Journal of Clinical Periodontology: 1979: 6: 83-92 Key words: Periodonial therapy - drugs - toc.al detivery Accepted for publication; June 29, 1578,
miciohiology.
Periodontal therapy by local delivery of tetracycline J. M. GOODSON, A. HAFFAJEE AND S. S. SOCRANSKY
Forsyth Dental Center, Boston, Mass., U.S.A. Abstract. The present investigation assessed the feasibility of treating periodontal disease by controlled delivery of antibacterial agents from within periodontal pockets. Tetracycline-filled hollow fibers placed in the gingival sulcus were shown to have a dramatic effect both on the periodontal mfcroflora and clinical manifestations of disease. Furthermore, it was found that drug-filled cellulose acetate holiow fibers are biologically compatible with tbe environment and can be manipulated by dental personnel to .provide drug therapy with less than 1/1000 the amount of tetracycline that would have been used for systemic therapy. Of theoretical importance is tbe observation that virtual elimination of spirochetes from the gingival sulcus is possible by a single placement of tetracycline-filled hollow fibers, and Rpirochetes, ones eliminated from a site, do not lapidl'y recolonize despite the persistence of viable organisms elsewhere in the mouth.
A fundamental principle of drug therapy is that the agent must reach the site of action in adequate concentration to be effective and be maintained at that site for an adequate duration to allow the effect to occur. From this point of view, it would appear that a controlled release suppository form of a drug placed within the periodontal pocket could be a highly effective method of administering antibacterial agents for periodontal therapy. Testing of antibacterial agents was prompted by the abundant evidence imphcating microorganisms as the primary cause of the periodontal diseases (EUison 1970, Genco et al. 1969, Keyes 1970, Socransky 1970, Socransky & Crawford 1977) and data suggesting that antibacterial agents eould be effective in the control of micro-
organisms which populate the periodontal pocket (Loesche 1976). Local treatment of periodontal disease with antibacterial agents has principally been by mouth rinses and to a lesser degree, topical application in an adhesive carrier. However effective these procedures may be in reducing the formation of supragingival plaque, there is no evidence and little reason to expect that they would reach the site of aetion in destructive periodontal disease. When considering treatment of this disease condition by antibacterial agents, it becomes necessary to devise methods of administration which estabhsh and maintain therapeutically effective concentrations of the agent within the periodontal pocket. In order to investigate the feasibility of treating periodontal disease by-controlled
0303-6979/79/020083-10802.50/0 © 1979 Munksgaard, Copenhagen
GOODSON, HAFFAJEE AND SOCRANSKY
V = 0.3 /il/c Fig. 1. Dimensions of cellulose acetate hollow fibers used for drug delivery to the periodontal einvironment. Dimensionen der Zellulose-Azetat Hohlfasern zur Applikation des Heilmittels in die unmittelbare Umgebung des Parodonts. Dimensions des fibres creuses d'acetate de cellulose utiiisees pottr Vadministration de medicaments dans le milieu parodontal.
delivery of antibacterial agents from within the periodontal pocket, small-diameter cellulose acetate hollow fibers were filled with tetracycline and tested under various conditions. Tests indicated that antibacterial levels could he sustained in the periodontal pocket for prolonged periods and could dramatically alter the microbial composition. Placement of drug-filled fibers into the periodontal pocket was associated with a decrease in clinical signs of disease without indications of local irritation. Materials and Methods Procedures
used for filling hollow
fibers.
Controlled delivery devices were prepared by filling commercially available cellulose acetate hollow fibers with tetracycline. The hollow fibers had an outside diameter of 250 }im, an inside diameter of 200 _«m and a wall thickness of 25 iim (Fig. 1). These fibers were manufactured by Dow Chemical Company and marketed by Bio-Rad Corpo-
ration for hollow fiber dialysis. The fibers were available in a wide range of permeability from nominal molecular weight cutoff values of 200 to 50,000 daltons when used for dialysis. Fibers loaded with drugs were the 200 dalton material (Bio-Fiber 20, Bio-Rad Laboratories, Richmond, CA). Tetracycline hydrochloride used to fill these fibers was obtained from USP generic capsule preparations of the drug. The capsules were opened and their contents dissolved in distilled water, centrifuged to remove the insoluble diluent used in the encapsulation process and lyophilyzed to dryness. The lyophilyzed powder thus obtained was redissolved in a small amount of water to make a concentrated solution for fiber loading. Fiber loads as measured by the weighed difference hetween a 1-cm segment of filled and empty fibers were determined for various concentrations of filling solutions. It was found that a saturated solution of tetracycline HCl contained approximately 23 % tetracycline (weight/volume) and little improvement in fill could be seen using more concentrated suspensions. Therefore,
Halliw Flhar
Fig. 2. Method used to fill hollow fibers with tetracycline hydrochloride. A 20 % solution is pumped into the fiber and allowed to dry prior to its utilization. Die Methodik Hohlfasern mit TetrazyklinHydrochlorid zu fUllen. Eine 20 %-ige Ldsung wird in die Faser gepumpt. Vor ihrer klinischen Anwendung wird die Easer getrocknet. Methode utilisee pour rempUr de chlorhydrate de tetracycline les fibres creuses. On pompe une solution a 20 % dans la fibre et on la laisse secher avant l'utilisation.
PERIODONTAL THERAPY BY LOCAL DELIVERY OF TETRACYCLINE
85
mum capacity with dried tetracycline hydrochloride. Fibers thus prepared were removed from the attached hypodermic needle and stored in closed polyethylene tubes under a nitrogen atmosphere.
ParlBilontil by LBCII Drug Daflviri
Fig. 3. Placement of drug-filled hoHow fibers for local treatment of periodontal disease. Single strands of tetracycline-filled hollow fibers are placed around the tooth and gently pressed below tbe margin of the gingiva. Applikation der mit dem Heilmittel beschickten Hohlfasern zur Lokalbehandling parodontaler Erkrankungen. Einzelstrange tetrazyklingefullter Hohlfasern werden um den Zahn herum gelegt und vorsichtig unter den Gingivalsaum gedrUckt. Pose des fibres creuses remplies du medicament pour le traitement local des parodontopathies. Les brins de fibres creuses sont places autour de la dent et presses delicatement en dessous du rebord gingival.
a 20 % solution was used for fiber filling procedures. Hollow fibers were prepared for loading by cementing (Dow # 891 silicone cemetit type A) into the lumen of sterile 26-gage hypodermic needles. After allowing the cement to dry for 12 h or more, the hypodermic needles were attached by a standard luer fitting (LDC # 107B8) to teflon tubing (1/16" O.D. X .031") which fit the inner bore of silicone pump tubing. The pump tubing was placed in a peristaltic pump (Sage model 375A) and the distal end of the tubing introduced into the 20 % tetracycline solution (Fig. 2). After 10 min or less, the fibers were filled with tetracycline solution. Pumping was maintained for 2-6 h while the fiber was dried in the air flow of a laminar flow hood. After this procedure, fibers were found to be filled virtually to maxi-
Method of placement of drug-filled hollow fibers. Drug-filled fibers were used in therapy by tying around the cervix of teeth to be treated and gently pressing into the periodontal pocket (Fig. 3). The relative size of these fibers can be appreciated by considering that they are 30 % smaller than the tip of commonly used periodontal probes (Fig. 4). Measurement of release kinetics from the periodontal pocket. The kinetics of release of tetracycline from fibers placed in the periodontal pocket was determined by removing fibers at various time intervals,
Fig. 4. The size of tetra cyciine-f ill ed hollow fibers relative to a maxillary cuspid (human skull speciman). Die Grosse von mit Tetrazyklin gefiillten Hohlfasern im Vergleich mit einem Oberkiefereckzahn (menschliches Schddelpraparat). Grandeur des fibres creuses rempUes de tetracyclities par rapport a une canine superieure (cratie humain).
86
GOODSON, HAFFAJEE AND SOCRANSKY
measuring the length of the removed fiber and placing in 3 ml of distilled water to allow the remaining contents to exhaust. The concentration of solutions thus obtained was measured spectrophotometrically at 276 nm and the amount of tetracycline left in the fiber calculated as the percent of the original fiber load. Enumeration of microbial fortns by darkfield examination. Darkfield microscopic examination of subgingival plaque samples was performed by direct enumeration of morphologically distinct forms. Samples taken by a sterile curette from the periodontal pocket were gently mixed with a drop of sterile saline on a microscope slide. A coverslip was then carefully placed to avoid trapping air bubbles and the edges sealed with a vaseline-paraffin mixture (1/1) to prevent evaporation and hinder oxygen diffusion. Samples were viewed with a Leitz Dialux microscope equipped with a darkfield condenser, 40 X darkfield objective, 1.25 X fluorescent incident light housing and 12.5 X eyepieces. Spirochetes were categorized according to the foliowing criteria. Single contoured, tightiy wound organisms were considered small spirochetes. Loosely wound, single to almost double contoured organisms clearly larger in diameter than the small spirochetes constituted the intermediate group, while clearly double contoured organisms were considered large spirochetes. Pure cultures of Treponetna denticola, Treponema orale, and Treponema tnacrodentium were employed as references. Fusiforms included nonmotile straight rods with tapered ends. Motile rods included straight or curved rods which demonstrated active motihty. Large "bacilluslike" organisms were considered a subgroup of motile rods, Coccal forms included organisms whose "length" did not exceed their "width" by more than 2:1, Filaments consisted of cells
whose length exceeded their diameters by more than 8:1. Short rods included nonmotile organisms with rounded or blunt ends whose length to diameter falls between coccal forms and filaments. At least 10 randomly selected fields and a minimum of 150 cells were examined for each sample and the percentage of each morphologic type determined. Methods for clinical testing. Methods used to evaluate the clinical disease condition included the gingival index hy the method of Loe & Silness (1963) and gingival fluid volume using the method described by Golub (1977). The latter method was carried out by isolation of the areas to be measured with cotton rolls and saliva ejection, gently
Tetracycycline
Releass
from Hollow Fibers
Remaining
1
3
3 Time [hr)
Fig. 5. Release kinetics of tetracycline frotn holiow fibers placed in the periodontal pociiet as determined by the amount remaining at specified times. Die Abgabe von Tetrazyklin aus Hohlfasern, die in parodotitale Taschen eingebracht worden sind — ermittelt durch das wahrend bestimmter Zeiteinheiten in der Faser verbUebene Heilmittel. Cinetique de la liberation de la tetracycline a partir des fibres creuses placees dans la poche parodontale, en se basant sur la determination de la quantite restant a des intervalles donnes. (release — liberation; remaining = reste; time = temps).
PERIODONTAL THERAPY BY LOCAL DELIVERY OF TETRACYCLINE drying the area with air and itisertitig a sterile filter paper strip (Periopaper, Harco) into the gingival crevice until slight resistance is felt, TTie strip was left in place for 3 sec and immediately read on an electronic gingival crevicular fluid meter (Periotron, Harco Electronics, Newport Beach, CA).
87
amination represented from 20 to 60 % of the periodontal flora hefore treatment in all quadratT.ts. After a single 24-h tetracycline treatment, spirochetes were eliminated from quadrant 1 and remained undetectable for the 2-week period in which the patient was available for testing (Fig. 8). This effect was not seen in the untreated quadrant (Fig, 9).
Results
The release properties of these fibers when placed within the periodontal pocket indicate that delivery is roughly exponential with a principal half-time of approximately 0.5 h so that 95 % of the drug load is released over the first 2 h. However, assay of tetracychne levels in gingival fluid after 24 h indicates that antibacterial levels of approximately 15 /.(g/ml exist at that time (Gordon et al. 1978). Kinetic analysis of data thus obtained indicated a reasonable fit to a two-exponential model (Fig. 5) in which the first eKponent represented release of 97.5 % of the drug with a time constant of 1/1.52 ^ 0.66 h. Tests for possible irritant effects were conducted hy measuring the gingival fluid volume for a period immediateiy following removal of the fiber after being in place for various time periods. Results of these tests in an experimental subject are illustrated in Fig. 6. The effects of repetitive application of fibers on crevicular fluid volume were investigated resulting in the data illustrated in Fig. 7. The data of both types of experiments indicate that there is no detectable change in crevicular fluid flow as a result of fiber placement. An initia! test was conducted on a patient with generalized gingivitis associated with high levels of large spirochetes. In this patient, treatment and control quadrants were selected for comparative testing. Tetracycline-filled hollow fibers were placed in quadrant 1, and quadrant 3 was left untreated. Spirochete counts by darkfield ex-
Fih.r inpl.»^ D.Shr 1 hr 2 hr 3 hr E hr 11 hr 24 ht
Fluii Valumt
g1 1 1 A Fihar
• 2
•••
A D O
0
o fi
1
D
1 «
1 T i m t , hr
Fig. 6. Measurement of gingival fluid as a test for possible irritant effects of the drug-filled hoiiow fiber. Fibers were placed in the periodonta! pocket for various times as indicated atid crevicular fluid measured over the 5-h interval following their removal. Filter paper strips were inserted as described but left in piace for 3 min. Messung der Gingivalfliissigkeit als Test moglicher mechatiisch irritierender Wirkung der mit dem Hellmittel beschickten Hohlfasern. Die Fasern wurde unterschiedllch lange m die Zahnfleischtasche inseriert. Datin wurde die Gingivalfliissigkeit wahrend 5 Stunden mehrmals gemessen. Die Filterpapierstrelfen wurden inseriert aber 3 Minuten in Situ belassen. Mesure du fluide gingival, afin de tester les effets irritants eventuels des fibres creuses remplies de medicament. Les fibres etaient placees dans la poche parodontale pendant des durees variables (voir itidicatiotxs «fiber in places) el le fluide crevieulaire etait mesure pendant l'intervalle de 5 heures suivant l'enlevement des fibres (fiber retnoved). Des bandelettes de papier flitre etaient introduites dans le sillon (voir description dans I'article) mais laissees en place pendant 3 minutes.
GOODSON, HAFFAJEE AND SOCRANSKY 188
eiNSIVAL -LUID
90 ; 80
70 68 58 48 38
28 18
1 M 1
ll i. , " 15
M
M
13
12
11
21
22 23
j J l|L 1
„
24
2S
26
27
28
24
25
26
27
28
INCREMENT IN GINGIVAL FLUID
1 F -23 L -40 D -80 I IB
17
16
15
14
13
12
11
21
22
23
Fig. 7. Gingiva! fluid volume measurements following repetitive placement of tetracycline-filled hoUovv' fibers. Fibers were inserted on the second, fifth and sixth appointments. Appointments are displayed as the first to the seventh from front to back. Tooth numbers indicated below each plot signify the quadrant {1 = upper right, 2 = upper left) and tooth number (1 = central incisor, S = third molar). Example: 13 ~ the upper right cuspid. The symbol M signifies missing teeth. Ordinate values are listed in microliters X 35 as calibrated using fetal calf serum. Messungen der Gingivalfliissigkeit nach wiederholter Applikation von mit Tetrazyklin gefiiUten Hohlfasern. Die Fasern wurden wdhrend des zweiten, des fUnften und des sechsten Besuches der Probanden appliziert. Die Besuche der Probanden werden vom ersten bis zutn siebenten von vorne nach hinten mit Strichen dargestellt. Die Zahnbezeichnungen utiter jedem »Plot« bezeichnen die Qtiaclranten (1 = oben rechts, 2 = oben links) und die Nummer des Zahnes (1 = zentraler Inzisiv, 8 - dritter Molar). Beispiel: 13 = der obere rechte Eckzalm. Das Symbol M bezeichnet einen fehlenden Zahn. Die Werte der Ordinate sind in Mikrolitern ausgedruckt X 35, kalibriert mit foetalem Kdlberserum. Mesures du volume de fluide gingival apres poses repetees de fibres creuses remplies de tetracycline. Les fibres ont ete introduites pendant la deuxieme, la cinquieme et la sixieme seance. Les seances sont representees de la premiere a la septicme d'avant en arriere. Les numeros des dents indiques sous chaque valeur designent le quadrant (1 = superieur droit, 2 — superieur gauche) et le numero de la dent (1 — incisive centrate, 8 = troisieme molaire). Exetnple: 13 = canine superieure droite. Le symbole M designe les dents manquantes. Les valeurs en ordonnees sont indiquees en microlitres X 35, stdvant le calibrage avec le serum fatal de veau. (increment = augmentation).
The clinical effects of this treatment are illustrated in Fig. 10. A marked reduction in Gingival Index values on the treated side was observed which was not ohserved on the control (untreated) side.
Discussion
The general ciinical impression substantiated by measurement was that the gingival condition of patients treated by this mode
PERIODONTAL THERAPY BY LOCAL DELIVERY OF TETRACYCLINE of therapy was improved by a single 24-h application. Although the therapeutic regime was not optimized, it was apparent that a major shift in microbial composition occurred subsequent to their placement. Placement of the fibers hy clinical personnel posed no particular problems except that the fibers used were somewhat fragile, requiring delicate handling. The procedure of placement of tetracycline-fiI]ed fibers was not painful to the patient nor was an objectional taste noticed. The delivery device used in this study em-
IQ
bodies the basic elements necessary for controlled drug delivery to the periodontal environment. The fundamental components are a drug-containing reservoir, a ratedetermining element and a biologically compatible platform. In the hollow fiber delivery system, the fiber wall functions both as the rate limiting element and as the biological platform. As a biological platform, the fiber must be capable of containing the drug within a medium which does not significantly irritate the tissues during the period of its placement.
X ORGANISMS BY DARKFIELD EXAMINATION SITE M 8-16-77
88 8-22-77
78 8-24-77
66 8-26-77
X se
30
10 SHALL I N T . U R G E SPIROCHETES
TINY BIG CUR. HOTILE RODS
COCC. FUSI
NON MOT. RODS
FILA.
Fig. 8. Percent of organisms by darkfield examination in the quadrant treated by tetracyclinefilled iioliow fibers. The first y axis mark indicates the first (pretreatment) appointment. Successive y axis marks indicate subsequent posttreatment values. Measurements were made 2 days before treatment followed by measurements taken 4, 6 and 8 days after treatment. Dunkelfelduntersuchung: Mikroorganismen in Prozent in den Quadranten, die mit den mit Tetrazyklin gefullten Hohlfasern behandelt wurden. Die erste y-Achse zeigt die Werte beim ersten Besuch der Probanden (vor Einleitung der Behandlung). Die weiteren y-Achsen geben die Werle, die nach der Behandlung registriert worden sind. Die Messungen wurden zwei Tage vor dem Beginn der Behandlung sowie vier, sechs und acht Tage nach der Behandlung vorgenommen. Poureentage de micro-organismes a l'examen en fond noir dans le qtiadrant traite par fibres creuses remplies de telracycline. Les premieres valeurs de y indiqtiees concernent la premiere seance (avant traitement), les valeurs successives de y indiquent ies valeurs succes.'sives apres traitement. Les mesures ont ete faites deux jours avant traitement, puis 4, 6 et 8 jours apres traitement.
GOODSON, HAFFAJEE AND SOCRANSKY
X ORGANISMS BY DARKFIELD EXAHINATIOH 35 8-16-77 88 8-22-77 78 8-24-77 68 8-26-77
X 58 48
ze 18
" SHAQ. INT. LARGE TINY BIS CUR. COCC. FUSI NON SPIROCHETES MOTILE (M)PS MOT. RODS
FILA.
Fig. 9. Percent of organisms by darkfield examination in tbe untreated control quadrant (lower left). Y axis marks correspond to the same time intervals as in Fig. 8. Dunkelfelduntersuchung: Mikroorganismen in Prozent in den unbehandelten Kontrollquadranten (unten links). Die y-Achsen entsprechen den Zeitintervalien der Fig. 8. Pourcentage de micro-organismes a I'examen en fond noir dans le quadrant temoin non traite (inferieur gauche). Les valeurs de y correspondent aux memes intervalles que dans la Fig. 8.
Cellulose acetate is a biologicaUy compatible polymer which has been used extensively in pharmaceutical preparations such as enteric coated capsules. No signs of increased redness or increased sulcus fiuid suggestive of irritant properties from either the drug or the fiber were observed with the placement of tetracycline-filled fibers for periods of 24 h. The theoretical reservoir capacity of this delivery system can be computed from the fiber dimensions given in Fig. 1. A fiber of these dimensions filled with a drug of a specific gravity equal to 1 g/cm^ would contain 314 //g/cm of fiber length. Experiments with tetracycline filling indicate that as much as 340 //g/cm can be loaded. Since antibacterial coticentrations of tetracycline are between 1 and 10 ^g/ml, 340 //g of drug
would be capable of raising 34-340 ml of fluid to therapeutic levels. Since the flow of gingival sulcus fluid from an individual pocket is seldom greater than 10 ^^l/h (Cimasoni 1974), the amount of drug in 1 cm of fiber delivered at a constant rate of 0.1 jxgfh would maintain a level of 10 /tg/ml for 3400 h or, 4.7 months when placed in the periodontal pocket. This example is not used to suggest that it would be necessarily advisable to treat periodontal disease by placing a drug-filled fiber in the pocket for over 4 months but to indicate that a reservoir of these dimensions is sufficient to contain adequate drug loads to be of therapeutic value when applied to the microregion of the periodontal pocket. It is of interest to consider the amount of
PERIODONTAL THERAPY BY LOCAL DELIVERY OF TETRACYCLINE
3
0
GMGHtL IKOEK
Fig. 10. Gingival index response resulting from treatment by tetracycline-filled hollow fibers. Veranderungen des Gingivalindex als Folge der Behandlung mit den mit Tetrazyklin gefiittten Hohlfasern. Influence du traitement par fibres cretises remplies de tetracyctine sur t'Indice Gingival. (Control = temoins).
tetracycline used in local treatment in comparison with that which would have been used in systemic therapy. With the fibers as designed, 3 mg of drug is administered to each quadrant for I day. With systemic therapy, 1000 mg would be given daily for periods of tbe order of 10 days. Thus a total dose reduction of more than 1000-fold was achieved by utilization of local delivery. This effectively reduces systemic side effects to negligible proportions. Even witb the administration of 250 mg daily for treatment of acne, adverse effects are rare (AMA Drug Evaluations 1977). Controlled delivery devices have been effective in a variety of applications. They have been successfully appiied to common household problems including insect control (the "no pest" strip), tic and flea control on domestic pets (tbe "90-day flea collar"), plant fertilization (with up to 5 years' sustained delivery). Uses in human therapy include such diverse applications as the delivery of pilocarpine to the eyes of patients with glaucoma, tbe delivery of progesterone by an intrauterine device, the delivery of
scopolamine by transdermal application for motion sickness (Michaels 3976) and the delivery of insulin to diabetics (Soeldner 1973). Research in drug delivery has also been initiated for the treatment of oral disease. Several groups of investigators are currently studying the feasibility of systems for intraoral delivery of fluoride for the treatment of dental caries (Mirth & Bowen 1976). In addition, methods for local delivery of local anesthetics to oral tissues have been studied (Giddon et al. 1968). The methods used in these studies, while demonstrating the potentiai of local drug delivery for oral disease therapy, have not been optimized for routine use in the treatment of periodontal disease. However, the research effort directed toward development of controlieddelivery devices for treatment of oral tissues indicates a recognition of its potential in therapy.
Zusammenfassung
Farodontatbehandlung mit lokaler Applikation von Tetrazyklin Die voriiegende Studie untersucht die Moglichkeit parodontale Krankheiten von der lnnenflache der Tasche her durch kontrollierte Gaben antibakterieller Heilmittel zu behandeln. Es zeigte sich, dass mit Tetrazyklin gefullte hohle Easern, die in den gingivalen Sulkus eingelegt wurden, sowohl die parodontale Mikroflora ais auch die klinisehen Manifestationen parodontaier Erkrankungen dramatisch beeinflussen konnen. Sie konnen vom Behandier so administriert werden, dass weniger als 1/1000 der Menge Tetrazyklin die zur System therapie benotigt wird, bereits parodontaltherapeutisch wirksam ist. Die Beobachtung, dass es moglicb ist im gingivalen Suikus befindliche Spirochaten durch einmalige Applikation von mit Tetrazyklin gefiillten Hoblfibem zu eliminieren, ist von theoretiscber Bedeutung. Es kommt nach Verbrauch des Heilmitteis nicht wieder zu schneller Rekolonisation der Spirochaten in dieser Region, obwobi diese Mikroorganismen sonst uberall in der Mundhohle lebend angetroffen werden.
GOODSON, HAFFAJEE AND SOCRANSKY Resume Traitement parodontal par I'administration de tetracycline localement Le but du present travail etait d'etudier la possibiiite de traiter les parodontopathies par l'administration surveiilee d'agents antimicrobiens a partir de I'interieur des poches parodontales. Des fibres creuses rempHes de tetracycline et placees dans le sillon gingivo-dentaire se sont revelees avoir un effet spectaculaire tant sur la microflore parodontaie que sur les manifestations cliniques de la maladie. De plus, on a trouve que des fibres creuses d'acetate de cellulose remplies de ce medicament etaient biologiquement compatibles avec le milieu environnant et susceptibles d'etre manipulees par le personnel dentaire pour assurer un traitement utilisant moins de 1/1000 de la quantite de tetracycHne qu'on utiiiserait pour un traitement general. Du point de vue theorique, il est important de noter qu'on a constate qu'il est possible d'eliminer les spirochetes du sillon gingivodentaire par une seule application de fibres creuses remplies de tetracycHne, et que les spirochetes, une fois qu'ils ont ete elimines d'une localisation, ne reforment pas rapidement les colonies, malgre )a persistence de microorganismes viables a d'autres endroits de la bouche. References AMA Drug Evaluations, 3rd ed. (1977) p. 740. Littleton, Mass.: Pubhshing Sciences Group. Cimasoni, G. (1974) The crevicular fluid. In: Monographs iti Oral Science, vol. 3, pp. 1122. New York: S. Karger. Ellison, S. A. (1970) Oral bacteria and periodontal disease. Journal of Dental Research 49, 198-202. Geneo, R. J., Evans, R. T. & Ellison, S. A, (1969) Dental research in microbiology with emphasis on periodontal disease. Journal of the Atnerican Dental Association 78, 10161036. Giddon, D. B., Quadland, M., Rachwail, P. C, Springer, J. & Tursky, B. (1968) Development of a method for comparing topical anesthet-
ics in different application and dosage forms. Journal of Oral Therapeutics and Pharmacology 4, 270-274. Golub, L. M. (1977) International Conference oti Research in the Biology of Periodontal Disease, Proceedings, in press. Gordon, J., Walker, C. B., Goodson, J. M. & Socransky, S. S. (1978) A sensitive assay for tetracycline in gingival fluid. In preparation. Keyes, P. H. (1970) Are periodontal pathoses caused by bacterial infections on cervicoradicular surfaces of teeth? Journal of Dental Research 49, 223-228. Loe, H. & Silness, J. (1963) Periodontal disease in pregnancy. 1. Prevalence and severity. Acta Odontologica Scandinavica 21, 533-551. Loesche, W. J. (1976) Chemotherapy of dental plaque infections. Oral Sciences Reviews 9. 65-107. Michaels, A. S. (1976) Synthetic polymeric membranes: Practical applications-Past, present and future, Ptire and Applied Chemistry 46, 93-204. Mirth, D. B. & Bowen, W. H. (1976) Chemotherapy: antimicrobials and methods of de* livery. In: Proceedings (Microbial Aspects of Dental Caries) ed. Stiles, H. M., Loesche, W. J. & O'Brien, G. C. Special supplement to Microbiological Abstracts, Vol, 1, pp. 249262. Socransky, S. S. (1970) Relationship of bacteria to the etiology of periodontal disease. Journal of Dental Research 49 (Supp. 2) 223-228. Socransky, S. S. & Crawford, A. (1977) Recent advances in the microbiology of periodonta] disease. In: Current Therapy, 5th ed. pp. 113. St. Louis: C. V. Mosby. Soeldner, J. S, (1973) Progress towards an implantabie glucose sensor and an artificial beta cell. Temporal Aspects of Therapeutics, pp. 181-204. New York, London: Plenum Press.
Address: M. Goodson Forsyth Dental Center 140 Fenway Boston, Mass. 02115 U.S.A.
miciohiology.
Periodontal therapy by local delivery of tetracycline J. M. GOODSON, A. HAFFAJEE AND S. S. SOCRANSKY
Forsyth Dental Center, Boston, Mass., U.S.A. Abstract. The present investigation assessed the feasibility of treating periodontal disease by controlled delivery of antibacterial agents from within periodontal pockets. Tetracycline-filled hollow fibers placed in the gingival sulcus were shown to have a dramatic effect both on the periodontal mfcroflora and clinical manifestations of disease. Furthermore, it was found that drug-filled cellulose acetate holiow fibers are biologically compatible with tbe environment and can be manipulated by dental personnel to .provide drug therapy with less than 1/1000 the amount of tetracycline that would have been used for systemic therapy. Of theoretical importance is tbe observation that virtual elimination of spirochetes from the gingival sulcus is possible by a single placement of tetracycline-filled hollow fibers, and Rpirochetes, ones eliminated from a site, do not lapidl'y recolonize despite the persistence of viable organisms elsewhere in the mouth.
A fundamental principle of drug therapy is that the agent must reach the site of action in adequate concentration to be effective and be maintained at that site for an adequate duration to allow the effect to occur. From this point of view, it would appear that a controlled release suppository form of a drug placed within the periodontal pocket could be a highly effective method of administering antibacterial agents for periodontal therapy. Testing of antibacterial agents was prompted by the abundant evidence imphcating microorganisms as the primary cause of the periodontal diseases (EUison 1970, Genco et al. 1969, Keyes 1970, Socransky 1970, Socransky & Crawford 1977) and data suggesting that antibacterial agents eould be effective in the control of micro-
organisms which populate the periodontal pocket (Loesche 1976). Local treatment of periodontal disease with antibacterial agents has principally been by mouth rinses and to a lesser degree, topical application in an adhesive carrier. However effective these procedures may be in reducing the formation of supragingival plaque, there is no evidence and little reason to expect that they would reach the site of aetion in destructive periodontal disease. When considering treatment of this disease condition by antibacterial agents, it becomes necessary to devise methods of administration which estabhsh and maintain therapeutically effective concentrations of the agent within the periodontal pocket. In order to investigate the feasibility of treating periodontal disease by-controlled
0303-6979/79/020083-10802.50/0 © 1979 Munksgaard, Copenhagen
GOODSON, HAFFAJEE AND SOCRANSKY
V = 0.3 /il/c Fig. 1. Dimensions of cellulose acetate hollow fibers used for drug delivery to the periodontal einvironment. Dimensionen der Zellulose-Azetat Hohlfasern zur Applikation des Heilmittels in die unmittelbare Umgebung des Parodonts. Dimensions des fibres creuses d'acetate de cellulose utiiisees pottr Vadministration de medicaments dans le milieu parodontal.
delivery of antibacterial agents from within the periodontal pocket, small-diameter cellulose acetate hollow fibers were filled with tetracycline and tested under various conditions. Tests indicated that antibacterial levels could he sustained in the periodontal pocket for prolonged periods and could dramatically alter the microbial composition. Placement of drug-filled fibers into the periodontal pocket was associated with a decrease in clinical signs of disease without indications of local irritation. Materials and Methods Procedures
used for filling hollow
fibers.
Controlled delivery devices were prepared by filling commercially available cellulose acetate hollow fibers with tetracycline. The hollow fibers had an outside diameter of 250 }im, an inside diameter of 200 _«m and a wall thickness of 25 iim (Fig. 1). These fibers were manufactured by Dow Chemical Company and marketed by Bio-Rad Corpo-
ration for hollow fiber dialysis. The fibers were available in a wide range of permeability from nominal molecular weight cutoff values of 200 to 50,000 daltons when used for dialysis. Fibers loaded with drugs were the 200 dalton material (Bio-Fiber 20, Bio-Rad Laboratories, Richmond, CA). Tetracycline hydrochloride used to fill these fibers was obtained from USP generic capsule preparations of the drug. The capsules were opened and their contents dissolved in distilled water, centrifuged to remove the insoluble diluent used in the encapsulation process and lyophilyzed to dryness. The lyophilyzed powder thus obtained was redissolved in a small amount of water to make a concentrated solution for fiber loading. Fiber loads as measured by the weighed difference hetween a 1-cm segment of filled and empty fibers were determined for various concentrations of filling solutions. It was found that a saturated solution of tetracycline HCl contained approximately 23 % tetracycline (weight/volume) and little improvement in fill could be seen using more concentrated suspensions. Therefore,
Halliw Flhar
Fig. 2. Method used to fill hollow fibers with tetracycline hydrochloride. A 20 % solution is pumped into the fiber and allowed to dry prior to its utilization. Die Methodik Hohlfasern mit TetrazyklinHydrochlorid zu fUllen. Eine 20 %-ige Ldsung wird in die Faser gepumpt. Vor ihrer klinischen Anwendung wird die Easer getrocknet. Methode utilisee pour rempUr de chlorhydrate de tetracycline les fibres creuses. On pompe une solution a 20 % dans la fibre et on la laisse secher avant l'utilisation.
PERIODONTAL THERAPY BY LOCAL DELIVERY OF TETRACYCLINE
85
mum capacity with dried tetracycline hydrochloride. Fibers thus prepared were removed from the attached hypodermic needle and stored in closed polyethylene tubes under a nitrogen atmosphere.
ParlBilontil by LBCII Drug Daflviri
Fig. 3. Placement of drug-filled hoHow fibers for local treatment of periodontal disease. Single strands of tetracycline-filled hollow fibers are placed around the tooth and gently pressed below tbe margin of the gingiva. Applikation der mit dem Heilmittel beschickten Hohlfasern zur Lokalbehandling parodontaler Erkrankungen. Einzelstrange tetrazyklingefullter Hohlfasern werden um den Zahn herum gelegt und vorsichtig unter den Gingivalsaum gedrUckt. Pose des fibres creuses remplies du medicament pour le traitement local des parodontopathies. Les brins de fibres creuses sont places autour de la dent et presses delicatement en dessous du rebord gingival.
a 20 % solution was used for fiber filling procedures. Hollow fibers were prepared for loading by cementing (Dow # 891 silicone cemetit type A) into the lumen of sterile 26-gage hypodermic needles. After allowing the cement to dry for 12 h or more, the hypodermic needles were attached by a standard luer fitting (LDC # 107B8) to teflon tubing (1/16" O.D. X .031") which fit the inner bore of silicone pump tubing. The pump tubing was placed in a peristaltic pump (Sage model 375A) and the distal end of the tubing introduced into the 20 % tetracycline solution (Fig. 2). After 10 min or less, the fibers were filled with tetracycline solution. Pumping was maintained for 2-6 h while the fiber was dried in the air flow of a laminar flow hood. After this procedure, fibers were found to be filled virtually to maxi-
Method of placement of drug-filled hollow fibers. Drug-filled fibers were used in therapy by tying around the cervix of teeth to be treated and gently pressing into the periodontal pocket (Fig. 3). The relative size of these fibers can be appreciated by considering that they are 30 % smaller than the tip of commonly used periodontal probes (Fig. 4). Measurement of release kinetics from the periodontal pocket. The kinetics of release of tetracycline from fibers placed in the periodontal pocket was determined by removing fibers at various time intervals,
Fig. 4. The size of tetra cyciine-f ill ed hollow fibers relative to a maxillary cuspid (human skull speciman). Die Grosse von mit Tetrazyklin gefiillten Hohlfasern im Vergleich mit einem Oberkiefereckzahn (menschliches Schddelpraparat). Grandeur des fibres creuses rempUes de tetracyclities par rapport a une canine superieure (cratie humain).
86
GOODSON, HAFFAJEE AND SOCRANSKY
measuring the length of the removed fiber and placing in 3 ml of distilled water to allow the remaining contents to exhaust. The concentration of solutions thus obtained was measured spectrophotometrically at 276 nm and the amount of tetracycline left in the fiber calculated as the percent of the original fiber load. Enumeration of microbial fortns by darkfield examination. Darkfield microscopic examination of subgingival plaque samples was performed by direct enumeration of morphologically distinct forms. Samples taken by a sterile curette from the periodontal pocket were gently mixed with a drop of sterile saline on a microscope slide. A coverslip was then carefully placed to avoid trapping air bubbles and the edges sealed with a vaseline-paraffin mixture (1/1) to prevent evaporation and hinder oxygen diffusion. Samples were viewed with a Leitz Dialux microscope equipped with a darkfield condenser, 40 X darkfield objective, 1.25 X fluorescent incident light housing and 12.5 X eyepieces. Spirochetes were categorized according to the foliowing criteria. Single contoured, tightiy wound organisms were considered small spirochetes. Loosely wound, single to almost double contoured organisms clearly larger in diameter than the small spirochetes constituted the intermediate group, while clearly double contoured organisms were considered large spirochetes. Pure cultures of Treponetna denticola, Treponema orale, and Treponema tnacrodentium were employed as references. Fusiforms included nonmotile straight rods with tapered ends. Motile rods included straight or curved rods which demonstrated active motihty. Large "bacilluslike" organisms were considered a subgroup of motile rods, Coccal forms included organisms whose "length" did not exceed their "width" by more than 2:1, Filaments consisted of cells
whose length exceeded their diameters by more than 8:1. Short rods included nonmotile organisms with rounded or blunt ends whose length to diameter falls between coccal forms and filaments. At least 10 randomly selected fields and a minimum of 150 cells were examined for each sample and the percentage of each morphologic type determined. Methods for clinical testing. Methods used to evaluate the clinical disease condition included the gingival index hy the method of Loe & Silness (1963) and gingival fluid volume using the method described by Golub (1977). The latter method was carried out by isolation of the areas to be measured with cotton rolls and saliva ejection, gently
Tetracycycline
Releass
from Hollow Fibers
Remaining
1
3
3 Time [hr)
Fig. 5. Release kinetics of tetracycline frotn holiow fibers placed in the periodontal pociiet as determined by the amount remaining at specified times. Die Abgabe von Tetrazyklin aus Hohlfasern, die in parodotitale Taschen eingebracht worden sind — ermittelt durch das wahrend bestimmter Zeiteinheiten in der Faser verbUebene Heilmittel. Cinetique de la liberation de la tetracycline a partir des fibres creuses placees dans la poche parodontale, en se basant sur la determination de la quantite restant a des intervalles donnes. (release — liberation; remaining = reste; time = temps).
PERIODONTAL THERAPY BY LOCAL DELIVERY OF TETRACYCLINE drying the area with air and itisertitig a sterile filter paper strip (Periopaper, Harco) into the gingival crevice until slight resistance is felt, TTie strip was left in place for 3 sec and immediately read on an electronic gingival crevicular fluid meter (Periotron, Harco Electronics, Newport Beach, CA).
87
amination represented from 20 to 60 % of the periodontal flora hefore treatment in all quadratT.ts. After a single 24-h tetracycline treatment, spirochetes were eliminated from quadrant 1 and remained undetectable for the 2-week period in which the patient was available for testing (Fig. 8). This effect was not seen in the untreated quadrant (Fig, 9).
Results
The release properties of these fibers when placed within the periodontal pocket indicate that delivery is roughly exponential with a principal half-time of approximately 0.5 h so that 95 % of the drug load is released over the first 2 h. However, assay of tetracychne levels in gingival fluid after 24 h indicates that antibacterial levels of approximately 15 /.(g/ml exist at that time (Gordon et al. 1978). Kinetic analysis of data thus obtained indicated a reasonable fit to a two-exponential model (Fig. 5) in which the first eKponent represented release of 97.5 % of the drug with a time constant of 1/1.52 ^ 0.66 h. Tests for possible irritant effects were conducted hy measuring the gingival fluid volume for a period immediateiy following removal of the fiber after being in place for various time periods. Results of these tests in an experimental subject are illustrated in Fig. 6. The effects of repetitive application of fibers on crevicular fluid volume were investigated resulting in the data illustrated in Fig. 7. The data of both types of experiments indicate that there is no detectable change in crevicular fluid flow as a result of fiber placement. An initia! test was conducted on a patient with generalized gingivitis associated with high levels of large spirochetes. In this patient, treatment and control quadrants were selected for comparative testing. Tetracycline-filled hollow fibers were placed in quadrant 1, and quadrant 3 was left untreated. Spirochete counts by darkfield ex-
Fih.r inpl.»^ D.Shr 1 hr 2 hr 3 hr E hr 11 hr 24 ht
Fluii Valumt
g1 1 1 A Fihar
• 2
•••
A D O
0
o fi
1
D
1 «
1 T i m t , hr
Fig. 6. Measurement of gingival fluid as a test for possible irritant effects of the drug-filled hoiiow fiber. Fibers were placed in the periodonta! pocket for various times as indicated atid crevicular fluid measured over the 5-h interval following their removal. Filter paper strips were inserted as described but left in piace for 3 min. Messung der Gingivalfliissigkeit als Test moglicher mechatiisch irritierender Wirkung der mit dem Hellmittel beschickten Hohlfasern. Die Fasern wurde unterschiedllch lange m die Zahnfleischtasche inseriert. Datin wurde die Gingivalfliissigkeit wahrend 5 Stunden mehrmals gemessen. Die Filterpapierstrelfen wurden inseriert aber 3 Minuten in Situ belassen. Mesure du fluide gingival, afin de tester les effets irritants eventuels des fibres creuses remplies de medicament. Les fibres etaient placees dans la poche parodontale pendant des durees variables (voir itidicatiotxs «fiber in places) el le fluide crevieulaire etait mesure pendant l'intervalle de 5 heures suivant l'enlevement des fibres (fiber retnoved). Des bandelettes de papier flitre etaient introduites dans le sillon (voir description dans I'article) mais laissees en place pendant 3 minutes.
GOODSON, HAFFAJEE AND SOCRANSKY 188
eiNSIVAL -LUID
90 ; 80
70 68 58 48 38
28 18
1 M 1
ll i. , " 15
M
M
13
12
11
21
22 23
j J l|L 1
„
24
2S
26
27
28
24
25
26
27
28
INCREMENT IN GINGIVAL FLUID
1 F -23 L -40 D -80 I IB
17
16
15
14
13
12
11
21
22
23
Fig. 7. Gingiva! fluid volume measurements following repetitive placement of tetracycline-filled hoUovv' fibers. Fibers were inserted on the second, fifth and sixth appointments. Appointments are displayed as the first to the seventh from front to back. Tooth numbers indicated below each plot signify the quadrant {1 = upper right, 2 = upper left) and tooth number (1 = central incisor, S = third molar). Example: 13 ~ the upper right cuspid. The symbol M signifies missing teeth. Ordinate values are listed in microliters X 35 as calibrated using fetal calf serum. Messungen der Gingivalfliissigkeit nach wiederholter Applikation von mit Tetrazyklin gefiiUten Hohlfasern. Die Fasern wurden wdhrend des zweiten, des fUnften und des sechsten Besuches der Probanden appliziert. Die Besuche der Probanden werden vom ersten bis zutn siebenten von vorne nach hinten mit Strichen dargestellt. Die Zahnbezeichnungen utiter jedem »Plot« bezeichnen die Qtiaclranten (1 = oben rechts, 2 = oben links) und die Nummer des Zahnes (1 = zentraler Inzisiv, 8 - dritter Molar). Beispiel: 13 = der obere rechte Eckzalm. Das Symbol M bezeichnet einen fehlenden Zahn. Die Werte der Ordinate sind in Mikrolitern ausgedruckt X 35, kalibriert mit foetalem Kdlberserum. Mesures du volume de fluide gingival apres poses repetees de fibres creuses remplies de tetracycline. Les fibres ont ete introduites pendant la deuxieme, la cinquieme et la sixieme seance. Les seances sont representees de la premiere a la septicme d'avant en arriere. Les numeros des dents indiques sous chaque valeur designent le quadrant (1 = superieur droit, 2 — superieur gauche) et le numero de la dent (1 — incisive centrate, 8 = troisieme molaire). Exetnple: 13 = canine superieure droite. Le symbole M designe les dents manquantes. Les valeurs en ordonnees sont indiquees en microlitres X 35, stdvant le calibrage avec le serum fatal de veau. (increment = augmentation).
The clinical effects of this treatment are illustrated in Fig. 10. A marked reduction in Gingival Index values on the treated side was observed which was not ohserved on the control (untreated) side.
Discussion
The general ciinical impression substantiated by measurement was that the gingival condition of patients treated by this mode
PERIODONTAL THERAPY BY LOCAL DELIVERY OF TETRACYCLINE of therapy was improved by a single 24-h application. Although the therapeutic regime was not optimized, it was apparent that a major shift in microbial composition occurred subsequent to their placement. Placement of the fibers hy clinical personnel posed no particular problems except that the fibers used were somewhat fragile, requiring delicate handling. The procedure of placement of tetracycline-fiI]ed fibers was not painful to the patient nor was an objectional taste noticed. The delivery device used in this study em-
IQ
bodies the basic elements necessary for controlled drug delivery to the periodontal environment. The fundamental components are a drug-containing reservoir, a ratedetermining element and a biologically compatible platform. In the hollow fiber delivery system, the fiber wall functions both as the rate limiting element and as the biological platform. As a biological platform, the fiber must be capable of containing the drug within a medium which does not significantly irritate the tissues during the period of its placement.
X ORGANISMS BY DARKFIELD EXAMINATION SITE M 8-16-77
88 8-22-77
78 8-24-77
66 8-26-77
X se
30
10 SHALL I N T . U R G E SPIROCHETES
TINY BIG CUR. HOTILE RODS
COCC. FUSI
NON MOT. RODS
FILA.
Fig. 8. Percent of organisms by darkfield examination in the quadrant treated by tetracyclinefilled iioliow fibers. The first y axis mark indicates the first (pretreatment) appointment. Successive y axis marks indicate subsequent posttreatment values. Measurements were made 2 days before treatment followed by measurements taken 4, 6 and 8 days after treatment. Dunkelfelduntersuchung: Mikroorganismen in Prozent in den Quadranten, die mit den mit Tetrazyklin gefullten Hohlfasern behandelt wurden. Die erste y-Achse zeigt die Werte beim ersten Besuch der Probanden (vor Einleitung der Behandlung). Die weiteren y-Achsen geben die Werle, die nach der Behandlung registriert worden sind. Die Messungen wurden zwei Tage vor dem Beginn der Behandlung sowie vier, sechs und acht Tage nach der Behandlung vorgenommen. Poureentage de micro-organismes a l'examen en fond noir dans le qtiadrant traite par fibres creuses remplies de telracycline. Les premieres valeurs de y indiqtiees concernent la premiere seance (avant traitement), les valeurs successives de y indiquent ies valeurs succes.'sives apres traitement. Les mesures ont ete faites deux jours avant traitement, puis 4, 6 et 8 jours apres traitement.
GOODSON, HAFFAJEE AND SOCRANSKY
X ORGANISMS BY DARKFIELD EXAHINATIOH 35 8-16-77 88 8-22-77 78 8-24-77 68 8-26-77
X 58 48
ze 18
" SHAQ. INT. LARGE TINY BIS CUR. COCC. FUSI NON SPIROCHETES MOTILE (M)PS MOT. RODS
FILA.
Fig. 9. Percent of organisms by darkfield examination in tbe untreated control quadrant (lower left). Y axis marks correspond to the same time intervals as in Fig. 8. Dunkelfelduntersuchung: Mikroorganismen in Prozent in den unbehandelten Kontrollquadranten (unten links). Die y-Achsen entsprechen den Zeitintervalien der Fig. 8. Pourcentage de micro-organismes a I'examen en fond noir dans le quadrant temoin non traite (inferieur gauche). Les valeurs de y correspondent aux memes intervalles que dans la Fig. 8.
Cellulose acetate is a biologicaUy compatible polymer which has been used extensively in pharmaceutical preparations such as enteric coated capsules. No signs of increased redness or increased sulcus fiuid suggestive of irritant properties from either the drug or the fiber were observed with the placement of tetracycline-filled fibers for periods of 24 h. The theoretical reservoir capacity of this delivery system can be computed from the fiber dimensions given in Fig. 1. A fiber of these dimensions filled with a drug of a specific gravity equal to 1 g/cm^ would contain 314 //g/cm of fiber length. Experiments with tetracycline filling indicate that as much as 340 //g/cm can be loaded. Since antibacterial coticentrations of tetracycline are between 1 and 10 ^g/ml, 340 //g of drug
would be capable of raising 34-340 ml of fluid to therapeutic levels. Since the flow of gingival sulcus fluid from an individual pocket is seldom greater than 10 ^^l/h (Cimasoni 1974), the amount of drug in 1 cm of fiber delivered at a constant rate of 0.1 jxgfh would maintain a level of 10 /tg/ml for 3400 h or, 4.7 months when placed in the periodontal pocket. This example is not used to suggest that it would be necessarily advisable to treat periodontal disease by placing a drug-filled fiber in the pocket for over 4 months but to indicate that a reservoir of these dimensions is sufficient to contain adequate drug loads to be of therapeutic value when applied to the microregion of the periodontal pocket. It is of interest to consider the amount of
PERIODONTAL THERAPY BY LOCAL DELIVERY OF TETRACYCLINE
3
0
GMGHtL IKOEK
Fig. 10. Gingival index response resulting from treatment by tetracycline-filled hollow fibers. Veranderungen des Gingivalindex als Folge der Behandlung mit den mit Tetrazyklin gefiittten Hohlfasern. Influence du traitement par fibres cretises remplies de tetracyctine sur t'Indice Gingival. (Control = temoins).
tetracycline used in local treatment in comparison with that which would have been used in systemic therapy. With the fibers as designed, 3 mg of drug is administered to each quadrant for I day. With systemic therapy, 1000 mg would be given daily for periods of tbe order of 10 days. Thus a total dose reduction of more than 1000-fold was achieved by utilization of local delivery. This effectively reduces systemic side effects to negligible proportions. Even witb the administration of 250 mg daily for treatment of acne, adverse effects are rare (AMA Drug Evaluations 1977). Controlled delivery devices have been effective in a variety of applications. They have been successfully appiied to common household problems including insect control (the "no pest" strip), tic and flea control on domestic pets (tbe "90-day flea collar"), plant fertilization (with up to 5 years' sustained delivery). Uses in human therapy include such diverse applications as the delivery of pilocarpine to the eyes of patients with glaucoma, tbe delivery of progesterone by an intrauterine device, the delivery of
scopolamine by transdermal application for motion sickness (Michaels 3976) and the delivery of insulin to diabetics (Soeldner 1973). Research in drug delivery has also been initiated for the treatment of oral disease. Several groups of investigators are currently studying the feasibility of systems for intraoral delivery of fluoride for the treatment of dental caries (Mirth & Bowen 1976). In addition, methods for local delivery of local anesthetics to oral tissues have been studied (Giddon et al. 1968). The methods used in these studies, while demonstrating the potentiai of local drug delivery for oral disease therapy, have not been optimized for routine use in the treatment of periodontal disease. However, the research effort directed toward development of controlieddelivery devices for treatment of oral tissues indicates a recognition of its potential in therapy.
Zusammenfassung
Farodontatbehandlung mit lokaler Applikation von Tetrazyklin Die voriiegende Studie untersucht die Moglichkeit parodontale Krankheiten von der lnnenflache der Tasche her durch kontrollierte Gaben antibakterieller Heilmittel zu behandeln. Es zeigte sich, dass mit Tetrazyklin gefullte hohle Easern, die in den gingivalen Sulkus eingelegt wurden, sowohl die parodontale Mikroflora ais auch die klinisehen Manifestationen parodontaier Erkrankungen dramatisch beeinflussen konnen. Sie konnen vom Behandier so administriert werden, dass weniger als 1/1000 der Menge Tetrazyklin die zur System therapie benotigt wird, bereits parodontaltherapeutisch wirksam ist. Die Beobachtung, dass es moglicb ist im gingivalen Suikus befindliche Spirochaten durch einmalige Applikation von mit Tetrazyklin gefiillten Hoblfibem zu eliminieren, ist von theoretiscber Bedeutung. Es kommt nach Verbrauch des Heilmitteis nicht wieder zu schneller Rekolonisation der Spirochaten in dieser Region, obwobi diese Mikroorganismen sonst uberall in der Mundhohle lebend angetroffen werden.
GOODSON, HAFFAJEE AND SOCRANSKY Resume Traitement parodontal par I'administration de tetracycline localement Le but du present travail etait d'etudier la possibiiite de traiter les parodontopathies par l'administration surveiilee d'agents antimicrobiens a partir de I'interieur des poches parodontales. Des fibres creuses rempHes de tetracycline et placees dans le sillon gingivo-dentaire se sont revelees avoir un effet spectaculaire tant sur la microflore parodontaie que sur les manifestations cliniques de la maladie. De plus, on a trouve que des fibres creuses d'acetate de cellulose remplies de ce medicament etaient biologiquement compatibles avec le milieu environnant et susceptibles d'etre manipulees par le personnel dentaire pour assurer un traitement utilisant moins de 1/1000 de la quantite de tetracycHne qu'on utiiiserait pour un traitement general. Du point de vue theorique, il est important de noter qu'on a constate qu'il est possible d'eliminer les spirochetes du sillon gingivodentaire par une seule application de fibres creuses remplies de tetracycHne, et que les spirochetes, une fois qu'ils ont ete elimines d'une localisation, ne reforment pas rapidement les colonies, malgre )a persistence de microorganismes viables a d'autres endroits de la bouche. References AMA Drug Evaluations, 3rd ed. (1977) p. 740. Littleton, Mass.: Pubhshing Sciences Group. Cimasoni, G. (1974) The crevicular fluid. In: Monographs iti Oral Science, vol. 3, pp. 1122. New York: S. Karger. Ellison, S. A. (1970) Oral bacteria and periodontal disease. Journal of Dental Research 49, 198-202. Geneo, R. J., Evans, R. T. & Ellison, S. A, (1969) Dental research in microbiology with emphasis on periodontal disease. Journal of the Atnerican Dental Association 78, 10161036. Giddon, D. B., Quadland, M., Rachwail, P. C, Springer, J. & Tursky, B. (1968) Development of a method for comparing topical anesthet-
ics in different application and dosage forms. Journal of Oral Therapeutics and Pharmacology 4, 270-274. Golub, L. M. (1977) International Conference oti Research in the Biology of Periodontal Disease, Proceedings, in press. Gordon, J., Walker, C. B., Goodson, J. M. & Socransky, S. S. (1978) A sensitive assay for tetracycline in gingival fluid. In preparation. Keyes, P. H. (1970) Are periodontal pathoses caused by bacterial infections on cervicoradicular surfaces of teeth? Journal of Dental Research 49, 223-228. Loe, H. & Silness, J. (1963) Periodontal disease in pregnancy. 1. Prevalence and severity. Acta Odontologica Scandinavica 21, 533-551. Loesche, W. J. (1976) Chemotherapy of dental plaque infections. Oral Sciences Reviews 9. 65-107. Michaels, A. S. (1976) Synthetic polymeric membranes: Practical applications-Past, present and future, Ptire and Applied Chemistry 46, 93-204. Mirth, D. B. & Bowen, W. H. (1976) Chemotherapy: antimicrobials and methods of de* livery. In: Proceedings (Microbial Aspects of Dental Caries) ed. Stiles, H. M., Loesche, W. J. & O'Brien, G. C. Special supplement to Microbiological Abstracts, Vol, 1, pp. 249262. Socransky, S. S. (1970) Relationship of bacteria to the etiology of periodontal disease. Journal of Dental Research 49 (Supp. 2) 223-228. Socransky, S. S. & Crawford, A. (1977) Recent advances in the microbiology of periodonta] disease. In: Current Therapy, 5th ed. pp. 113. St. Louis: C. V. Mosby. Soeldner, J. S, (1973) Progress towards an implantabie glucose sensor and an artificial beta cell. Temporal Aspects of Therapeutics, pp. 181-204. New York, London: Plenum Press.
Address: M. Goodson Forsyth Dental Center 140 Fenway Boston, Mass. 02115 U.S.A.
