents are willing to participate in this study and will be able to follow up Clinical & Radiographic Criteria for Case Selection Signs and symptoms of irreversible pulpitis as well as inter-radicular, or periapical root resorption as a result of infective or inflammatory conditions that may render the tooth hopeless and indicated for extraction

Clinical Criteria (include):

1. Spontaneous pain
2. Intraoral Abscess
3. Extra oral Abscess
4. Tender to percussion
5. Presence of abnormal mobility other than that associated with exfoliation

Radiographic Criteria include:

1. Radiolucency in furcation area 2. Periapical root resorption or excessive bone destruction and/or perforation in coronal third of roots as a result of infective or inflammatory conditions.

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Exclusion Criteria:

• Patients with systemic disease 2. Patients who cannot attend follow up. 3. Primary molars that are unrestorable 4. Primary molars exhibiting pathology of permanent tooth follicle

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Triple antibiotic paste; Pulpectomy for primary molars, triple antibiotic mix is used as obturating material mixed with Macrogol and Polyethylene glycol & small amount of Zinc oxide powder to obtain workable , radio opaque mix	Procedure: Pulpectomy for primary molars + triple antibiotic mix; complete extirpation of infected pulp from primary molars. Following instrumentation and copious irrigation ,the root canals are filled with one of .Following instrumentation and copious irrigation ,the root canals are filled with a triple antibiotic mix mixed with a Carrier ( MP) as an obturating material
Experimental: 3mixstatin; Pulpectomy for primary molars, 3 Mixstatin ( mix of simvastatin and triple antibiotic mix ) is used as obturating material mixed with Macrogol and Polyethylene glycol & small amount of Zinc oxide powder to obtain workable , radio opaque mix	Procedure: Pulpectomy for primary molars + 3mixstatin; complete extirpation of infected pulp from primary molars. Following instrumentation and copious irrigation ,the root canals are filled with one of .Following instrumentation and copious irrigation ,the root canals are filled with 3mixstatin (triple antibiotic mix + simvastatin) as an obturating material mixed with a Carrier ( MP) as an obturating material
Experimental: simvastatin; Pulpectomy for primary molars, simvastatin is used as obturating material mixed with Macrogol and Polyethylene glycol & small amount of Zinc oxide powder to obtain workable , radio opaque mix	Procedure: Pulpectomy for primary molars + simvastatin; complete extirpation of infected pulp from primary molars. Following instrumentation and copious irrigation ,the root canals are filled with simvastatin as mixed with a Carrier ( MP) as an obturating material

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Over All Success Rate ( as a percentage)	For each group Number of cases exhibiting success criterion at 12 months / Total number of cases x 100 At the end of the follow up period, the cases are considered successful if they exhibited ALL the following criteria: Absence of tenderness to percussion; No abnormal mobility; Absence of swelling and fistula; Absence or decrease of furcation radiolucency; Absence or decrease of radicular radiolucency; Absence of Internal/external root resorption or other pathological changes The cases were considered as total (overall) failures if they failed clinically at the 3, 6 or 12 months; or when they failed radiographically at the 12 months follow-up. Otherwise they will be considered as a success.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bone density changes in Region of Interest ROI	measured by :Digora image analysis software i.e. Digora for windows software DFW Measuring Unit :Relative pixel values using an 8-bit scale from full black (0) to full white (255)	12 months

Collaborators and Investigators

• Sponsor: Cairo University
• Investigators: Study Chair: Sherif B El Tawil, DDS, Cairo University; Study Director: Dina El Beshlawy, Cairo University

Publications and helpful links

General Publications

• Asl Aminabadi N, Maljaei E, Erfanparast L, Ala Aghbali A, Hamishehkar H, Najafpour E. Simvastatin versus Calcium Hydroxide Direct Pulp Capping of Human Primary Molars: A Randomized Clinical Trial. J Dent Res Dent Clin Dent Prospects. 2013 Winter;7(1):8-14. doi: 10.5681/joddd.2013.002. Epub 2013 Feb 21.
• Sakoda K, Yamamoto M, Negishi Y, Liao JK, Node K, Izumi Y. Simvastatin decreases IL-6 and IL-8 production in epithelial cells. J Dent Res. 2006 Jun;85(6):520-3. doi: 10.1177/154405910608500608.
• Aminabadi NA, Huang B, Samiei M, Agheli S, Jamali Z, Shirazi S. A Randomized Trial Using 3Mixtatin Compared to MTA in Primary Molars with Inflammatory Root Resorption: A Novel Endodontic Biomaterial. J Clin Pediatr Dent. 2016;40(2):95-102. doi: 10.17796/1053-4628-40.2.95.
• Takushige T, Cruz EV, Asgor Moral A, Hoshino E. Endodontic treatment of primary teeth using a combination of antibacterial drugs. Int Endod J. 2004 Feb;37(2):132-8. doi: 10.1111/j.0143-2885.2004.00771.x.
• Doneria D, Thakur S, Singhal P, Chauhan D, Keshav K, Uppal A. In Search of a Novel Substitute: Clinical and Radiological Success of Lesion Sterilization and Tissue Repair with Modified 3Mix-MP Antibiotic Paste and Conventional Pulpectomy for Primary Molars with Pulp Involvement with 18 Months Follow-up. Contemp Clin Dent. 2017 Oct-Dec;8(4):514-521. doi: 10.4103/ccd.ccd_47_17.
• Nakornchai S, Banditsing P, Visetratana N. Clinical evaluation of 3Mix and Vitapex as treatment options for pulpally involved primary molars. Int J Paediatr Dent. 2010 May;20(3):214-21. doi: 10.1111/j.1365-263X.2010.01044.x.
• Okamoto Y, Sonoyama W, Ono M, Akiyama K, Fujisawa T, Oshima M, Tsuchimoto Y, Matsuka Y, Yasuda T, Shi S, Kuboki T. Simvastatin induces the odontogenic differentiation of human dental pulp stem cells in vitro and in vivo. J Endod. 2009 Mar;35(3):367-72. doi: 10.1016/j.joen.2008.11.024.
• Seto H, Ohba H, Tokunaga K, Hama H, Horibe M, Nagata T. Topical administration of simvastatin recovers alveolar bone loss in rats. J Periodontal Res. 2008 Jun;43(3):261-7. doi: 10.1111/j.1600-0765.2007.01024.x.
• Chen S, Yang JY, Zhang SY, Feng L, Ren J. Effects of simvastatin gel on bone regeneration in alveolar defects in miniature pigs. Chin Med J (Engl). 2011 Dec;124(23):3953-8.

Study record dates

Study Major Dates

• Study Start (Anticipated): September 1, 2018
• Primary Completion (Anticipated): September 1, 2019
• Study Completion (Anticipated): January 1, 2020

Study Registration Dates

• First Submitted: June 8, 2018
• First Submitted That Met QC Criteria: June 30, 2018
• First Posted (Actual): July 13, 2018

Study Record Updates

• Last Update Posted (Actual): July 13, 2018
• Last Update Submitted That Met QC Criteria: June 30, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: simvastatin; non vital; deciduous; 3mixstatin; triple antibiotic mix; 3 mix
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Anti-Bacterial Agents; Simvastatin
• Other Study ID Numbers: 3Mixstatin

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No