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Single-dose Concentrations of Tinidazole in Gingival Crevicular Fluid, Serum, and Gingival Tissue in Adults with Periodontitis V. Liew, G. Mack, P. Tseng, M. Cvejic, M. Hayden and N. Buchanan J DENT RES 1991 70: 910 DOI: 10.1177/00220345910700050901 The online version of this article can be found at: http://jdr.sagepub.com/content/70/5/910
Published by: http://www.sagepublications.com
On behalf of: International and American Associations for Dental Research
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Single-dose Concentrations of Tinidazole in Gingival Crevicular Fluid, Serum, and Gingival Tissue in Adults with Periodontitis V. LIEW, G. MACK', P. TSENG, M. CVEJIC', M. HAYDEN', and N. BUCHANAN' Penodontics Unit, Westmead Hospital Dental Clinical School, Westmead, NSW 2145, Australia, and 1Paediatric Phannacology Unit, Westmead Hospital
Previous studies have shown that metronidazole is effective in the treatment of subgingival microflora associated with destructive periodontitis. The aim of this study was to determine whether tinidazole, a close analogue of metronidazole, would reach sufficient concentrations in serum, gingival crevicular fluid, and gingival tissue, to inhibit putative periodontopathic bacteria. Ten adult patients with moderate to advanced periodontitis took a single 2-g dose of tinidazole orally. Samples were assayed by high-performance liquid chromatography. The concentrations of tinidazole in serum and GCF were in a similar range (3.2-46.5 ,ug/mL). Tinidazole was not detected in the GCF in three of the patients. The drug was found in gingival tissue obtained at two h (0.17 + 0.14 pug/mg) and six h (0.15 + 0.18 ,ug/mg) after oral administration. The mean concentration of tinidazole in serum at 24 h (13 ± 3.0 ,ug/mL) is greater than the minimum inhibitory concentration for anaerobic bacteria as reported by others. The present data suggest that a single 2-g oral dose of tinidazole may lead to the presence of potentially bactericidal levels of tinidazole for up to 24 h in the periodontal pockets of some patients with periodontitis. J Dent Res 70(5):910-912, May, 1991
Introduction. Bacterial plaque is believed to be the main etiological agent of periodontal disease (Slots, 1979). The subgingival microflora associated with destructive periodontitis is predominantly Gram-negative and anaerobic (Tanner et al., 1979; Van Palenstein Helderman, 1981). It has been reported that bacteria may actually invade gingival tissue (Saglie et al., 1982; Manor et al., 1984). Metronidazole is effective against strictly anaerobic bacterial species and has been shown to reduce the numbers of these organisms and result in improved clinical parameters in patients with periodontitis (Loesche et al., 1981, 1984; Lindhe et al., 1983; Van Oosten et al., 1987). Metronidazole is present in sufficient concentrations in both serum and gingival crevicular fluid (GCF) to inhibit a wide range of suspected periodontopathic bacteria (Britt and Pohlod, 1986). Tinidazole, a close analogue of metronidazole, has fewer side-effects, no active metabolites (Nilsson-Ehle et al., 1981), and its serum half-life is approximately twice that of metronidazole (Wood and Monro, 1975; von Konow and Nord, 1982). In addition, it has an antimicrobial activity equal to, or better than, that of metronidazole (Wiist, 1977). To our knowledge, there has been only one paper (Pritchard and Higgins, 1987) in the dental literature reporting the use of tinidazole in the treatment of periodontal disease, despite these apparent advantages over metronidazole. The concentration of tinidazole in gingival tissues and GCF has not been reported. Received for publication September 17, 1990 Accepted for publication January 7, 1991
910
The purpose of this study was to determine the concentration of tinidazole in GCF, serum, and gingival tissues in adult patients with periodontitis after a single oral 2-g dose of the antibiotic.
Materials and methods. Ten volunteer adult patients attending the Westmead Hospital Dental Clinical School, who had moderate to advanced periodontitis requiring periodontal surgery, were selected to participate in the study. The selection of patients was based on the criteria that they were otherwise healthy and had at least four periodontal sites with probing depths greater than 5 mm. None of the patients was on concurrent medication. The patients, nine males and one female, were aged between 37 and 69 years. Their body weight (mean ± S.D.) was 49.7 ± 11.7 kg, and, on a mg/kg basis, each patient received a mean tinidazole dose of 27.9 ± 5.9 mg/kg. Each patient was administered a single oral dose of 2 g tinidazole (Fasigyn 4 x 500 mg, Pfizer, Australia) which was swallowed whole. GCF and blood samples were taken prior to drug administration and at 0.5, one, two, four, six, and 24 h after oral administration of the antibiotic. Five patients underwent periodontal surgery two h after drug administration, while the other five underwent surgery six h after drug administration. This study was approved by the Research, Ethics, and Drug Committee of Westmead Hospital. GCF was sampled from sites on the facial surfaces of teeth away from the surgical area. Supragingival debris was carefully removed with a curette, and the teeth were isolated with cotton rolls. The GCF was collected by the filter paper method described by Brill (1962). This involved placing a 2 x 5 mm strip of Whatman 3MM Chromatography paper (Whatman Lab Sales Ltd., Maidstone, Kent, UK) into the gingival crevice at each site until minimal resistance was felt. The strips were left at each site for 30 to 60 s. The volume of GCF absorbed by the filter paper was measured with a Periotron unit (Harco Electronics Ltd., Winnipeg, Canada) calibrated daily with human serum. After the Periotron reading was recorded, the strips of filter paper were stored in a sealed plastic container at 40C until analyzed. For a sample of the gingival tissue, a standard inverse bevel incision (Kieser, 1974) was made in the surgical area before a mucoperiosteal flap was lifted. The remaining collar of marginal gingiva was used as the biopsy specimen. This was lightly rinsed and stored moist with normal saline in plastic wrap at 40C. Blood samples were obtained by venipuncture and centrifuged. Serum and GCF were stored frozen at - 20'C while the biopsy specimen was refrigerated at 40C. All samples were assayed within a week of collection. High-performance liquid chromatography (HPLC) was used to assay all the samples. Briefly, the method involved the use of a 10-gim C18 Bondapak column with various compositions of methanol or acetonitrile and phosphate buffer as the mobile phase. Tinidazole and internal standards, ciprofloxacin and metronidazole, were detected at 280 nm. Serum samples were de-proteinized with an equal volume of acetonitrile, and the
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TINIDAZOLE IN BODY FLUIDS OF PERIODONTAL PATIENTS
Vol. 70 No. 5
supernatant was injected directly onto the column. The biopsy specimens were manually homogenized in distilled water, extracted in acetonitrile, and back-extracted in a mixture of methylene chloride and propanol. The organic layer was evaporated with nitrogen gas at 40'C and reconstituted in the appropriate mobile phase. Tinidazole concentrations in GCF were measured by mixing the filter paper with 100 L1 of acetonitrile, under the assumption that all the tinidazole would be in the organic phase. This was then injected directly onto the column. Standard curves with concentrations ranging between 5 and 60 [xg/mL for serum and between 1 and 5 jxg/mL for GCF were found to be linear (r>0.999). The inter-day and intra-day coefficients of variation were found to be less than 10%, 12%, and 12% for serum, GCF, and biopsy, respectively. The results are presented as means and standard deviations for each sampling time for serum, GCF, and biopsy measurements. Differences between mean levels in serum and GCF with time were assessed by independent and paired t tests. Differences between biopsy specimens collected at two and six h were assessed using independent t tests.
Results. The patients did not report any adverse drug reaction after receiving 2 g of tinidazole, and all patients had detectable serum levels of tinidazole. In the GCF, however, tinidazole concentrations either were not detected or were barely detectable in three of the patients. These three patients were excluded from the overall analysis with respect to both serum and GCF concentrations. As seen in Table 1, the mean level of tinidazole in GCF never exceeded that in serum. Mean serum tinidazole concentrations were not significantly different from those in GCF at any time interval (independent t test, p >0.05). With respect to individual patients' profiles, serum and GCF levels of tinidazole were similar (paired t test, p >0.05) with the exception of one patient, who had consistently higher GCF levels, compared with serum concentrations [t(5) = 2.57, p 0.05) (Table 2). There was a large variability in the concentrations of tinidazole found in the tissues, not only among patients, but also between two biopsy specimens obtained from different periodontal sites.
Discussion. Serum concentrations of tinidazole in this study were similar to those obtained by Wood and Monro (1975). However, there TABLE 1
CONCENTRATION OF TINIDAZOLE IN SERUM AND GINGIVAL CREVICULAR FLUID FOLLOWING A SINGLE 2-g ORAL DOSE Tinidazole Concentration (pug/mL) Serum (n = 7) GCF (n = 7) Time Mean ± S.D.
(hours) 0.5 1 2 4 6 24
7.5 27.9 49.5 41.4 34.7 13.3
± ± + ± + ±
9.3 17.1 22.5 15.5 7.3 3.0
3.2 27.7 37.3 41.2 25.1 10.1
± ± ± ± ± ±
7.8 19.9 22.6 18.1 15.1 10.6
911
appears to be a discrepancy between the half-life of elimination: 19.6 h, obtained in this study, compared with 12.5 h, as reported by Wood and Monro (1975). The apparently longer half-life found in this study can be explained by the slow elimination of tinidazole by two of the patients. They had individual half-lives of 28.5 and 43 h. In one of these patients, renal function may be impaired, as indicated by increased creatinine levels (data not presented). Tinidazole appears to penetrate well into the gingival tissue, as evidenced by the levels obtained in GCF. The half-life of tinidazole in GCF was shorter than that in serum in most of the patients. In one patient, the half-life in GCF was estimated to be 25.4 h, as opposed to a half-life of 9.9 h in serum. In three of the patients, tinidazole was either not found or not measurable in GCF. The reason for this observation is unknown. It is also uncertain why results of the gingival biopsy concentrations of tinidazole were so variable. It was assumed that tinidazole would be distributed evenly around the periodontal sites. Whether the extent of periodontal destruction and local inflammation affects drug penetration remains to be investigated. Wood and Monro.(1975) suggested that the pharmacokinetics of tinidazole and metronidazole are not dose-dependent over the dosing range of 0.15 to 2 g. A single 2-g dose of metronidazole has been shown to lead to higher peak serum concentrations of biologically active compounds than does tinidazole. However, the longer half-life of tinidazole results in higher serum concentrations, which may result in a greater therapeutic effect (Wood and Monro, 1975). Since the concentration of tinidazole in GCF was found to mirror that in serum, this would imply that tinidazole may have a more sustained effect than metronidazole in suppressing anaerobic periodontopathic bacteria. Additionally, the longer half-life of tinidazole would provide for a more convenient dosing schedule in the treatment of chronic or acute periodontitis, where metronidazole has already been shown to have good therapeutic effect (Shinn, 1962; Loesche et al., 1981, 1984; Lindhe et al., 1983; Van Oosten et al., 1987). In the period of 24 h after drug administration, the mean serum and GCF concentrations of tinidazole were higher than the minimum inhibitory concentration (MIC) reported for commonly found anaerobic bacteria (Wust, 1977). A tinidazole concentration of 3.1 pLg/mL inhibited, while 6.3 pLg/mL was bactericidal to, most species of anaerobic bacteria tested, including putative periodontopathogens such as Bacteroides, Fusobacterium, and Veillonella species (Wiist, 1977). Another study found that tinidazole was bacteriostatic for human oral anaerobic bacteria at a MIC of < 1 [xg/mL (Heimdahl et al., 1982). Salivary levels of tinidazole have been found to be of the same magnitude as that in serum (von Konow and Nord, 1982; Heimdahl et al., 1982). A recent study reported that the
TABLE 2 TINIDAZOLE CONCENTRATION IN SAMPLES OF GINGIVAL TISSUES AT TWO AND SIX HOURS AFTER A SINGLE 2-g ORAL DOSE Concentration Concentration Patient 2 Hours (Lg/lmg) Patient 6 Hours (pug/mg) 1 6 0.07 0.48 2 0.43 7 0.02 0.13 8 0.17 3 4 0.18 9 0.06 10 5 0.04 0.01 Mean 0.17 0.15 0.16 S.D 0.20
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912
J Dent Res May 1991
LIEW et al.
adjunctive use of tinidazole with conventional periodontal therapy altered the subgingival microflora of patients with generalized moderate to advanced periodontitis (Pritchard and Higgins, 1987). There was a significant reduction in counts for anaerobes and black-pigmented Bacteroides species for up to six months. The results of this study suggest that tinidazole is present in GCF in some patients at sufficiently high concentrations to inhibit anaerobic species in periodontal pockets or periodontal tissue for up to at least 24 h after a single 2-g dose. This may have implications in the therapy.of periodontitis and other orofacial infections.
Acknowledgment. We thank Pfizer Pty. Ltd. (Australia) for the supply of pure tinidazole. REFERENCES BRILL, N. (1962): The Gingival Pocket Fluid. Studies of its Occurrence, Composition and Effect, Acta Odontol Scand 20(Suppl. 32):1-115. BRITT, M.R. and POHLOD, D.J. (1986): Serum and Crevicular Concentrations after a Single Oral Dose of Metronidazole, J Periodontol 57:104-107. HEIMDAHL, A.; VON KONOW, L.; and NORD, C.E. (1982): Effect of Tinidazole on the Human Oral Microflora: A Comparison Between High Single and Low Repeated Doses, J Antimicrob Chemother 10(Suppl. A):157-164. KIESER, J.B. (1974): An Approach to Periodontal Pocket Elimination, Br J Oral Surg 12:177-195. LINDHE, J.; LILJENBERG, B.; ADIELSSON, B.; and BORGESSEN, I. (1983): Use of Metronidazole as a Probe in the Study of Human Periodontal Disease, J Clin Periodontol 10:590-601. LOESCHE, W.J.; SYED, S.A.; MORRISON, E.C.; LAUGHTON, B.; and GROSSMAN, N.S. (1981): Treatment of Periodontal Infections due to Anaerobic Bacteria with Short-term Treatment with Metronidazole, J Clin Periodontol 8:29-44. LOESCHE, W.J.; SYED, S.A.; MORRISON, E.C.; KERRY, G.A.;
HIGGINS, T.; and STOLL, J. (1984): Metronidazole in Periodontitis. I. Clinical and Bacteriological Results After 15 to 30 Weeks, J Periodontol 55:325-335. MANOR, A.; LEBENDIGER, M.; SHIFFER, A.; and TOVEL, H. (1984): Bacterial Invasion of Periodontal Tissues in Human Gingival Tissues in Advanced Periodontitis in Humans, J Periodontol 55:567-573. NILSSON-EHLE, I.; URSING, B.; and NILSSON-EHLE, P. (1981): Liquid Chromatographic Assay for Metronidazole and Tinidazole: Pharmacokinetic and Metabolic Studies in Human Subjects, Antimicrob Agents Chemother 19:754-760. PRITCHARD, J.R. and HIGGINS, T.J. (1987): Tinidazole in Clinical Periodontics-The Effects upon the Subgingival Microflora, J Dent Res 66:821, Abst. No. 35. SAGLIE, R.; NEWMAN, M.G.; CARRANZA, F.A.; and PATTISON, G.L. (1982): Bacterial Invasion of Gingiva in Advanced Periodontitis in Humans, J Periodontol 53:217-222. SHINN, D.L.S. (1962): Metronidazole in Acute Ulcerative Gingivitis, Lancet 1:1191. SLOTS, J. (1979): Subgingival Microflora and Periodontal Disease, J Clin Periodontol 6:351-382. TANNER, A.C.R.; HAFFER, C.; BRATITHALL, G.T.; VISCONTI, R.A.; and SOCRANSKY, S.S. (1979): A Study of the Bacteria Associated with Advancing Periodontal Disease in Man, J Clin Periodontol 6:278-307. VAN OOSTEN, M.A.C.; MIKX, F.M.H.; and RENGLI, H.H. (1987): Microbial and Clinical Measurements of Periodontal Pockets During Sequential Periods of Nontreatment, Mechanical Debridement and Metronidazole Therapy, J Clin Periodontol 14:197-204. VAN PALENSTEIN HELDERMAN, W.H. (1981): Microbial Etiology of Periodontal Disease, J Clin Periodontol 8:261-280. VON KONOW, L. and NORD, C.E. (1982): Concentrations of Tinidazole and Metronidazole in Serum, Saliva and Alveolar Bone, JAntimicrob Chemother 10 (Suppl. A): 165-172. WOOD, B.A. and MONRO, A.M. (1975): Pharmacokinetics of Tinidazole and Metronidazole in Women After Single Large Oral Doses, Br J Vener Dis 51:51-53. WUST, J. (1977): Susceptibility of Anaerobic Bacteria to Metronidazole, Ornidazole and Tinidazole and Routine Susceptibility Testing by Standardized Methods, Antimicrob Agents Chemother 11:631-637.
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Single-dose Concentrations of Tinidazole in Gingival Crevicular Fluid, Serum, and Gingival Tissue in Adults with Periodontitis V. Liew, G. Mack, P. Tseng, M. Cvejic, M. Hayden and N. Buchanan J DENT RES 1991 70: 910 DOI: 10.1177/00220345910700050901 The online version of this article can be found at: http://jdr.sagepub.com/content/70/5/910
Published by: http://www.sagepublications.com
On behalf of: International and American Associations for Dental Research
Additional services and information for Journal of Dental Research can be found at: Email Alerts: http://jdr.sagepub.com/cgi/alerts Subscriptions: http://jdr.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav Citations: http://jdr.sagepub.com/content/70/5/910.refs.html
>> Version of Record - May 1, 1991 What is This?
Downloaded from jdr.sagepub.com at UNIVERSITE LAVAL on July 6, 2014 For personal use only. No other uses without permission.
Single-dose Concentrations of Tinidazole in Gingival Crevicular Fluid, Serum, and Gingival Tissue in Adults with Periodontitis V. LIEW, G. MACK', P. TSENG, M. CVEJIC', M. HAYDEN', and N. BUCHANAN' Penodontics Unit, Westmead Hospital Dental Clinical School, Westmead, NSW 2145, Australia, and 1Paediatric Phannacology Unit, Westmead Hospital
Previous studies have shown that metronidazole is effective in the treatment of subgingival microflora associated with destructive periodontitis. The aim of this study was to determine whether tinidazole, a close analogue of metronidazole, would reach sufficient concentrations in serum, gingival crevicular fluid, and gingival tissue, to inhibit putative periodontopathic bacteria. Ten adult patients with moderate to advanced periodontitis took a single 2-g dose of tinidazole orally. Samples were assayed by high-performance liquid chromatography. The concentrations of tinidazole in serum and GCF were in a similar range (3.2-46.5 ,ug/mL). Tinidazole was not detected in the GCF in three of the patients. The drug was found in gingival tissue obtained at two h (0.17 + 0.14 pug/mg) and six h (0.15 + 0.18 ,ug/mg) after oral administration. The mean concentration of tinidazole in serum at 24 h (13 ± 3.0 ,ug/mL) is greater than the minimum inhibitory concentration for anaerobic bacteria as reported by others. The present data suggest that a single 2-g oral dose of tinidazole may lead to the presence of potentially bactericidal levels of tinidazole for up to 24 h in the periodontal pockets of some patients with periodontitis. J Dent Res 70(5):910-912, May, 1991
Introduction. Bacterial plaque is believed to be the main etiological agent of periodontal disease (Slots, 1979). The subgingival microflora associated with destructive periodontitis is predominantly Gram-negative and anaerobic (Tanner et al., 1979; Van Palenstein Helderman, 1981). It has been reported that bacteria may actually invade gingival tissue (Saglie et al., 1982; Manor et al., 1984). Metronidazole is effective against strictly anaerobic bacterial species and has been shown to reduce the numbers of these organisms and result in improved clinical parameters in patients with periodontitis (Loesche et al., 1981, 1984; Lindhe et al., 1983; Van Oosten et al., 1987). Metronidazole is present in sufficient concentrations in both serum and gingival crevicular fluid (GCF) to inhibit a wide range of suspected periodontopathic bacteria (Britt and Pohlod, 1986). Tinidazole, a close analogue of metronidazole, has fewer side-effects, no active metabolites (Nilsson-Ehle et al., 1981), and its serum half-life is approximately twice that of metronidazole (Wood and Monro, 1975; von Konow and Nord, 1982). In addition, it has an antimicrobial activity equal to, or better than, that of metronidazole (Wiist, 1977). To our knowledge, there has been only one paper (Pritchard and Higgins, 1987) in the dental literature reporting the use of tinidazole in the treatment of periodontal disease, despite these apparent advantages over metronidazole. The concentration of tinidazole in gingival tissues and GCF has not been reported. Received for publication September 17, 1990 Accepted for publication January 7, 1991
910
The purpose of this study was to determine the concentration of tinidazole in GCF, serum, and gingival tissues in adult patients with periodontitis after a single oral 2-g dose of the antibiotic.
Materials and methods. Ten volunteer adult patients attending the Westmead Hospital Dental Clinical School, who had moderate to advanced periodontitis requiring periodontal surgery, were selected to participate in the study. The selection of patients was based on the criteria that they were otherwise healthy and had at least four periodontal sites with probing depths greater than 5 mm. None of the patients was on concurrent medication. The patients, nine males and one female, were aged between 37 and 69 years. Their body weight (mean ± S.D.) was 49.7 ± 11.7 kg, and, on a mg/kg basis, each patient received a mean tinidazole dose of 27.9 ± 5.9 mg/kg. Each patient was administered a single oral dose of 2 g tinidazole (Fasigyn 4 x 500 mg, Pfizer, Australia) which was swallowed whole. GCF and blood samples were taken prior to drug administration and at 0.5, one, two, four, six, and 24 h after oral administration of the antibiotic. Five patients underwent periodontal surgery two h after drug administration, while the other five underwent surgery six h after drug administration. This study was approved by the Research, Ethics, and Drug Committee of Westmead Hospital. GCF was sampled from sites on the facial surfaces of teeth away from the surgical area. Supragingival debris was carefully removed with a curette, and the teeth were isolated with cotton rolls. The GCF was collected by the filter paper method described by Brill (1962). This involved placing a 2 x 5 mm strip of Whatman 3MM Chromatography paper (Whatman Lab Sales Ltd., Maidstone, Kent, UK) into the gingival crevice at each site until minimal resistance was felt. The strips were left at each site for 30 to 60 s. The volume of GCF absorbed by the filter paper was measured with a Periotron unit (Harco Electronics Ltd., Winnipeg, Canada) calibrated daily with human serum. After the Periotron reading was recorded, the strips of filter paper were stored in a sealed plastic container at 40C until analyzed. For a sample of the gingival tissue, a standard inverse bevel incision (Kieser, 1974) was made in the surgical area before a mucoperiosteal flap was lifted. The remaining collar of marginal gingiva was used as the biopsy specimen. This was lightly rinsed and stored moist with normal saline in plastic wrap at 40C. Blood samples were obtained by venipuncture and centrifuged. Serum and GCF were stored frozen at - 20'C while the biopsy specimen was refrigerated at 40C. All samples were assayed within a week of collection. High-performance liquid chromatography (HPLC) was used to assay all the samples. Briefly, the method involved the use of a 10-gim C18 Bondapak column with various compositions of methanol or acetonitrile and phosphate buffer as the mobile phase. Tinidazole and internal standards, ciprofloxacin and metronidazole, were detected at 280 nm. Serum samples were de-proteinized with an equal volume of acetonitrile, and the
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TINIDAZOLE IN BODY FLUIDS OF PERIODONTAL PATIENTS
Vol. 70 No. 5
supernatant was injected directly onto the column. The biopsy specimens were manually homogenized in distilled water, extracted in acetonitrile, and back-extracted in a mixture of methylene chloride and propanol. The organic layer was evaporated with nitrogen gas at 40'C and reconstituted in the appropriate mobile phase. Tinidazole concentrations in GCF were measured by mixing the filter paper with 100 L1 of acetonitrile, under the assumption that all the tinidazole would be in the organic phase. This was then injected directly onto the column. Standard curves with concentrations ranging between 5 and 60 [xg/mL for serum and between 1 and 5 jxg/mL for GCF were found to be linear (r>0.999). The inter-day and intra-day coefficients of variation were found to be less than 10%, 12%, and 12% for serum, GCF, and biopsy, respectively. The results are presented as means and standard deviations for each sampling time for serum, GCF, and biopsy measurements. Differences between mean levels in serum and GCF with time were assessed by independent and paired t tests. Differences between biopsy specimens collected at two and six h were assessed using independent t tests.
Results. The patients did not report any adverse drug reaction after receiving 2 g of tinidazole, and all patients had detectable serum levels of tinidazole. In the GCF, however, tinidazole concentrations either were not detected or were barely detectable in three of the patients. These three patients were excluded from the overall analysis with respect to both serum and GCF concentrations. As seen in Table 1, the mean level of tinidazole in GCF never exceeded that in serum. Mean serum tinidazole concentrations were not significantly different from those in GCF at any time interval (independent t test, p >0.05). With respect to individual patients' profiles, serum and GCF levels of tinidazole were similar (paired t test, p >0.05) with the exception of one patient, who had consistently higher GCF levels, compared with serum concentrations [t(5) = 2.57, p 0.05) (Table 2). There was a large variability in the concentrations of tinidazole found in the tissues, not only among patients, but also between two biopsy specimens obtained from different periodontal sites.
Discussion. Serum concentrations of tinidazole in this study were similar to those obtained by Wood and Monro (1975). However, there TABLE 1
CONCENTRATION OF TINIDAZOLE IN SERUM AND GINGIVAL CREVICULAR FLUID FOLLOWING A SINGLE 2-g ORAL DOSE Tinidazole Concentration (pug/mL) Serum (n = 7) GCF (n = 7) Time Mean ± S.D.
(hours) 0.5 1 2 4 6 24
7.5 27.9 49.5 41.4 34.7 13.3
± ± + ± + ±
9.3 17.1 22.5 15.5 7.3 3.0
3.2 27.7 37.3 41.2 25.1 10.1
± ± ± ± ± ±
7.8 19.9 22.6 18.1 15.1 10.6
911
appears to be a discrepancy between the half-life of elimination: 19.6 h, obtained in this study, compared with 12.5 h, as reported by Wood and Monro (1975). The apparently longer half-life found in this study can be explained by the slow elimination of tinidazole by two of the patients. They had individual half-lives of 28.5 and 43 h. In one of these patients, renal function may be impaired, as indicated by increased creatinine levels (data not presented). Tinidazole appears to penetrate well into the gingival tissue, as evidenced by the levels obtained in GCF. The half-life of tinidazole in GCF was shorter than that in serum in most of the patients. In one patient, the half-life in GCF was estimated to be 25.4 h, as opposed to a half-life of 9.9 h in serum. In three of the patients, tinidazole was either not found or not measurable in GCF. The reason for this observation is unknown. It is also uncertain why results of the gingival biopsy concentrations of tinidazole were so variable. It was assumed that tinidazole would be distributed evenly around the periodontal sites. Whether the extent of periodontal destruction and local inflammation affects drug penetration remains to be investigated. Wood and Monro.(1975) suggested that the pharmacokinetics of tinidazole and metronidazole are not dose-dependent over the dosing range of 0.15 to 2 g. A single 2-g dose of metronidazole has been shown to lead to higher peak serum concentrations of biologically active compounds than does tinidazole. However, the longer half-life of tinidazole results in higher serum concentrations, which may result in a greater therapeutic effect (Wood and Monro, 1975). Since the concentration of tinidazole in GCF was found to mirror that in serum, this would imply that tinidazole may have a more sustained effect than metronidazole in suppressing anaerobic periodontopathic bacteria. Additionally, the longer half-life of tinidazole would provide for a more convenient dosing schedule in the treatment of chronic or acute periodontitis, where metronidazole has already been shown to have good therapeutic effect (Shinn, 1962; Loesche et al., 1981, 1984; Lindhe et al., 1983; Van Oosten et al., 1987). In the period of 24 h after drug administration, the mean serum and GCF concentrations of tinidazole were higher than the minimum inhibitory concentration (MIC) reported for commonly found anaerobic bacteria (Wust, 1977). A tinidazole concentration of 3.1 pLg/mL inhibited, while 6.3 pLg/mL was bactericidal to, most species of anaerobic bacteria tested, including putative periodontopathogens such as Bacteroides, Fusobacterium, and Veillonella species (Wiist, 1977). Another study found that tinidazole was bacteriostatic for human oral anaerobic bacteria at a MIC of < 1 [xg/mL (Heimdahl et al., 1982). Salivary levels of tinidazole have been found to be of the same magnitude as that in serum (von Konow and Nord, 1982; Heimdahl et al., 1982). A recent study reported that the
TABLE 2 TINIDAZOLE CONCENTRATION IN SAMPLES OF GINGIVAL TISSUES AT TWO AND SIX HOURS AFTER A SINGLE 2-g ORAL DOSE Concentration Concentration Patient 2 Hours (Lg/lmg) Patient 6 Hours (pug/mg) 1 6 0.07 0.48 2 0.43 7 0.02 0.13 8 0.17 3 4 0.18 9 0.06 10 5 0.04 0.01 Mean 0.17 0.15 0.16 S.D 0.20
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912
J Dent Res May 1991
LIEW et al.
adjunctive use of tinidazole with conventional periodontal therapy altered the subgingival microflora of patients with generalized moderate to advanced periodontitis (Pritchard and Higgins, 1987). There was a significant reduction in counts for anaerobes and black-pigmented Bacteroides species for up to six months. The results of this study suggest that tinidazole is present in GCF in some patients at sufficiently high concentrations to inhibit anaerobic species in periodontal pockets or periodontal tissue for up to at least 24 h after a single 2-g dose. This may have implications in the therapy.of periodontitis and other orofacial infections.
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