第18章

CHAPTER EIGHTEEN




Antimicrobial Treatment Based Upon The Nonspecific Plaque Hypothesis (NSPH)





I. Introduction

II. Prophylactic Chemotherapeutic Agents

A. Penicillin

l. Animal studies

2. Human Dentifrice studies

3. Systemic Prophylactic Treatment for Medical Reasons

4. Summary

B. Fluoride

l. Mechanism of Action

a. chemical effects

b. antimicrobial effects

2. Topical Application

a. dentifrices

b. gels and mouthrinses

l) Cheektowaga gel studies

2) Scandinavian fluoride studies

3) slow release systems

4) summary

C. Chlorhexidine

l. Plaque inhibition

2. Substantivity

3. Anticaries studies

4. Regulatory status in the United States

D. Fluoride and Chlorhexidine Combinations

III. Summary



Chapter 18

Antimicrobial treatment based upon the nonspecific plaque hypothesis (NSPH)

第十八章

根據非特定性牙菌斑假說的抗菌治療

I. 前言

II. 有化學治療效果的潔牙藥物?Prophylactic Chemotherapeutic Agents

A. 青黴素

l. 動物實驗

2. 人類牙膏實驗

3. 為了身體健康的系統性潔牙治療?Systemic Prophylactic Treatment for Medical Reasons

4. 總結

B. 氟化物

l. 作用機轉

a. 化學作用

b. 抗菌作用

2. 局部塗抹

a. 含氟牙膏

b. 氟膠與含氟漱口水gels and mouthrinses

l) Cheektowaga gel studies

2) Scandinavian fluoride studies

3) 慢性釋放slow release systems

4) 總結

C. Chlorhexidine

l. 抑制牙菌斑Plaque inhibition

2. 獨立性?Substantivity

3. 抗蛀牙實驗

4. 在美國的管控狀況

D. 氟化物與Chlorhexidine 綜合體

III. 總結



INTRODUCTION



The nonspecific plaque hypothesis (NSPH) and its reliance upon mechanical debridement has held sway in preventive dentistry since the time of Miller in 1890. It has failed to prevent or even reduce the incidence of dental decay judging by the data presented in Chapters 13 and 15. There is no convincing longitudinal study of several years duration, with the important exception of the Swedish studies conducted by Axelsson and Lindhe, which demonstrates the effectiveness of the mechanical approach (although in these studies the concurrent fluoride treatments could have accounted for a significant amount of the caries reduction) in reducing or preventing dental infections in a susceptible population. However, professional mechanical debridement at two-week to two-month intervals is neither practical nor economically feasible for most patients. Thus, 1) if brushing and flossing as practiced by most patients is not effective in caries control; 2) if dietary counseling goes unheeded; and 3) if new sucrose substitutes or food additives are restricted by government regulations, then the future for caries control using these methods is bleak. Alternative treatment tactics and/or strategies need to be devised.



Chemical antimicrobial agents would be an obvious choice as a means of controlling plaque mass. Miller recognized their potential in his classic treatise on the oral flora. In the succeeding 90 years, there have been sporadic reports of clinical success with various antimicrobial agents. Unfortunately, these results either could not be reproduced or were ignored. The dental literature is now replete with clinical trials of antimicrobial agents that give contradictory conclusions, resulting in a negative attitude concerning the eventual usefulness of any drug. In this chapter some of these problems will be addressed from the perspective of the NSPH and in the following chapter, these issues will be discussed within the framework of the specific plaque hypothesis (SPH).



前言

自從1890年Miller的時代以來，非特定型牙菌斑假說nonspecific plaque hypothesis (NSPH)及其需依靠機械性的潔牙在預防性牙科中是被懷疑的。依據13-15章所顯示的資料，機械性的潔牙無法成功的預防或減少牙齒的蛀牙。沒有可信的長期追朔性研究，除了瑞典的研究Axelsson & Lindhe所做的重要研究，此研究證實了機械性潔牙在特定族群中減低或預防蛀牙的效用(雖然在這些研究中，持續的塗氟治療可減少蛀牙)，然而，兩星期到兩個月的專業潔牙對大多數人是既不實際又昂貴的，所以若以下三個假設正確，則預防蛀牙的前景是黑暗的，1)若刷牙和使用牙線對多數患者在蛀牙控制是無效的，2)如果飲食諮詢沒有被重視，3)若新的蔗糖替代物或食物添加物被政府規範控制。所以必須發展替代的治療方式。



化學性的抗菌藥物對控制牙菌斑形成明顯是不錯的選擇，MILLER在他的經典論文中提到這些抗菌藥物在口腔生態的作用。在接下來的90年，只有零星的幾篇報告提出使用不同的抗菌藥物有臨床效用。不幸的，這些結果不是無法被複製，就是被忽略。現在牙科文獻充滿了許多抗菌藥物的臨床試驗，但結論是矛盾的，使得使用這些藥物有負面的疑問。在本章節這些問題會被以NSPH的觀點討論，並且在接下來的章節，這些議題會被在SPH的架構下探討。



PROPHYLACTIC CHEMOTHERAPEUTIC AGENTS



A prophylactic agent for plaque control would have to be extraordinarily safe, as all ages would be using it frequently over a lifetime, much in the manner that toothpaste is now used. In fact, the acceptance by the public of toothpastes and even mouthrinses, has encouraged investigators to adapt these vehicles for the delivery of prophylactic agents so potent that they will inhibit, on contact, all microbial forms on the tooth surface. What is not appreciated is that for an agent to be this effective, it must attack chemical structures such as double bonds, disulfide bonds and ionic groups, etc., which are universally present in biological material. Agents with this capability are likely to have cytotoxic effects on the host tissue. In the United States, the Food and Drug Administration (FDA) will scrutinize any agent both for safety and effectiveness. An agent capable of "sterilizing or disinfecting" the tooth surface most likely will not be safe in an absolute (or legal) sense. Those agents found to have a high degree of effectiveness relative to safety in all probability will be regulated initially as prescription items. Thus the NSPH's requirement for an agent which can continuously inhibit plaque formation, introduces a safety consideration that might preclude such an agent from being used (or sold) in a manner analogous to toothpaste and mouthrinses. The fulfillment of regulatory requirements is expensive and accordingly, the cost of treatment will increase, which in turn will act as a deterrent to universal usage of the agent.



No drug has yet been accepted as a prophylactic agent in preventing plaque formation. Despite the problems inherent in the legacy of the nonspecific plaque hypothesis, some promising drugs have been found, which may eventually make remarkable therapeutic agents. In this regard, the experimental data on the prophylactic usage of three diverse agents, penicillin, fluoride and chlorhexidine will be discussed.



However, if these antimicrobial agents were used only in those patients with evidence of a dental infection, or known to be at risk to such an infection, i.e., children at the time of tooth eruption, then treatment could be directed at the elimination or reduction of the specific odontopathogen(s) in the plaque. The treatment would be intense but of a short duration, i.e., one to two weeks, thereby avoiding most if not all the complications of antimicrobial therapy encountered when therapy is open ended. These considerations should be kept in mind when reading this chapter.



Prophylactic chemotherapeutic agents

潔牙藥劑prophylactic agent在牙菌斑控制是極度安全的，因為各個年齡層的人都會在一生中經常的使用，這些潔牙藥劑多半是牙膏，事實上，被大眾所接受的牙膏甚至是漱口水，已經鼓勵研究者探討，以抗菌藥物有效的加入這些潔牙藥劑來抑制在牙齒表面上微生物的形成，不被激賞的是，若這些潔牙媒介很有效，他一定會破壞雙鍵，雙硫鍵，或離子鍵等等，這些都在宇宙中存在的生物物質，有這些作用的媒介可能對宿主組織有細胞毒性，在美國，FDA以安全性和有效性來監控所有藥劑，任何可以在牙齒表面消毒滅菌的媒介，可能在法律上定義是不安全的，這些被證實相對於安全有極度效用的媒介，會以開處方簽的方式被管制，因此，NSPH的需求，對於潔牙藥劑可以持續的限制牙菌斑形成，導致將藥劑放入牙膏和漱口水有安全考慮而有疑慮，這種管制上的要求是非常昂貴並且會增加治療的費用，因此，對於普遍使用此藥劑是反向的動力。



在預防牙菌斑形成上，還沒有藥物被當做抗菌媒介，除了既存的NSPH問題，一些有可能成為有效的治療性藥物被發現，因此，在這章節將會討論其他三種藥物penicillin, fluoride, chlorhexidine。



然而，如果這些抗菌藥物只被使用在這些有蛀牙或有蛀牙危險的人身上，例如正在長牙的孩子，則這種治療可以減少在牙菌斑中特殊的odontopathogens，這種治療是集中但短時間，例如一到兩個星期，如果治療還未結束，則此抗菌治療會產生合併症，在讀此章節必須將這些因素考慮進去。



Penicillin



Animal Studies. Shortly after penicillin was shown to dramatically cure certain bacterial infections in humans, McClure found that penicillin added to the diet and drinking water, essentially prevented decay in rats. The results were readily reproducible, and other antibiotics, especially those capable of inhibiting Gram-positive organisms, were found to be almost as effective (See Table 8-3). Approximately 3000 to 5000 units of penicillin were given daily over the duration of the experimental period to animals weighing between 250 and 400 g. If we convert this dosage to equivalent human values, approximately 750,000 units were given per 50 kg body weight, which is well within the recommended dosage for the treatment of acute infections in humans. Thus, the levels used in the animal experiments would assure inhibitory levels of penicillin on the mucous membranes. Inasmuch as penicillin G was used, which is rapidly destroyed by the acidic pHs in the stomach, the effect of the penicillin could be attributed to a local, topical action in the oral cavity.



青黴素

動物實驗

在青黴素證實對在人類細菌感染有強大治療效果後，MaClure發現在飲食或飲水中加入青黴素，可預防老鼠的蛀牙，這些結果可被重複複製，且其他抗生素，尤其是那些可抑制gram-positive微生物的抗生素，是一樣有效的。(見tablr8-3)在實驗期間，每天給予約250-400克的動物大約3000-5000 units的青黴素，如果我們換算此劑量在人類身上，在50公斤重的人身上則可被給予約750.000 units，此劑量建議在治療人類急性感染。所以，用在動物實驗上的程度可以保證黏膜上青黴素的inhibitory level，因為當使用penicillin G時，其會很快的被胃酸破壞，因此認為青黴素的效用在口腔中局部的作用是有效的。



Human Dentifrice Studies. The animal studies prompted clinical trials of penicillin. No information, other than the animal data, was available as guidelines to determine the drug dosage and treatment schedule. From 100 to 1000 units of penicillin were incorporated into a gram of tooth powder which was used from two to three times a day over the period of one year. If the instructions were explicitly followed (the majority of the brushing was unsupervised), and the brushing was thorough, then from 200 units/day to about 3000 units/day were applied to the dento-gingival surfaces. Three out of four of these largely unsupervised studies showed neither benefit nor toxicity associated with the treatment (Table 18-1). However, the study conducted by Zander in school children showed a dramatic 55 percent reduction in the DMFS score.



人類牙膏實驗

動物實驗中激勵了青黴素的臨床試驗，除了動物實驗的數據，沒有其他數據可提供做為準則，來決定藥物劑量及治療時間表，從100-1000 units的青黴素被放入一克的牙粉中，每天使用2-3次一年，如果確實遵守這個準則，(大多數人刷牙是沒有在被指導下完成)，且刷牙仔細完成，則每天使用在牙齒及牙齦表面約有2000到3000 units。這些大且未被指導下的研究有四分之三顯示這個治療沒有好處也沒有壞處(見table18-1)，然而，這個由Zander在學童身上做的實驗，在DMFS score有55% 明顯的下降。



Table 18-1

Effect of Penicillin Dentifrices on Human Caries



Table 18-1

含青黴素牙膏在人類蛀牙的影響



Reference

Dosage

Brushing % Reduction in DMFS After 1 Year

Hill & Kniesner, 1949. J. Dent. Res. 28:263 1000 u/g powder 2 x unsupervised 0

Hill et al., 1953. J. Dent. Res. 32:448 1000 u/g dentifrice 1 x supervised and 2 x unsupervised 16

Walsh & Smart, 1951. New Zealand Dent. J. 47:118 100 u/g 2 x unsupervised 0

Zander, 1950. J. Amer. Dent. Assoc. 40:569 500 u/g powder 1 x supervised and 2 x unsupervised 55





The dosages in these studies, based on data obtained from laboratory rodents, were woefully inadequate when transferred to the dimensions of the human. At best, the oral flora was exposed to the penicillin for only minutes a day, whereas, in the animal experiments, the flora encountered the antibiotic whenever the animals ate or drank. Negative results were to be expected. The finding, in one study, that the penicillin dentifrice worked, was remarkable and should have encouraged additional investigations. This did not occur, since at this time the medical profession was becoming aware of the problems of penicillin resistance in pathogenic bacteria, and of penicillin sensitivity in humans, and was advocating discretion in the use of penicillin, especially in instances where acute infections were not involved. Combined with the generally negative results of the penicillin dentifrice studies, this mood of caution led to a moratorium on the use of penicillin for the treatment of dental caries and/or periodontal disease. In retrospect, this has been a wise decision, as penicillin is too valuable a drug in life-threatening infections to have its use compromised by incorporation into a dentifrice which is used daily.



根據實驗白老鼠的數據得到這些實驗的劑量，很遺憾的是不足夠轉換成人類的規模，最好口腔生態一天能被暴露在青黴素中幾分鐘，反之，在動物實驗中，每當動物吃東西或喝水，其口腔生態群就會遇到抗生素，負面的結果是被預期的，在一個研究中發現，含青黴素的牙膏作用是顯著的，且鼓勵更多研究者探討。但這並沒有被實驗，因為當時致病菌對青黴素抗藥性的問題，及在人類對青黴素過敏，使得使用青黴素有疑慮。特別是一些急性感染沒有被包括在內。與其他研究含青黴素牙膏有負面結果實驗連結，這種擔心導致暫停使用青黴素

在治療牙科蛀牙及牙周病，回顧以前，這是一個明智的決定，因為青黴素是對生命有危險的感染太有價值的藥物，而不需用在每天使用的牙膏中，來抵銷青黴素的效用。



Systemic Prophylactic Penicillin Treatment. Certain Group A streptococcal infections elicit an antibody response that is capable of cross reactions with host proteins found in the heart valve and glomeruli of the kidney. The resulting inflammatory response causes tissue damage and serious organ dysfunction. If the infection is aborted, so as to prevent the host antibody response, no damage appears to occur. Individuals who have been diagnosed as having prior sensitization to these streptococcal antigens, i.e., patients with rheumatic fever or glomerular nephritis, are given daily doses of 200,000 units or more of penicillin so as to prevent any future Group A streptococcal infections. These patients represent the only medical situation where continuous prophylactic treatment with antimicrobials is recommended. As the treatment is systemic, some penicillin will enter the oral cavity via saliva and/or the gingival crevice fluid. This raises the possibility that the antibiotic given for medical purposes could coincidentally improve the dental health of the individuals. Two retrospective cross-sectional studies on rheumatic fever patients have shown a statistically significant reduction in caries scores when compared to control subjects. Littleton and White compared the number of decayed, missing and filled surfaces (DMFS scores) in treated children with those found in untreated children of the same age, living in the same community. If only the DMFS scores in children whose penicillin treatment started prior to the eruption of the permanent teeth are considered, a significant 55 percent reduction in scores is observed after two and a half years of treatment (Table 18-2).



含青黴素的系統性潔牙治療

在心臟瓣膜及腎臟的絲球體中發現，一些group A的strptococcai感染引發出與宿主蛋白質交互影響的抗體反應，這些發炎反應會造成組織破壞及嚴重的器官衰竭，若是發炎中止，預防宿主的抗體反應發生，則不會對宿主有破壞影響。有些個體被診斷出對這些streptococcal antigen抗原敏感，例如有風濕熱或腎絲球炎患者，每天被給予200.000 units的青黴素來預防任何未來group A streptococcai感染，這些病人是唯一須持續預防性給抗生素的醫學特例。若治療是全身性的，一些青黴素會進入口腔環境，借由口水或牙齦溝液傳遞。這樣可以提高抗生素提供醫學目的的可能性，並同時改善個體牙齒健康。兩個在風濕熱病人身上的回朔性研究retrospective cross-sectional studies，顯示當跟對照組比較，對蛀牙分數的降低，在統計學上是有意義的。Littleton & White比較蛀牙數量，缺牙數及填補牙面(DMFS scores)，在比較相同年齡且居住相同社區受治療孩童及沒有治療孩童，若只考慮那些在恆牙長出前使用青黴素治療的孩童的DMFS scores，治療2.5年後發現有55%的顯著降低。(Table 18-2)



Table 18-2

Effect of Long-term Penicillin Treatment on Dental Caries



Reference Penicillin Untreated

Littleton & White*, 1964. J. Amer. Dent. Assoc. Age

number examined

DMFS 9.7 yrs

51

2.2 ± 0.4 9.5 yrs

362

4.8 ± 0.3

*Daily medication with 200,000 units penicillin started before 7 years of age.

Penicillin Untreated Siblings

Handelman et al., ** 1966. J. Oral. Ther. DMFS 0.67 ± 1.1 1.5 ± 0.4

** 200,000 units of penicillin/day.



Table 18-2

長期使用青黴素治療在牙科蛀牙上的影響



Handelman et al. found a 56 to 69 percent reduction when the DMFS scores of treated children were compared with their siblings (Table 18-2). When the patients were removed from the prophylactic regimen, their caries experience gradually increased over a period of years. This observation would suggest that the penicillin indeed was responsible for the caries reduction. Handelman and Hawes found that the salivary flora, including streptococci which were isolated from the antibiotic subjects, were less sensitive in vitro to low levels of penicillin and tetracycline than the salivary flora obtained from control patients. The organisms were still sensitive to therapeutic levels of the antibiotics, and the development of this resistance did not present a clinical problem to the subjects on the prophylactic regimen. The antibiotic resistance of the organisms in the treated subjects tended to return to preantibiotic levels on the completion of therapy. No signs of drug toxicity were observed.



This latter study showed the treated groups to average about 0.4 to 0.7 new DMFS per year, a remarkably low incidence of decay. The control groups also had a low incidence, i.e., about 1.6 per year. Thus, while the percent reductions in caries between the treated and untreated were impressive, they amounted to an actual reduction of about one surface per year. This degree of prevention is minimal relative to the expense and risks of systemic penicillin treatment as a prophylactic dental regimen. Both studies provide evidence that penicillin given daily can reduce decay without causing untoward side effects. Thus, they contribute to the hypothesis that antimicrobial agents are of value in the treatment of dental disease.



Handelman et al發現在受治療的孩童與其兄弟姐妹比較，DMFS scores減少了56-69% (Table 18-2)，當這些病人被移出潔牙的治療組，他們的蛀牙會在幾年間顯著的提高。這個發現指出青黴素的確對蛀牙的減少有幫助。Handelman & Hwaes發現在口水生態系中，包括被從抗菌個體分離出的streptococci，在與對照組病人口水生態系比較，在動物實驗中對低劑量的青黴素及四環黴素較不敏感。這些微生物依舊對治療性抗生素的濃度是敏感的，對潔牙治療的個體來說，產生這些抵抗力，不會是臨床的問題。抗生素的抗藥性在治療的個體上偏向回覆到在治療完成前的抗生素濃度，且沒有發現有藥物毒性。



之後的研究顯示，治療的組別平均一年有0.4-0.7新的DMFS產生，是顯著相當低的蛀牙率。在對照組同樣有低的蛀牙率，像是每年1.6 DMFS scores，所以，當這些蛀牙的降低，在受治療及未受治療的組別間是令人印象深刻的，這幾乎是每年一個牙面的減少。這個預防跟系統性青黴素治療用在潔牙治療的風險及花費的相關性很低，這些研究提供每天給予青黴素來減低蛀牙且不會造成副作用的證據，所以，他們建議抗菌藥物對治療牙科疾病是有用的假說。



Summary: Penicillin Studies. Penicillin will prevent dental decay in animal models. Its efficacy is so reliable that penicillin is the positive control against which all other antimicrobial agents should be compared. Several clinical investigations, in which a penicillin dentifrice was used, failed to expose the oral flora to what would appear to be adequate levels of penicillin. Despite this under-treatment, one of four studies showed an impressive 55 percent reduction in caries increment after one year of treatment. Two retrospective epidemiological studies in young individuals on a prophylactic penicillin schedule for medical purposes, showed significant percentage reductions in caries levels in the treated subjects when compared to untreated control subjects. This fragmentary human data is suggestive that penicillin could act as a prophylactic agent in caries reduction. This would be an unwarranted usage of an indispensable medical agent and should not be done.



總結: 青黴素研究Summary: Penicillin studies

青黴素在動物中可預防蛀牙，相對於其他抗菌藥物的效用，青黴素對蛀牙的正向控制可被信賴，幾個臨床研究發現，使用含青黴素牙膏，卻無法達到足夠的青梅素濃度暴露在口腔生態中，除了這些under-treatment，四分之一的研究顯示，在一年的治療後，有高達55%蛀牙的降低，兩個回朔性流行病學的研究年輕人使用預防性青黴素治療醫學目的medical purpose，當與其他未受治療的個體比較，顯示蛀牙有顯著的減低，這些零星的人類數據建議，青黴素可被當作潔牙藥使用來減低蛀牙，這些必需的醫學藥物是沒有證據且不該被使用。



Fluoride



Mechanism of Action. The experience with penicillin demonstrated that the dental profession will not ethically be able to use a medically important agent for the prophylactic treatment of nonlethal infections such as dental decay and periodontal disease. Drugs either unsuitable for use in systemic infections or uniquely involved in the biology of the teeth should be evaluated for their anticaries or anti-periodontitis potential. The latter category would include fluoride, whose remarkable anticaries effect in water fluoridation has been adequately documented. The precise mechanism(s) by which fluoride protects against decay is not known. The fluoride could exchange with a hydroxyl group in the apatite crystal, forming a more stable and therefore less acid soluble crystal. The fluoride could enter into void spaces of the apatite crystal structure, thereby adding their hydrogen-bonding tendency to the forces which hold the crystal together. According to these explanations, the fluoride acts to increase the tooth's threshold to a noxious bacterial product, i.e., acid, and has no obvious antimicrobial action against the plaque flora. This may not be true, as small levels of fluoride, especially in an acid environment, inhibit bacteria in vitro. In the next sections we shall describe both physical-chemical and antimicrobial actions of fluoride which most likely act in concert in vivo to reduce dental decay.



氟



作用機制

使用青黴素的經驗使牙科專業人員無法使用一種醫學上重要的藥劑來做為不會致命感染的預防性治療，例如蛀牙及牙周病。這些藥物不管是否適合使用在系統性感染，或是獨特涉及牙齒的生態都應該被評估他的抗蛀牙及抗牙周病的功效。最近包含引水加氟的氟化物就是有很好抗蛀牙的作用，且被充分證明的。氟化物保護蛀牙的機制是不明確的，但是氟可以與hydroxyl group交換離子成為apatite crystal，成為一種更穩定且更不易被酸蝕的結晶體。氟可以進入apatite crystal結構中的孔洞空間，因此可以加強鞏固結晶體相連的氫鍵能力。根據這些解釋，氟扮演增加牙齒對抗有害細菌產物的閾值的角色，例如：酸，沒有明顯的抗菌作用對抗牙菌斑菌落。特別是在酸性環境中，若氟的量較少，在動物實驗抗菌中這也許不是正確的，下一段我們會解釋氟化物在動物實驗中，抗蛀牙的物理化學及抗菌作用。



Chemical Effects. Physical-chemical arguments best explain why fluoride, taken systemically in water, can confer protection to the unerupted tooth. However, fluoride also exerts an effect after the teeth erupt, that is both chemical and antimicrobial in nature. The multiple aspects of this topical fluoride effect has made it difficult to unequivocally separate out the component parts. In vitro studies indicate that the amounts of fluoride that would be found in plaque, i.e., 1 to 10 ppm F, enhance the formation and rate of precipitation of hydroxyapatite from saturated calcium phosphate solutions (Fig. 18-1). In the absence of fluoride the more soluble octacalcium phosphate would be the kinetically-favored precipitate. If this phenomenon occurs at the plaque-enamel interface, then hydroxyapatite would be formed from the saturated calcium phosphate solutions that are maintained in the plaque by statherin and the other proline-rich proteins that are found in the acquired enamel pellicle (See "Inhibitors of Calcium-Phosphate Precipitation" in Chap. 10). Fluoride in this fashion would maintain the integrity of the apatitic lattice in the tooth surface beneath the plaque, as it would replenish the apatite ions solubilized by acids produced during plaque metabolism, with new apatite formed in the periods between eating, and especially during sleep.



化學作用

物理化學的爭議解釋了為什麼氟，借由水從系統性吸收，可以賦予還未萌發的牙齒保護，然而，氟也可在牙齒萌發後發揮功效，這同時是化學及抗菌作用。多方面的局部氟化物作用，使要明確的分離構成要素很困難。在動物實驗指出，在牙菌斑中發現氟化物的量，約1-10ppm F，從飽和磷酸鈣液中增加hydroxyapatite的形成及沉積速率可知(圖18-1)，在缺乏氟的情況下，越多溶解的octacalcium phosphate會有更多的動力沉積kinetically-favored precipitate?。若是這種現象出現在牙菌斑牙釉質之間，hydroxyapatite會從滲透的磷酸鈣液中形成，這些磷酸鈣會藉由在牙釉質pellicle中的statherin和其他富含proline的蛋白質在牙菌斑中被維持(詳情請查閱第十章磷酸鈣沉積的阻斷)。氟可以藉由在牙菌斑代謝期間酸溶解產生apatite離子，維持牙菌斑之下牙齒表面apatite lattice的完整，在吃東西與特別是睡眠之間有新的apatite產生。



But fluoride does more than just maintain an intact tooth surface. Muhler reported in l960 that the reversal rate for surfaces diagnosed as carious was two to three percent after topical application of water, but 22 to 25 percent after the application of stannous fluoride. This ability of fluoride to arrest caries is associated with a net transport of fluoride into the enamel lesion, presumably in the form of fluorapatite. Some of this fluoride could also be bound by organic components present within the lesion, such as bacterial cells, or salivary proteins (See "White Spot Hypothesis" in Chap. 19).



不過氟不僅只是維持完整無缺的牙齒表面，Muhler在1960年表示，診斷為蛀牙表面上的反轉率在局部塗水後是2-3%，但在塗氟化亞錫後是22-25%，氟化物阻止蛀牙的能力與氟運送到牙釉質蛀牙的能力有關，推測是以fluorapatite的形式。某些氟化物也可藉由存在在蛀牙中的有機物質，例如細菌細胞或唾液中蛋白質傳送(查閱第十九張白班假說)。



Antimicrobial Effects This ability of fluoride to enhance remineralization of the tooth surface and to arrest certain incipient lesions has a strong physical chemistry basis, as is illustrated in Figure 18-1. However, some of this beneficial effect may be attributed to an antimicrobial effect of the fluoride on the bacteria within the lesion and at the enamel-plaque interface. Early studies by Bibby and later by Wright and Jenkins showed that fluoride could inhibit acid production by salivary bacteria. This inhibition was dependent upon pH in that, at pH 5.0, only one to two ppm of fluoride were inhibitory, whereas at pH 7.0 complete inhibition was not observed even with l0- to l00-fold higher levels of fluoride. Glucose uptake and intracellular polysaccharide (ICP) synthesis, but not extracellular polysaccharide synthesis, exhibited a similar acid-amplified inhibition by fluoride. Fluoride had been known to inhibit enolase, which would adequately explain the inhibition of acid production, but this did not seem to explain the inhibition of glucose uptake and ICP synthesis, as these activities occur at enzyme steps prior to the glycolytic pathway. This suggested that fluoride might interfere with metabolism at multiple sites within the cell. This issue was clarified by the demonstration of the important role of the phosphotransferase system in sugar transport in the oral streptococci (See "Phosphotransferase System" in Chap. 9).



抗菌作用

氟促進牙齒表面再礦化和阻止一些初期蛀牙的能力有很強的物理化學根基，如同圖18-1。然而，一些有益的作用可能歸咎於氟在蛀牙及牙釉質牙菌斑中對細菌的抗菌作用。早期Bibby和之後Wright及Jenkins的研究顯示，氟可以阻止唾液中的細菌產酸。這個抑制作用取決於唾液中的pH值，當pH 5.0時，1-2 ppm可被氟抑制，然而在pH 7.0時，就算用10-100倍高濃度的氟也無法觀測到完整的抑制作用。葡萄糖攝取及intracellular polysaccaride (ICP)的合成，不是extracellular polysaccharide合成，顯示類似氟抵抗酸擴大的作用，氟被視為可以抑制enolase，說明了如何抵抗酸的產生，但是因為這些活動發生在葡萄糖解之前的酵素步驟，所以無法解釋葡萄糖攝取及ICP合成對酸的抑制作用。這些解釋了氟可能妨礙不同細胞中不同位置的代謝，證明phosphotransferase系統在口腔鏈球菌中糖分運輸的重要角色，幫助釐清這些爭議(查閱第九章phospohtransferase系統)。



Whole cells of S. mutans, S. sanguis and S. salivarius possess fluoride-sensitive glucose transport systems. An inhibition of glucose uptake could satisfactorily account for all of the metabolic lesions seen with fluoride. However, the isolated enzymes, such as the phosphotransferase system, phosphoglucomutase or hexokinase, were not inhibited by fluoride. This indicated that still other uptake mechanisms existed that were fluoride sensitive, or that some other enzyme system that impacted on these transport mechanisms was sensitive.



S. mutans, S. sanguis, S. salivarius的所有細胞擁有對氟敏感的葡萄糖傳遞系統，對葡萄糖攝取的抑制能夠令人滿意地解釋所有與氟一起被看見的代謝損害。然而，被分離的酵素，像是phosphotransferase系統、phosphoglucomutase或hexokinase並不會被氟抑制，這表示還是有其他對氟敏感的機制存在，或是其他在這些傳遞代謝中被影響的酵素系統也是敏感的。



The most attractive of these possibilities was the dependence of the phosphotransferase system upon phosphoenol pyruvate (PEP) for its energetics. As PEP is formed by the action of enolase, the inhibition of enolase would reduce glucose uptake via the phosphotransferase system and cause a concurrent reduction in glycolysis and ICP synthesis. Thus the ability of fluoride to inhibit a single enzyme, enolase, would account for all the observed metabolic lesions (See Fig. 9-9).



這些可能性最吸引人的是phosphotransferase系統對phosphenol pyruvate (PEP)能量的依靠。PEP的形成是靠enolase的作用，對enolase的抑制會減低葡萄糖經由phophotransferase系統的攝取，且產生醣酵解glycolysis和ICP合成同步的減少，所以氟抑制單一酵素系統，enolase，的能力，將會解釋所有觀察到的代謝損害(見圖9-9)。



What has not been appreciated until recently is the mechanism by which acid potentiated the fluoride effect and how this phenomenon could operate in vivo to inhibit cariogenic organisms. A model proposed by Whitford and his colleagues (Figure 18-2) has provided insights into how this can occur. Two assumptions are made l) that the uncharged HF is the form of fluoride that enters into the cell, and 2) that the intracellular pH is about 7.0. At an extracellular pH of 7.0 most of the fluoride exists in the form of F- and does not enter the cell. The small amounts of HF which enter the cell dissociate, but the concentration of liberated F- is too low to inhibit enolase, so that the cellular metabolism continues unabated. At an extracellular pH of 5.0, most of the fluoride is in the form of HF which can be readily taken up by the cell. This internalized HF rapidly dissociates at the intracellular pH of 7, releasing enough F- to inhibit enolase and thereby curtailing cellular metabolism. Thus, an acid pH in the external environment results in a flux of F- into the cell, which converts what would appear to be innocuous levels of fluoride in the external environment, into lethal amounts in the cell cytoplasm.



直到最近之前都沒被賞識的是，酸使氟的作用成為可能的機制，還有這些現象如何能在人體中被運作來抑制產生蛀牙的微生物。一個由Whitford與其同事提出的模組(圖18-2)提供此現象如何發生的解釋。兩個假定被提出 1)氟以不帶電的HF形式進出細胞 2)細胞內pH值約7.0。在細胞外pH值7.0時，氟以F-形式存在且不會通過細胞。少量的HF進入細胞使其分離，但釋放出的F-濃度太低來抑制enolase，所以細胞代謝持續不衰退。若細胞外pH值5.0時，大多氟會以HF形式出現且可立即被細胞吸收。此內在化的HF在細胞外pH值7時快速的分離，釋放出足夠的F-來抑制enolase，因而削減了細胞代謝。因此，在細胞內環境是酸性的pH值時，會有F-傾向進入細胞內的結果，轉變氟從在外在環境無害的量，到在細胞質內致命的量。



These antienzymatic effects of fluoride, were never seriously considered as important reasons for the effectiveness of water fluoridation, because the salivary levels of fluoride, i.e., 0.1 ppm, are too low to cause these effects in vitro. This argument can now be challenged. Harwick and Leach have shown that plaque concentrates fluoride and that an average of about 67 ppm of fluoride (range from six to l80 ppm) can be found in plaques in subjects consuming fluoridated water. Much of this fluoride is bound in a biologically unavailable form, but about ten percent of the fluoride appears to be in the ionic form, raising the possibility that antimicrobial and pharmacological effects could be derived from this plaque fluoride. Plaques obtained from individuals living in a fluoridated community have higher levels of fluoride than plaques obtained from people living in nonfluoridated communities. These plaques form less acid from sucrose in vitro, than plaques removed from people living in nonfluoridated areas and tend to have lower percentages of S. mutans.



氟化物的這些抗酵素作用，從未被認真的討論作為飲水加氟的重要原因，因為唾液中的氟，在動物實驗中，要產生這些作用，約0.1ppm會太低。這個爭論現今被挑戰，Harwick和Leach表示，在攝取飲水加氟個體的牙菌斑中可發現，牙菌斑集中濃縮氟至平均約67ppm的氟(從6-180ppm)，這些氟大多數以生物性無法取得的形式被抓住，但約有10%的氟以離子形式出現，增加從牙菌斑中取得氟抗菌及藥物作用的可能性，在飲水加氟社區的個體中取得的牙菌斑中，氟的濃度會比沒有住在飲水加氟社區的人低。與住在非飲水加氟社區中的人們相比，在動物實驗中，從蔗糖中形成較不酸的牙菌斑且傾向有較少比例的S. mutans。



This plaque fluoride is thought to be mainly of salivary origin. However, the low pHs found in plaque after exposure to food items could solubilize calcium fluoride or possibly fluorapatite present within the enamel surface layer. In fact, the low pHs which could solubilize this enamel fluoride would, according to the model described in Figure 18-2, simultaneously potentiate the antienzymatic effects of the released fluoride on the plaque bacteria. If this is so, then the high fluoride levels in the outer surface layers of enamel represent a latent reservoir of an antimicrobial agent. This possibility was tested in vitro by incubating a resting cell suspension of S. mutans with sucrose and either hydroxyapatite (HAP) or fluorapatite (FAP). The metabolic activity of the suspension was measured as lactic acid production at 2, 5, l0, 20 and 30 minutes (Table 18-3). Lactic acid production in the presence of HAP was linear over the time period measured. However, lactic acid production was reduced in the FAP mixture after ten minutes and was significantly so after 20 and 30 minutes of incubation.



大多認為這些牙菌斑中的氟是從唾液中來的，然而，在吃飯後牙菌斑中低pH值會溶解在牙釉質表面的氟化鈣或可能出現的fluorapatite，事實上，低pH值會根據圖18-2的描述溶解牙釉質中的氟，同時可能使從牙菌斑細菌釋放出氟的抗酵素作用發生，如果是這樣，在牙釉質表面高濃度的氟代表一個潛在抗菌物的倉庫，在動物實驗中這個可能性，以培養蔗糖和S. mutans的休止細胞懸浮液，還有hydroxyapatite(HAP)或fluorapatite(FAP)被測試，在2, 5, 10, 20及30分鐘，測試此懸浮液的代謝作用視為乳酸的產生(表18-3)，在HAP的存在下，隨時間線性測量乳酸的產生，然而，乳酸產生在FAP混合物中，十分鐘後會下降，且在培養20及30分鐘後有顯著的下降。



Analysis of the buffer indicated that five to ten ppm of fluoride had been released from the FAP by the microbial metabolism. Some of this fluoride presumably had entered the S. mutans cells and caused the reduction in further lactic acid production. This phenomenon was confirmed in a separate experiment in which S. mutans was incubated with l.5 mg HAP and l.0 mg FAP (Table l6-4). Under these conditions there was no inhibition of lactic acid formation, indicating that the HAP, being more acid soluble than the FAP, was preferentially demineralized, leaving the fluoride ions bound within the FAP crystal structure. This indicated that demineralization of the FAP was necessary for the expression of the FAP-mediated inhibition noted in the first experiment.



分析緩衝液顯示5-10 ppm的氟會從HAP中，經由微生物代謝被釋放出來，某些氟推測會進入S. mutans的細胞中，減少進一步的乳酸產生，這種現象在一個S. mutans與1.5mg HAP及1.0mg FAP一起培養的獨立實驗被證實(表16-4)，在此狀況下，沒有抑制產生乳酸的現象出現，表示HAP比FAP更易被酸溶解，且更優先的被去礦化，留下氟離子在FAP結晶結構中鍵結，顯示FAP的去礦化在第一個實驗中發現FAP間接抑制的說法是必要的。



If the experiments described in Table l8-3 accurately depict events that can occur at the plaque-enamel interface, then any delivery system, be it topical or systemic, which deposits fluoride in the outer enamel layer, is simultaneously increasing the resistance of the tooth to acid solubilization and loading the enamel with an antimicrobial agent that is acid activated. Thus when and if plaque metabolism solubilizes this enamel layer, the released fluoride would be quickly taken up by the bacteria, which would in turn shut down their metabolic activity and thereby abort any further solubilization of the enamel. It is not surprising then that fluorides, even when used in suboptimal dosages or treatment schedules, have proved to be remarkably effective. In the following section we shall examine the benefits that can be derived from topical fluorides when used according to the nonspecific plaque hypothesis, i.e., in subjects with and without active caries who were treated on a daily basis.



若是在表18-3的形容正確的描繪出在牙菌斑及牙釉質間發生的作用，不管何種傳遞系統，局部或系統性，在牙釉質外層沉積氟，會同時增加牙齒對酸溶解的抵抗力，且使牙釉質有以酸激發的抗菌作用，所以當或若牙菌斑代謝溶解牙釉質層，釋放出的氟會很快的被細菌吸收，且相對的關閉它們的代謝作用，因此破壞其他牙釉質的溶解，不令人意外的，氟就算使用不是那麼理想的劑量或治療時間表，還是被證實明顯的有效。在接下來的段落，我們會依照非特定性牙菌斑假說，來檢視局部氟化物衍生出的好處，例如每天治療有或沒有活耀蛀牙的個體。



Topical Application. Bibby and Cheyne independently reported, in the early l940s, that infrequent topical applications of l000 ppm fluoride to the tooth surface caused about a 40 to 50 percent reduction in new carious lesions in children. This therapeutic result was assumed to reflect the ability of the fluoride to reduce the acid solubility of the enamel. The result could also be explained on the basis of the fluoride reducing and/or eliminating S. mutans or other specific cariogenic organisms from the plaque or incipient lesion. However, the scientific evidence for bacterial specificity was not in place, and in fact, the specificity argument in regard to lactobacilli was at that time under challenge (See "Lactobacillus Era" in Chap. 7). Emphasis was therefore given to the physical-chemical explanation, and experiments were designed to find the fluoride compound which most reduced enamel solubility in vitro. These studies led to the selection of stannous fluoride as the agent of choice and this compound was subsequently incorporated into a dentifrice marketed under the trademark Crest®.



局部使用

Bibby和Cheyne個別提到，在1940年代早期，1000ppm的氟很少量的使用，且局部塗佈在牙齒表面會在小朋友新蛀牙有40-50%的減少。這治療性的結果反映了氟對抗酸溶解牙釉質的能力，此結果同時解釋了氟減少抑制牙菌斑或其蛀牙中的S. mutans及其他特定產生蛀牙的微生物的基礎。然而，細菌獨特性的科學證據不存在，且事實上，一些關於lactobacilli的爭議同時被挑戰(查閱第七章"lactobacillus era")，物理化學性的解釋被重視，且實驗被設計來證實在動物中氟化物是否能減少很多牙釉質的溶解，這些實驗選擇氟化亞錫當作標的物，且氟化物被放入牙膏(crest)中製造上市。



Fluoride Dentifrices The introduction of a dentifrice with a potential preventive and/or therapeutic claim perturbed the dentifrice market and led to a large number of industry-supported clinical trials of fluoride dentifrices of various formulations. These studies have demonstrated that the regular usage of fluoride dentifrices reduces caries incidence by about 25 percent, when compared to controls using the same dentifrice minus the fluoride component. A summary of the average percent caries reduction obtained with supervised and unsupervised tooth brushing, and in children residing in fluoridated and nonfluoridated communities who used these dentifrices, is given in Table l8-4.



含氟牙膏

有可能的預防及治療效果的牙膏簡介聲稱，擾亂了牙膏市場，且使得很多廠商支持做出不同形式含氟牙膏的臨床實驗，這些研究指出，與使用相同但含較少氟化物的牙膏對照比較，正常規律使用含氟牙膏會減少約25%的蛀牙率，表18-4總結在有專業潔牙指導及沒有指導下，及住在有飲水加氟及沒有飲水加氟社區的小朋友，平均蛀牙率的降低。



Few improvements have been made in the fluoride dentifrice formulations since the early l960s. This has in part been due to the FDA regulations which make product development inordinately expensive, but also in part to the contentment of the dental profession, industry and the public with the status quo. New concepts have not been developed. One such concept would be to increase the substantivity of the fluoride at the enamel surface. Substantivity describes an association between an agent (fluoride) and a substrate (tooth) which is greater or more prolonged than would be expected with simple mechanical deposition. Substantivity was first appreciated in dentistry in studies dealing with chlorhexidine (See "Substantivity of Chlorhexidine" in this chapter).



從1960年代早期，有一些含氟牙膏構想的改善提出來，這部分因為FDA的規定使得產品的發展非常的昂貴，但也是因為牙科專業、工業及大眾對現狀的滿意度，新的觀念還未發展出來，一個此類型的觀念是增加氟在牙釉質表面的substantivity，substantivity是形容一個在氟及牙齒間的關聯，比預期簡單的機械性沉積來的大且時更耗時。Substantivity在牙科實驗中第一次與chlorhexidine同樣被賞識(查閱本章"substantivity of chlorhesidine")。



Schemes can be devised to enhance the substantivity of fluorides in dentifrices. One such dentifrice, sold in Europe under the trade name Elmex® combines the fluoride with amino groups. The amino groups, by virtue of their positive charges, bind to the many negative charges available on the tooth and acquired enamel pellicle and thereby, prolong the availability of the fluoride at the tooth surface. Substantivity of fluoride should also be enhanced by acid conditions, as more fluoride would be deposited within the enamel surface. Accordingly, an acidulated fluoride dentifrice could be expected to yield even better clinical results than those shown in Table 18-5. These considerations suggest that the dentifrice manufacturers may have taken an extremely effective chemotherapeutic agent and packaged it in a form which is convenient and safe, but which has not fully evolved to realize the full prophylactic and/or therapeutic potential of the fluoride.



增強牙膏中氟的substantivity被提出，一個在歐洲販售類似的牙膏(Elmex)將氟與胺基族群結合，此胺基族群的正電效力與很多在牙齒及acquired enamel pellicle上出現的負電結合，延長了氟在牙齒表面的供應，氟的substantivity也可被酸性環境加強，則更多的氟會沉積在牙釉質表面，因此，預期酸化的含氟牙膏會產生甚至比在表18-5顯示的更好臨床結果。這些考量建議牙膏廠商使用極度有效的化學治療性藥物，且以方便又安全的形式包裝，但是沒有完全發展去了解氟預防或治療的可能性。



Fluoride Gels and Mouthrinses: Other investigations have shown that periodic applications of fluorides in vehicles, such as gels, mouthrinses and tablets have achieved an even greater caries reduction than obtained with the dentifrices.



氟膠及含氟漱口水

其他研究顯示定期的氟化物攝取，例如氟膠、含氟漱口水和氟錠可比含氟牙膏降低更多的蛀牙。



l) Cheektowaga Study. A clinical trial of fluoride gels conducted in 11 to 14-year- old children in Cheektowaga, N.Y., resulted in a 75 percent reduction in DMFS scores. The children were given 0.5 percent fluoride, either as a neutral sodium fluoride (NaF) or acidulated phosphate fluoride (APF) gel, each school day during a 2l-month period. The gels were added to custom-fitted plastic trays which were then inserted over the teeth and held in place for a six-minute period under supervision. A neutral pH placebo gel, of identical composition minus the fluoride, served as a control. After 21 months of treatment the 305 children remaining in both fluoride groups had a 75 to 80 percent reduction in new DMFS incremental scores compared to the control group (Table l8-5).



1)Cheektowaga研究

一個在Cheektowaga, N.Y.11-14歲孩童所研究的氟膠臨床實驗，顯示DMFS降低75%。在21個月中每個上學日，給予這些孩童0.5%的氟，neutral sodium fluoride (NAF)或acidulated phosphate fluoride (APF)的氟膠，在專業指導下，將氟膠加入塑膠牙托中放入孩童口中塗佈牙齒，維持六分鐘，一個相同成分但氟含量較少的中性安慰劑當成對照，在21個月的治療之後，305個孩童在兩個含氟的組別，與對照組比較，降低75-80%新的DMFS發生(表18-5)。



Significantly more fluoride was incorporated into the tooth surfaces by the APF gel (Table 18-5). However, this was not associated with a demonstrable clinical difference in caries scores as would have been predicted if the tooth fluoride levels determined the degree of demineralization of the enamel that can occur as a result of microbial acid production in the plaque. The high tooth fluoride levels in the APF group raised the possibility that this fluoride could protect the enamel in future years. This was investigated by reexamining the children 23 months after the cessation of the gel treatment. One hundred and twenty seven APF-treated children showed a 63 percent reduction in new caries increment compared to the control children, but surprisingly the 115 children treated with the neutral NaF exhibited a 55 percent reduction (Table 18-6). Thus both fluorides exerted a residual effect on caries reduction that was independent of the level of the fluoride originally incorporated into the tooth.



APF氟膠在牙齒表面有明顯較多的氟吸收(表18-5)，然而，這與顯而易見臨床蛀牙分數(當牙齒氟濃度決定牙釉質去礦化的程度可當作牙菌斑中微生物產酸的結果)的差異無關，在APF組中牙齒有高濃度氟，會提高氟在未來幾年保護牙釉質的可能性，藉由在治療期間後23個月重複檢測這些孩童來調查，與對照組的孩童比較，127個APF氟膠治療的孩童顯示了降低63%的新蛀牙，但令人驚訝的是，115個以中性NaF氟膠治療的孩童顯示降低55%的新蛀牙(表18-6)。所以，兩種氟對蛀牙的降低都有殘存的效用，且與初期氟的濃度併入牙齒表面無關。



This suggested that the initial fluoride effect was mediated by an antimicrobial mechanism which changed the plaque flora from a cariogenic flora to a flora of lesser virulence. The pooled plaque from smooth surfaces was subsequently cultured and found to contain low proportions of S. mutans in both the control and fluoride-treated subjects. This was interpreted as indicating that the fluoride effect was not mediated by an antimicrobial mechanism. However, this bacteriology was performed some two years after the period of active treatment and microbial changes that occurred during treatment would not necessarily persist for two or more years. Also it is not known whether plaque taken from single caries-prone sites such as fissures or approximal areas would have shown similar findings. Lastly, it is conceivable that constant exposure to fluoride could have selected for fluoride-resistant strains of S. mutans with reduced capacity to form acids (See "Fluoride-Resistant S. mutans" in Chap. 19). These counter arguments leave intact the contention that the anticaries activity of the fluoride was achieved by an antimicrobial mechanism.



這顯示起初的氟作用是以抗菌機制傳遞，會改變牙菌斑中菌種從易蛀牙到毒性較低的菌種，隨後培養牙齒平滑表面的牙菌斑發現在對照組及使用氟化物治療組，S. mutans的比例皆下降，這解釋說明了氟化物作用並不是以抗菌機制傳遞，然而，主動治療及微生物改變發生於治療期間不會持續超過兩年或更久，這期間後兩年完成此細菌學?，並且不管牙菌斑從單一高蛀牙率區域，像是溝隙或牙齒鄰接面是否會顯示相同的發現是未知的。近期，持續的暴露在氟的環境下，可以篩選出減低的產酸能力的fluoride-resistant stains of S. mutans(抗氟菌株)，是可被理解(查閱第十九章:Fluoride-Resistant S. mutans")。 此反對的爭議，留下完整論點說明，氟抗蛀牙的能力是經由抗菌機制完成。



2) Scandinavian Fluoride Studies. The Cheektowaga study has not profoundly influenced subsequent dental therapy, as critics consider the daily gel treatment impractical. The demands of the NSPH have discouraged responsible officials from initiating this type of program. If such a treatment has to be performed on every child every school day for an unspecified period of years, then more money is needed than any group or agency in the United States is willing to provide at this time. Clearly such extensive prophylactic treatment will occur only when the cost of restorative care is so prohibitive, that prevention becomes a viable economic alternative. This situation can be found in several Scandinavian countries where the caries rate is high and the government is financing the treatment.



2) Scandinavian 氟化物實驗

Cheektowaga實驗並沒有深刻的影響接下來的牙科治療，因為評論顧及到每天使用氟膠治療是不實際的，NSPH的需求勸阻負責的官員施行此制度，若這種治療要施行在每位學童在非特定幾年中的每個上學日，在同時美國沒有任何團體或機構願意負擔這相當龐大的經費，明顯的，這廣泛的預防性治療只會在恢復健康的照護經費過高時被執行，使預防成為經濟上可行的替代品。這種情況會在一些高蛀牙率Scandinavian國家發生，其政府則會提供給這些治療資金。



The absence of water fluoridation in some of these countries has complicated the task of caries control, but also has promoted greater reliance by the dental profession on the usage of topical fluorides. The impressive 90 percent reduction in dental caries in the Karlstad study (Fig. 13-3), was achieved by combining mechanical debriding with the usage of a five percent monofluorophosphate (MFP) prophylactic paste. This study was not designed to separate out how much of the effect was due to mechanical debridement, how much to dental education and how much to the usage of fluoride. This issue was addressed by the Danish studies which showed that toothbrushing instructions and dental health information had little effect on caries incidence (Table 15-2) and that professional cleanings at biweekly intervals using a nonfluoridated paste caused about a 60 percent decrease in caries (Table 15-6). In a separate study, 10- to 11-year-old children were given a topical application of two ml of a three percent solution of sodium MFP once every two weeks during the school term. The control group received no topical treatment but did continue with the monthly usage of a 0.2 percent sodium fluoride mouthrinse. No attempts were made to improve eating habits, oral hygiene or to influence the choice of toothpaste by the children.



在一些沒有飲水加氟的國家可能會使蛀牙的控制複雜化，但同時會提高更多牙科專業人士對使用局部氟化物的信賴。在Karlstad study中，此實驗結合使用5% monofluorophosphate (MFP)潔牙膏機械性潔牙，得到令人印象深刻的90%蛀牙的降低(圖13-3)，此實驗不是被設計來分離機械性潔牙的效果有多少，或是牙科健康教育或使用氟化物的成效有多少，一個丹麥的實驗顯示刷牙指導及牙科健康教育對蛀牙降低效果有限(表15-2)，且兩周一次使用非含氟牙膏專業性潔牙會減低60%的蛀牙，此實驗釐清了前述的疑問。在一個個別的實驗中，3% 2-3ml的MFP兩周一次在上學日期間給予10-11歲孩童，對照組沒有給予局部治療，但每個月持續使用0.2%NaF漱口水，沒有刻意改善飲食習慣，口腔衛生或改變孩童使用牙膏的選擇。



The fluoride group had a significantly lower caries experience than the control group after both one and two years (Table 18-7). This was measured by a decrease in both the number of carious surfaces and filled surfaces. What was most impressive was the apparent reversal of many incipient lesions in the fluoride group. Forty two of l09 surfaces, which had been judged carious at the initial examination, were judged sound after one year. In the control group only two of 75 initially carious surfaces were judged sound at the end of the first year. This trend of reversals in the fluoride group continued on into the second year. The net caries increment obtained by adding together the increment of new carious surfaces and new filled surfaces was 2.93 in the fluoride group and 12.05 in the control group. Thus the two-minute application of the MFP in the absence of any plaque removal resulted in about a 75 percent reduction in total caries.



在一年及兩年後，使用氟化物組別較對照組有顯著較低的蛀牙(表18-7)，測量蛀牙面及填補牙面的減少來決定，最令人印象深刻的是，在氟化物組別，發現初期蛀牙逆轉，在109個牙面中，有42個面在實驗初期被斷定是有蛀牙的，一年後發現變成完整堅固的，在對照組中，75個初期蛀牙的牙面只有2個在一年後變成完整堅固的，這逆轉的趨勢在氟化物組別持續到第二年，將新蛀牙的牙面及新填補牙面相加得到蛀牙增加淨值，在氟化物組別是2.93，在對照組則是12.05，所以在沒有任何牙菌斑移除下，給予兩分鐘的MFP，會減少約75%的蛀牙。



Melsen and her colleagues attributed this improvement to a chemical effect of the fluoride on the hydroxyapatite lattice, especially in regard to explaining the remineralization of the incipient lesions. However, the 300 ppm of fluoride that the tooth surfaces were exposed to could also have exerted an antimicrobial effect on the plaque flora by the mechanisms illustrated in Figure 18-2. The fluoride could kill, in situ, any organisms that had already invaded the incipient lesion, a phenomenon which could account for the observed caries reversals (See "White Spot Hypothesis" in Chap. 19).



Melsen及其同事將此進步改善歸咎於氟化物在hydroxyapatite lattice的化學作用，特別是關於解釋初期蛀牙的再礦化，然而，牙齒表面暴露在300 ppm的氟化物之下可以在牙菌斑菌株群有抗菌作用，在圖18-2，氟可以在原處殺死任何已經侵犯初期蛀牙的微生物，此現象可以說明觀察到的蛀牙逆轉(查閱第十九章"白班假說White Spot Hypothsis")。



The professional application of fluoride could account then for a major proportion of the caries reduction observed in the Karlstad study. Such applications would be more cost efficient than the full prophylactic regimen used by the Swedish investigators. Even so, the treatment of patients at two-week intervals is not practical for most clinicians in a private practice situation such as exists in the United States. Could there then be some way to optimize the fluoride treatment so that it could be given at less frequent intervals? Is there some means by which the substantivity of the fluoride could be enhanced? One such way is the usage of a fluoride varnish which can be painted on the teeth and from which the fluoride is slowly released over a period of several hours. An organic based product containing 0.2 percent sodium fluoride Duraphat® has been shown to significantly reduce decay in the primary dentition when applied at 6-month intervals to very young children (Table 18-8). It is of interest that in this study the most refractory of all tooth surfaces to topical fluoride treatment, i.e., the occlusal surface, exhibited a significant reduction in caries incidence.



在Karlstad的研究中，專業塗氟可被視為降低蛀牙的重大成因之一，塗氟比瑞典研究者使用的預防療法的花費更有效率，即使是如此，兩周一次的治療對多數美國的私人診療現狀還是不實際的。有沒有什麼方法能在比較不頻繁情況下最有效的進行氟化物治療?有沒有什麼方法能使氟的substantivity被增強?其中一種方法是使用氟漆塗佈在牙齒表面，使氟能緩慢的在未來幾小時中釋放，Duraphat是一種含0.2%的NaF的有機產品，且被證實六個月一次塗佈在很小的孩童乳牙齒列上會有顯著減低蛀牙的效果(表18-8)，有趣的是在此實驗中，所有牙面對局部塗氟治療最有抵抗力的咬合面，顯示有明顯的蛀牙降低



3) Slow Release Systems. In the future, depot delivery systems for fluoride will be available. In the United States, the National Caries Program is developing the technology for the controlled release of fluoride to the teeth over extended periods of time. This would include the usage of sustained release fluoride tablets that provide both a rapid local release of fluoride in the mouth followed by a slower release from the intestinal tract after the tablet is swallowed. Another approach is the use of an aerosol that would deposit a layer of fluoride microcapsules embedded in an adhesive on the surfaces of the teeth.



3)緩慢釋放系統Slow Release Systems

未來，將可得到氟的傳遞系統，在美國，國家蛀牙方案正在發展其科技來控制氟經過延長時間在牙齒的釋放，這將包括使用氟錠維持其釋出，同時提供在口腔中快速局部的釋放，及在氟錠吞入後緩慢藉由腸道吸收而釋出，另一個方法則是，使用氣溶膠沉積一層氟的薄層包埋形成牙齒表面的黏劑。



The most promising approach is the fabrication of a small device which can be attached directly to the tooth surfaces or to an intraoral appliance such as a lingual bar, which would slowly release fluoride after coming in contact with oral fluids. Design parameters for devices which would release l.0, 0.5, 0.2 or 0.02 mg of fluoride per day for a period of six months have been prepared, but have not been clinically tested in humans. These devices, when perfected, will release fluoride at a constant, predetermined linear rate for a period of weeks, up to six months, without need for maintenance or adjustment.



最有效的方法是發展一個小小的裝置，可直接接觸牙齒表面或一個口中的裝置，例如一個舌側棒，可在與口中液體接觸後緩慢的釋放氟，設計此裝置的變數，是在六個月的期間，設計每天釋放1.0, 0.5, 0.2, 0.02mg的氟，但沒有被在人類上做臨床測試，這種裝置，若是完美的，不需要維持或調整就會持續以被設定的速率在幾周到六個月釋出氟。



This means that the devices can be placed by the dentist with the assurance that each ml of saliva which flows over the tooth surfaces will bring a known amount of fluoride into contact with the teeth and the plaque. These devices will be designed so that no acute fluoride toxicity will occur if the device was swallowed and all the fluoride became available at once for systemic absorption. There is the possibility that fluoride-resistant cariogenic organisms might eventually be selected for in the plaque. Such fluoride-resistant organisms were observed when xerostomia patients were treated daily with a one percent sodium fluoride gel (See "Rampant-Caries-Radiation Xerostomia Patients" in Chap. 19). However, these fluoride-resistant S. mutans strains may no longer be cariogenic (See "Fluoride Resistance in S. mutans" in Chap. 19). Thus the safety and efficacy of these slow release devices appear to be extraordinarily high. They should yield clinical results superior to those achieved by the studies described in this and the succeeding chapter.



這表示牙醫師將此裝置放入口內，確保流在牙齒表面每毫升的唾液能將既定量的氟與牙齒及牙菌斑接觸。設計此裝置能避免當裝置吞下且所有的氟一次系統性吸收造成的急性氟中毒，抗氟且造成蛀牙的微生物可能最終被選擇存在牙菌斑中，在每天使用1%的NaF氟膠治療的口乾患者身上，可被觀察到此微生物(查閱第十九章"放射線治療的口乾患者的猛爆性蛀牙Rampant-Caries-Radiation Verostomia Patients")，然而，此抗氟性的S. mutans可能不再是會造成蛀牙的菌種(查閱第十九章S. mutans的抗氟性Fluoride Resistance in S. mutans")，所以這種緩慢釋放氟的裝置其安全性與效率似乎是很高的，他們應該做出優於在此章及下一章描述到的研究的臨床結果。



4) Summary: Fluoride. Fluoride is a chemotherapeutic agent that has no important medical usages and appears to be an unusually safe and effective cariostatic agent. After 30 years of clinical usage, there have been no reports of host sensitivity, bacterial resistance or suprainfection. When given in therapeutic dosages, it can essentially prevent caries. Even when given in suboptimal dosages in dentifrices, a 20 to 30 percent reduction in caries is noted. Fluoride may work by suppressing or eliminating S. mutans from its main, if not only oral reservoir, the tooth surface. In this sense, intensive topical fluoride treatment may effect a bacteriological cure of caries which would not be seen with water fluoridation or with fluoride dentifrices, and this would explain the persistent anticaries action of topical fluorides. Future investigations should address themselves to finding the optimal treatment schedule, i.e., one that can be easily implemented and which will provide maximum benefit. This would seem best done according to the tenets of the specific plaque hypothesis (See Chap. 19).



4)總結: 氟化物

氟是一個化學性治療的藥劑，沒有重大的醫學上使用，且似乎是非常安全及有效的抗蛀牙藥物，在臨床使用三十年後，沒有任何宿主過敏、細菌抗藥性或前感染?，當以治療劑量給予，本質上可用來預防蛀牙，即使以低劑量放入牙膏中，也有20-30%蛀牙的減低，氟可用來抑制或減低不只是口腔中還有牙齒表面的S. mutans，在此觀念下，加強的局部氟化物治療有對抗蛀牙的抗菌作用，這可能不會在飲水加氟或含氟牙膏中發現，解釋了局部塗氟持續的抗蛀牙作用，未來的研究應導向發現理想的治療時間表，例如可簡單的被實行和提供最大的效用，這最好應根據特定牙菌斑假說的原則來實現(查閱第十九章)。



Chlorhexidine



The dental profession has a long but sporadic history of seeking antimicrobial agents, which could be effective when applied topically in the oral cavity. While it now appears that it has had such an agent in topical fluorides, this awareness is of very recent origin. The inability to recognize fluoride as a clinically useful antimicrobial agent probably derived from the different goals of studies involving fluoride and those involving such obvious antimicrobial agents as surfactants, antibiotics, etc. Fluoride studies usually had caries reduction as their therapeutic endpoint and patients in these studies were expected to have an immediate effect on plaque formation, long-term studies were not necessary, and accordingly, experimental designs of a shorter duration were introduced, in which the goal of treatment was the inhibition and/or reduction of plaque formation. In this manner the therapeutic endpoint determined the clinical design and resulted in separate lines of development for fluoride agents and for antimicrobial agents. These separate lines are finally converging and are a cause for optimism in terms of future caries control. But first the clinical studies which led to the recognition of chlorhexidine as an effective antiplaque agent will be described.



Chlorhexidine



牙科專業對尋找局部使用在口腔中有效抗菌藥物有很長但廣泛的歷史，當發現像局部氟化物的藥物，已經是非常近代的事，氟無法被辨識為一個臨床有用的抗菌藥物，可能包含氟及牽涉明顯的抗菌藥物，例如界面活性劑或抗生素的不同實驗目標取得，研究氟的實驗通常有蛀牙減低療效的結果，加入這些實驗的患者被期待其牙菌斑的生成有立即的效果，長期的實驗則不需要，因此，提出設計短期的實驗，實驗的目標在於抑制牙菌斑的形成，此方法中，治療性結果決定了臨床的設計，導致分開的氟化物及抗菌藥物的發展，這分開的兩條線終於會合，且根據未來蛀牙控制有樂觀態度。最初導向認定chlorhexidine為一個有效抗牙菌斑藥劑的臨床實驗將被描述。



Plaque Inhibition. Plaque inhibition studies are firmly based on the nonspecific plaque hypothesis' contention that plaque overgrowth is the factor most responsible for causing dental disease. A variety of clinical indices were developed to measure plaque on the surfaces of the teeth, e.g., the Oral Hygiene Index, the Navy Plaque Index, the Quigley-Hein Index, the Löe and Silness Plaque Index and others. These subjectively-measured indices provided a means by which the efficacy of an antimicrobial agent to prevent or remove plaque could be documented. Clinical trials of a variety of agents were conducted in which the subjects went without toothbrushing or other oral hygiene procedures for three to seven days. The subjects during this period would either use a placebo mouthrinse or dentifrice, or an experimental mouthrinse or dentrifice. The amount of plaque was assessed by one or more of the clinical indices, using examiners who had previously been checked to determine their ability to reproduce their own scores when using the stated index.



抑制牙菌斑

抑制牙菌斑的實驗是根據非特定型牙菌斑假說的內容，表示牙菌斑的增生是最主要造成牙科疾病的原因，發展許多種類臨床實驗來測量牙齒表面的牙菌斑，例如oral Hygiene Index、the Navy Plaque Index和Quigley-Hein Index、Loe and Silness Plaque Index等等。這些主觀的測量分數提供測量記錄一個抗菌藥物抑制或去除牙菌斑的能力，臨床追蹤許多種類的藥物實行在沒有刷牙的個體或其他潔牙程序三到七天，在此期間這些個體使用漱口水或牙膏的安慰劑，或是實驗性的漱口水或牙膏。用一個或一個以上的臨床分數評估牙菌斑的量，這些檢查者先前有被試驗來決定當使用這些評分方法，他們是否有能力重現它們的評分。



No agent emerged from these studies until Löe and his colleagues demonstrated that chlorhexidine, a bisbiguanide that had been used as a skin disinfectant, had a remarkable antiplaque activity. Löe was able to demonstrate this effect in an experimental gingivitis model that was conducted in adult volunteers. In the gingivitis model, volunteers were brought into a state of excellent oral health by a supervised program of mechanical cleansing. Once optimal health was achieved, all mechanical procedures were withdrawn and plaque was allowed to accumulate. The amount of plaque and the degree of gingivitis were carefully monitored during a three-week period. The plaque appeared to reach its maximal bulk after four to five days, but gingival inflammation was not detected until after two to three weeks. When the plaque was removed at day 21 and oral hygiene procedures were restored, the gingivitis disappeared within five to seven days. The results could be replicated by simply removing again the oral hygiene procedure.



之前這些研究沒有提出任何藥物，直到Loe和同事證實chlorhexidine是一種bisbiguanide，曾經使用做來皮膚消毒劑，有顯著的抗牙菌斑能力， Loe的一個實驗在成人志願者的實驗性牙齦炎模組中證實了這個效用，在牙齦炎模型中，志願者在一個專業指導機械性潔牙的計畫下達到極好的口腔衛生，當達到理想的口腔衛生，停止所有機械性潔牙程序，使牙菌斑慢慢堆積，在三周內仔細觀察牙菌斑堆積的量和牙齦炎的程度，在四到五天後，牙菌斑會達到最高量，但直到二到三周後才有牙齦發炎現象產生，當牙菌斑在第21天被移除，恢復潔牙程序，牙齦炎會在五到七天後消失，這個結果可簡單的在再次移除潔牙程序後被重複。



The gingivitis model provided a means of evaluating various antimicrobial agents for their ability to prevent a plaque-associated marginal gingivitis. Antibiotics such as vancomycin, polymyxin and tetracycline given in mouthwashes had an initial effect in preventing plaque, but then failed, as antibiotic-resistant organisms emerged and led to plaque accumulations. No plaque, let alone plaque overgrowth, was observed when the volunteers used a 0.2 percent chlorhexidine mouthrinse two times daily. The salivary flora showed about an 85 to 90 percent reduction in total counts during this period and the tooth surfaces appeared to be bacteria free.



牙齦炎模型提供評估種種抗菌藥物預防牙菌斑產生的牙齦炎的能力，抗生素像是萬古黴素、四環黴素或polymyxin加入漱口水中，初期有抗牙菌斑作用，但是當微生物抗藥性產生，牙菌斑開始堆積後則無效。當志願者一天兩次使用0.2%chlorhexidine漱口水後，即使放任牙菌斑產生，也沒有牙菌斑在志願者口中發現，唾液中微生物菌株顯示在實驗期間，整體總量減少85-90%，且牙齒表面是沒有細菌黏著的。



Substantivity. Chlorhexidine has been extensively tested in Europe and found to be an exceptional antiplaque agent. Other antimicrobials tested under similar conditions were unable to match the antiplaque capabilities of chlorhexidine, even though in vitro they were bactericidal for plaque organisms. This is shown in Table 18-9, where the two chlorhexidine mouthrinses were superior to the other antimicrobials tested, except possibly for the positively-charged benzalkonium chloride, in their ability to prevent plaque accumulation. What makes chlorhexidine so unique in its ability to operate in vivo? Does it kill plaque microbes faster than the other antimicrobials, or does it possess characteristics that allow it to persist in the oral environment?



Substantivity

Chlorhexidine在歐洲被廣泛的實驗，且發現是很好的抗牙菌斑藥劑，即使在體外實驗是抗牙菌斑細菌的藥物，其他抗微生物藥物在相似的情況下測試，則無法達到像chlorhexidine抗牙菌斑的能力。表18-9顯示兩種chlorhexidine漱口水優於其他抗微生物藥劑，除了可能是帶正電 的benzalkonium chloride，有抗牙菌斑堆積的能力。什麼讓chlorhexidine在人體實驗中的效果如此卓越？他會比其他抗菌藥物更快殺死牙菌斑中的微生物嗎？抑或是他有使其效用持續在口腔中的特性呢？



Several hours after a chlorhexidine mouthrinse had been used, samples of saliva were inhibitory in vitro for test organisms. Unlike other antimicrobials, chlorhexidine is not rapidly cleared from the oral cavity. The strongly-positively-charged chlorhexidine absorbs to oral structures and then is slowly released in an active form. In terms of dosage, each mouthrinse acted as a loading dose in which the oral surfaces served as depots or reservoirs for the agent. Between mouthrinses, the surfaces released the chlorhexidine, which in turn exerted an immediate local antibacterial effect. Thus, the duration of action of the chlorhexidine was not limited to the minute's exposure during the actual mouthrinse, but lasted for a period of several hours. Apparently no other antimicrobial agent tested previously had a similar prolonged duration of action, and this would account for their failure. This simple principle of antimicrobial therapy, i.e., the bringing of the drug into contact with the bacteria for a time period sufficient for an effect to occur, had fortuitously been met by chlorhexidine.



在使用chlorhexidine漱口水數小時後，唾液樣本是抑制的在體外培養其中的微生物，不同於其他抗菌藥物，chlorhexidine在口腔中不會很快的被清除掉，chlorhexidine很強的正電性positively-charged會被口腔組織吸收，緩慢主動的釋放出來，至於劑量，個別漱口水以一個載荷劑量?在口腔中表面(當作儲存室)起作用，在個別漱口水之間，口中表面釋放chlorhexidine，接著發揮一個立即且局部的抗菌作用。所以，chlorhexidine作用的期間不只侷限在實際漱口的幾分鐘內，而是延長到數小時後，明顯的，沒有其他之前測試過的抗菌藥物能有類似延長的作用效果，這可被視為其他藥物的不足，這個抗菌治療簡單的原則是，例如將藥物在足夠時間內帶到與細菌接觸產生作用，chlorhexidine幸運的符合此條件。



This ability of an agent to prolong its presence in an environment is known as substantivity and was previously mentioned in regard to the ability of fluoride to enter the tooth surface (See "Fluoride Dentrifices" in this chapter). The substantivity of chlorhexidine in the oral cavity has been investigated by Bonesvoll and his colleagues. The kinetics of chlorhexidine uptake by the oral surfaces from a mouthrinse and its subsequent release into the saliva have been studied with chlorhexidine containing a radioactive carbon marker. Approximately 30 percent, i.e., 5.5 to 6.0 mg of the chlorhexidine present in 10 ml of a 0.2 percent mouthrinse, is retained in the mouth. Distilled water after-rinses will release about 25 percent of the bound chlorhexidine. If acidic after rinses are used, then about 65 percent of the chlorhexidine is removed. In the latter instance, the ability of the chlorhexidine to prevent plaque formation was also reduced by about 65 percent. These experiments provide convincing evidence that the success of the chlorhexidine is due to its retention in the oral cavity and not due to any intrinsic superiority in regard to its bactericidal activity. An examination of chlorhexidine's chemical structure (Fig. 18-3) suggests that the net basic charge due to the amino groups is important for substantivity.



藥物在環境中延長其存在的能力就是substantivity，之前依據氟化物進入牙齒表面的能力提到substantivity(查閱此章節"含氟牙膏")。Bonesvoll及其同事研究口腔中chlorhexidine的substantivity，chlorhexidine的動力在漱口水及其後釋放到唾液中在口腔中被攝取，研究其動力學與含有放射性碳標的物的chlorhexidine，約30%，在0.2%10ml的漱口水中有5.5-6.0mg的chlorhexidine留存在口中，用蒸餾水漱口後會釋放約25%鍵結的chlorhexidine，若漱口後使用產酸的食物，則65%的chlorhexidine會被移除，在其後的例子中，chlorhexidine抗牙菌斑形成的能力會下降約65%。這些實驗，由於根據其細菌活性的內在優勢，提供可信的證據，chlorhexidine化學成分的實驗(圖18-3)暗示substantivity由於胺基的淨鹼性帶電性是很重要的。



In this model proposed by Rolla (Fig. 18-3), the positively-charged amino groups on chlorhexidine form ionic bonds with the negatively-charged carboxyl groups on the oral mucosa and the acquired pellicle. Thus, instead of being expectorated following usage, some 30 percent of the chlorhexidine remains bound to these surfaces. The ionic nature of the bond is easily demonstrated by introducing a small cation, such as the hydrogen ion, into the environment and observe, as was done above, that an acid after-rinse elutes about 65 percent of the bound chlorhexidine from these surfaces. Hydrogen ions would not be abundant enough in the saliva to cause this elution, so that another cation must be responsible for the slow release of chlorhexidine in vivo. Rolla proposed that calcium, the most prevalent cation in the saliva, could serve this function and in Figure 18-3, calcium ions are seen displacing chlorhexidine from the mucosal surface. This released chlorhexidine possesses all its antimicrobial activity and would presumably attach to negatively-charged bacterial surfaces and cause their death. In this manner microbial growth on the tooth and oral surfaces would be effectively disrupted.



在由Rolla提出的模型中(圖18-3)，在chlorhexidine上帶正電的胺基形成離子鍵，與在口腔黏膜及pellicle班膜上帶負電的唆基鍵結，所以，除了使用後被吐出的唾液以外，約30%的chlorhexidine還是黏著在這些表面上，鍵結的離子特性可藉由導入小的陽離子進入此環境，例如氫離子，簡單的被證明，且如同以上的做法來觀察，在漱口後接觸到酸性會從這些表面上洗提掉約65%黏著的chlorhexidine。氫離子不足以固著在唾液中來造成這樣的洗提，所以在體內應該有其他陽離子會使chlorhexidine能緩慢的釋放出來。Rolla提出，鈣離子，在唾液中最普遍的陽離子，可以提供這樣的功能(查閱圖18-3)，鈣離子從黏膜表面取代chlorhexidine，此釋放出來的chlorhexidine具備所有抗菌作用，且可能會連結到細菌表面上的負電，造成細菌的死亡，在此方式下，微生物在牙齒及口腔黏膜上的生長將會有效的被瓦解。



Anticaries Studies. Chlorhexidine has not been extensively evaluated as an anticaries agent. Part of this is due to its bitter taste and staining characteristics, which minimize its usage in the long-term studies required to show caries reduction. In an experimental caries model (See Table 11-8), 0.2 percent chlorhexidine mouthrinses were shown to prevent the white spot lesions associated with incipient caries. This would reflect a therapeutic usage of the chlorhexidine, as it was used in subjects who were experiencing a severe sucrose challenge and who were likely to develop carious lesions. In this model, volunteers were given hourly sucrose rinses in the absence of oral hygiene procedures for a 21-day period. The buccal smooth surfaces of the teeth were carefully examined with the aid of a dissecting microscope and scored for caries according to well-described criteria. In the absence of chlorhexidine, an 86 percent caries increment occurred, whereas with chlorhexidine there was a 17 percent caries increment. This impressive five-fold reduction speaks well for the potential efficacy of chlorhexidine in the treatment of dental caries.



抗蛀牙實驗

Chlorhexidine沒有廣泛的被當作抗蛀牙藥物來評估，其中一部分原因是他比較苦的味道還有造成染色的性質，且需長期實驗才能達到蛀牙減低的效果，造成其在實驗中使用上的減少。在一個實驗性蛀牙模型(見表11-8)中，含0.2%Chlorhexidine漱口水顯示能預防早期蛀牙的白斑，在一些高攝取蔗糖及高蛀牙率的個體中，這反映了使用Chlorhexidine的治療效果，在此模型中，每小時給予志願者蔗糖水漱口，在沒有施行潔牙動作持續21天，在牙齒頰側平滑面使用解剖顯微鏡仔細的觀察，依照詳細解釋的標準來記錄蛀牙，在沒有使用Chlorhexidine的組別中，發現蛀牙增加86%，而在有使用Chlorhexidine的組別中，蛀牙只有增加17%，蛀牙有五倍的降低顯示Chlorhexidine在牙科蛀牙治療的潛在效用。



Regulatory Status in the United States. Antiseptics are substances which, when applied to living tissue, kill or prevent the growth of microorganisms. They are too toxic to be administered systemically, so that a prime consideration concerning their usefulness is their therapeutic index. The therapeutic index is the relationship between the concentration that is effective against microorganisms and the concentration that produces harmful effects, such as local tissue irritation or interference with the mechanism of healing and tissue repair. Chlorhexidine has a high therapeutic index and appears to be one of the safest antiseptics known, causing no complications in healing when applied to such sensitive tissue as open burns. These considerations have led the FDA to approve a four percent chlorhexidine preparation Hibiclens® as a skin disinfectant. A preparation containing considerably less chlorhexidine, i.e., 0.12%, and intended for use in the mouth as an antigingivitis agent, was approved as a prescription medication in the late 1980s.



在美國管理的現況

消毒劑是放在活的組織上，殺死或避免微生物之增生的物質，它們的毒性以系統性給予會太強，所以主要效用的考量在於他們的治療指數，此治療指數是，有效抗微生物的濃度與造成傷害濃度之間的關係，例如局部組織刺激或組織恢復及修復機制的交互關係，Chlorhexidine有很高的治療指數，且顯然是目前所知安全的消毒劑，當使用在像開放性燒傷之敏感組織的癒合，也不會造成任何合併症，此考量使得FDA核准4%Chlorhexidine的Hibiclens做為皮膚消毒劑，使用較低濃度Chlorhexidine，例如0.12%，用在口腔中當作抗牙齦炎藥物，在1980晚期也核准使用做處方藥物。



This approval as a prescription medication has to do with certain unique side effects of chlorhexidine which, though not harmful in nature, are of some concern. The bitter taste of chlorhexidine is disagreeable and will require masking to make it palatable. Some individuals complained of a lingering effect that interfered with taste perception. However, the main problem is that related to the staining of the teeth. Frequent usage invariably leads to a yellow-brown stain on the teeth, which darkens with continued usage. This stain is readily removed by a dental polishing. Silicate restorations which become stained may have to be replaced. In a few individuals the use of daily mouthrinses over a four-month period was associated with desquamation and soreness. More recent studies of two or more years duration showed no mucous membrane disturbances associated with daily usage of a l0 ml mouthrinse containing 0.2 percent chlorhexidine. No blood, kidney or liver abnormalities were observed. The salivary flora was reduced by about 20 to 50 percent, without producing a detectable shift in the proportions of Gram-positive or Gram-negative organisms. The number of subjects from whom S. mutans could be isolated from saliva decreased during the treatment. In other clinical studies, S. mutans was found to be uniquely sensitive to low levels of chlorhexidine, while S. sanguis and various Capnocytophaga species can acquire a resistance to low levels of chlorhexidine. These data indicate that strong bacterial resistance to chlorhexidine, especially of cariogenic species, is not likely to occur with repeated usage of the drug.



此處方藥物的核准，Chlorhexidine還是有某些副作用，雖然不會造成傷害，但還是有一些疑慮。Chlorhexidine比較苦的味道是比較討厭的，且必須要掩蓋其味道使其能較令人接受。某些人抱怨其殘餘的作用會影響他們的味覺。然而，主要的問題還是在於造成牙齒的染色，頻繁的使用總是造成牙齒表面有黃棕色的染色，且會隨著持續使用染色更深，這些染色可以用牙科打磨快速的移除，含矽的填補物被染色後則可能須重新填補。在一些患者中，四個月連續每天的使用漱口水，會與脫皮脫削和疼痛有關，更多兩年或以上的近代實驗顯示，每天使用含有0.2%Chlorhexidine10ml的漱口水與口腔黏膜異常disturbance無關，沒有發現任何血液、腎臟或肝臟異常。唾液中微生物菌株群減少20-50%，且沒有產生測量的到之格蘭氏陽性或陰性菌的轉移。在治療的期間，可從唾液中分離出S. mutans的個體數目有減少。在其他的臨床研究，發現S. mutans對低濃度的Chlorhexidine是很敏感的，但S. sanguis和其他種Capnocytophaga細菌對低濃度的Chlorhexidine卻有抵抗力，這些資料顯示，重複使用這個藥物，並且特別是造成蛀牙的菌種，不會造成對Chlorhexidine有強的抵抗力。



Why then the FDA's reluctance to approve chlorhexidine as an over the counter agent? This is related to the stain which occurs with frequent usage. Although the stain is essentially a cosmetic problem, the FDA apparently does not want to approve an agent which will cause the user to seek professional treatment to undo a consequence of drug usage. This presumably would be an unwarranted escalation of cost to the consumer. The stain only occurs after several weeks usage and would not be a problem if the chlorhexidine were used for short periods of time, i.e., one to three weeks, as would be indicated by the specific plaque hypothesis.



為什麼FDA對核准Chlorhexidine可在市面上取得的藥品是很勉強的呢?這與其在經常使用下造成的染色有關，雖然這個染色只是美觀上的問題，但FDA明顯的不願意認可，會造成使用者尋求專業治療來消除藥物使用之合併症的藥品，這想必對消費者的花費會是無根據增多，染色只會在數周的使用後發生，且當Chlorhexidine短暫的使用，例如一到三周，特定性牙菌斑假說指出這並不會是問題。



Fluoride and Chlorhexidine Combinations



Could fluorides and chlorhexidine be combined in a single antimicrobial treatment schedule? Both antimicrobials are broad spectrum in their ability to inhibit bacteria and are substantive via different mechanisms at the tooth-plaque interface. Fluoride, by virtue of its ability to penetrate the enamel surface, could cause killing of those bacteria which have already invaded the incipient lesion. Chlorhexidine, because of its positive charge, would not penetrate these sites, so that its spatial range of activity would be confined to the tooth surface. Chlorhexidine would be active at neutral pHs, whereas fluoride would be most effective at acidic pHs. These spatial and pH considerations suggest that the two agents together would be more effective when used singly. In addition, the acidic pHs which characterize a cariogenic plaque should release both agents from the tooth surface and in the case of the fluoride, enhance its entry into the bacterial cell. Thus, a combination of these agents would be expected to yield impressive clinical reductions in dental decay.



氟化物與Chlorhexidine結合使用



氟化物與Chlorhexidine能否在單一抗菌治療中結合使用呢？兩種抗菌藥劑都有廣泛性抑制細菌的能力，且有在牙齒牙菌斑界面憑藉不同的機制作用的本質，氟，有能穿越牙釉質表面的能力，且可以殺死已經侵入初期蛀牙的細菌，Chlorhexidine，因為其帶正電性，不能穿越這些地區，所以其作用範圍侷限在牙齒表面，Chlorhexidine在中性pH值是有活性的，但氟則是在酸性pH值環境下效率較高，這個作用範圍及pH值得考量，顯示這兩種藥劑結合使用會比單獨使用來的有效，另外，容易造成蛀牙的牙菌斑酸性pH值，會從牙齒表面同時釋放出這兩種藥劑，在使用氟的情況下，加強其進入細菌細胞中，所以，結合這兩種藥劑，在牙科蛀牙預期會產生令人滿意的臨床效果。



Luoma and his colleagues evaluated the anticariogenic effect of mouthrinses and toothpastes containing either fluoride or a fluoride-chlorhexidine combination in children 11 to 15 years of age, and known to have high caries activity, i.e., an average DMFS of about 29 (Table 18-10). After the initial examination the children were randomly assigned to a chlorhexidine-fluoride group, a fluoride group, a placebo group and a control group, did not participate in the study except for the clinical examinations. The children brushed their teeth daily without toothpaste at school (200 days/year) under the supervision of a dental nurse. This was followed by rinsing for two minutes with ten ml of a solution containing either 0.044 percent fluoride (NaF) plus 0.05 percent chlorhexidine, 0.044 percent fluoride or placebo. The children, in addition, brushed their teeth at home with a toothpaste having the same composition as their respective rinsing solutions.



Luoma及其同事評估，在高蛀牙率11-15歲的孩童中，例如平均有29個DMFS(表18-10)，使用含氟或含氟與Chlorhexidine結合漱口水及牙膏的抗蛀牙能力，在實驗剛開始所有孩童被隨機的分配到氟化物及Chlorhexidine結合組，氟化物組，安慰劑組，及對照組。沒有參加臨床檢查則不納入此實驗，在牙科護士的指導下，每個孩童在每個上學日(一年兩百天)不用牙膏刷牙，接著使用含0.044% NaF及0.05% Chlorhexidine漱口水10ml漱口兩分鐘，除此之外，每個孩童在家使用與學校漱口水相同成分的牙膏刷牙。



This study design did not permit an evaluation of the effect of chlorhexidine alone on caries incidence, but did demonstrate the magnitude of the placebo effect, which in this case was about 20 percent (Table 18-10). Fluoride alone was able to significantly reduce caries incidence compared to the no-treatment control group, but not when compared to the placebo group. In this context other studies which had no placebo group need to be reevaluated, i.e., the Karlstad study (Figure 13-3). The chlorhexidine plus fluoride group had a significantly lower caries incidence than both the placebo and control groups. This reduction manifested itself on the approximal (73 percent reduction compared to control) and smooth (66 percent reduction) surfaces. On the occlusal surfaces the chlorhexidine-fluoride combination was without effect, probably due to the inability of these charged molecules to penetrate into the depths of the fissure. Mild staining of the teeth was observed only in a small proportion of the chlorhexidine-treated subjects.



在此實驗設計沒有允許評估單獨使用Chlorhexidine在蛀牙產生的影響，但是卻證明了安慰劑的重大影響，在此實驗中約有20%(表18-10)。單獨使用氟與沒有使用任何治療藥物的對照組比較，蛀牙有明顯的降低，在此背景下，其他沒有安慰劑組別的研究必須被重新評估，例如Karlstad的實驗(圖13-3)，在Chlorhexidine加入氟的組別與安慰劑及對照組比較，有明顯更低的蛀牙率，這個降低量證實在鄰接面(與對照組相比有73%的降低量)，在平滑面(有66%的降低)，在咬合面，Chlorhexidine與氟的結合組別並沒有特別的作用，可能是因為其帶電分子無法穿入溝隙的深度中，牙齒輕微的染色只在一小部分的Chlorhexidine組別中的個體發現。



This investigation indicates that fluoride and chlorhexidine can be used in combination in order to obtain an additive or possibly synergistic effect on caries reduction. The significant decline in caries was achieved with a daily dosage that for fluoride, was about one tenth of that used in the Cheektowaga studies and for chlorhexidine, was about one fourth of that used in most plaque inhibition studies. Whether this fluoride-chlorhexidine combination will be considered safe enough to be dispensed as a nonprescription mouthrinse or dentifrice, which could be used by the public in an unsupervised fashion, remains to be seen. The therapeutic principle seems to be valid.



此研究調查顯示，氟與Chlorhexidine結合使用可得到一個對蛀牙減低的附加或協同作用，每天使用能讓蛀牙明顯降低的氟劑量是在Cheektowaga研究中的十分之一，而Chlorhexidine的劑量在多數牙菌斑抑制實驗中，則是約四分之一。氟與Chlorhexidine的結合做為非處方簽漱口水或牙膏的配方，是被大眾視為可在不需指導下使用，其是否被視為足夠安全仍舊被關注，不過治療的原則是有根據的。



SUMMARY



Penicillin, fluoride and chlorhexidine can reduce dental caries incidence in children when taken daily on an open-ended treatment schedule. Penicillin, or any other medically important antibiotic, need not and should not be used to achieve these results. In the successful studies the agents achieved some degree of prolonged contact time with the plaque flora: the penicillin by daily systemic administration; the fluoride and chlorhexidine by unique substantive characteristics of the agent on the tooth surfaces. These results validate the therapeutic principle of using antimicrobials to treat dental decay. Daily treatments are expensive to deliver and can give rise to cosmetic concerns such as tooth staining with chlorhexidine and enamel mottling with fluoride. Additional studies are needed to determine the optimal dose levels of fluoride and/or chlorhexidine, optimal length of treatment periods and better criteria for patient selection. This last consideration is at the center of the distinction between the nonspecific and specific plaque hypotheses and will be addressed in the next chapter.



總結



青黴素、氟化物及Chlorhexidine當孩童每天使用可以降低蛀牙發生率，青黴素或其他醫學重要的抗生素，不需且不該被用來達到降此蛀牙的目的，在成功的研中，這些藥劑達到某種與牙菌斑菌株群延長接觸的程度：每天系統性給予青黴素，氟及Chlorhexidine在牙齒表面藥劑獨特堅固的性質。這些結果使使用抗菌藥物來治療牙科蛀牙的治療原則有效，每天給予治療是很昂貴的，且在美觀上的疑慮增高，例如使用Chlorhexidine造成牙齒的染色，或使用氟造成牙釉質氟斑，還需要額外的研究來決定氟或Chlorhexidine理想的劑量，理想使用的時間，及選擇病人的條件。最後的考量，在接下來的章節會闡述非特定及特定牙菌斑假說之間差異的主軸。