Drug Interactions in Dentist

DentalPharmacology

458 DentalUpdate October 2009

Robin A Seymour

Drug Interactions in DentistryAbstract: An increasing number of our patients are on medication of various types. This increase in prescribed medicines also raises the significant issue of potential drug interactions between those drugs used in dental practice and those taken by the patient. This article addresses those interactions and, where appropriate, puts them into perspective and attempts to quantify the risk. Mechanisms of relevant drug interactions are also discussed. Certain categories of drugs are more likely to be involved in interactions and again these are highlighted. Drug interactions relevant to dentistry can for the most part be prevented. A careful drug history should be taken from each patient and updated on a regular basis.Clinical Relevance: This article highlights drug interactions that can arise in dental practice and how they can be avoided and managed.Dent Update 2009; 36: 458470

Drug interactions are quite simply an interaction between two or more medications that the patient may be prescribed. In the dental setting, such interactions may occur between those drugs prescribed or administered in dental practice and the patients current medication.

It is now widely recognized that our patients are living longer and retaining their teeth into old age. One major contribution to this increase in life expectancy is improved medication and a greater choice of drugs to treat the frequent age-related illnesses. It has been estimated that 75% of the population over the age of 55 are taking medication in order to sustain various bodily functions.1 As the number of patients taking one or more drugs increases, the risk of drug interactions between the patients medication and those drugs commonly prescribed in dental practice, will also increase. As new drugs are developed and come into clinical practice, the risk of drug interactions should always be considered.

Broad principles of drug interactions

Drug interactions can involve

a variety of mechanisms and their significance can relate to certain categories of drugs and/or their pharmacological properties. For example, a drug with a low therapeutic index, that is also extensively protein bound, is susceptible to drug interactions. The therapeutic index of a drug is a measure of the ratio of the median lethal dose (LD

50) to the median effective dose

(ED50

). The lethal dose is the dose of drug required to be lethal for 50% of a group of animals. ED

50is the dose required to

produce a response in 50% of subjects

Robin A Seymour, Professor of Restorative Dentistry, School of Dental Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4BW, UK.

tested. The therapeutic index of a drug gives some idea of its margin of safety. A drug with a low (narrow) therapeutic index is potentially less safe than a drug with a high (wide) therapeutic index (eg warfarin and digoxin).

Other principles of drug interaction can be considered in terms of pharmacokinetic and pharmacodynamic properties. Pharmacokinetic interactions can be further categorized under the headings of absorption, distribution, metabolism and excretion.

Figure 1. Interaction between tetracyclines and various metallic ions found in antacids.

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October 2009 DentalUpdate 459

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Pharmacokinetic interactions

Drug absorption

Most drugs are absorbed in the upper part of the gastro-intestinal tract. Absorption depends upon factors such as a drugs ability to survive the low gastric pH, the effect of food, and the formation of irreversible complexes with other drugs or constituents of food. Benzylpenicillin is deactivated by gastric acid and so can only be given by injection. The pH of the stomach affects the absorption of the antifungal agent ketoconazole, where the acidic conditions aid dissolution prior to absorption. Drugs which reduce the acidity of the stomach, such as antacids, H

2receptor

blockers (ranitidine) and proton-pump inhibitors (omeprazole) will reduce the absorption of ketoconazole.2

Tetracyclines form chelates with divalent and trivalent cations (eg Al3+, Bi2+,Ca2+, Fe2+, Mg2+, Zn2+) (Figure 1). Chelated tetracyclines are poorly absorbed, resulting in reduced antimicrobial activity. Salts of aluminium, calcium and magnesium are the main ingredients of antacids; also the ACE-inhibitor quinapril contains magnesium carbonate. These drugs should be avoided if a patient is prescribed tetracyclines. In addition, some food substances contain calcium ions, especially dairy products, and hence patients prescribed tetracyclines should be advised not to take milk, indigestion remedies or medicines containing iron or zinc at the same time of day. Incompatible preparations should be taken 23 hours apart. Ideally, tetracyclines should be taken on an empty stomach or 60 minutes before or after food.3

Drug distribution

When a drug is absorbed from the gastrointestinal tract it is often distributed in the bloodstream bound to plasma protein. The bound portion is considered pharmacologically inert, whereas the so-called free or unbound portion may interact with the receptor binding site. The number of binding sites is limited and other drugs compete for the protein bindingsite, resulting in an increase in the free pharmacologically active portion.

Displacement of one drug from its binding site by another drug that competes for the same binding site will have a significant effect on the amount

of free or pharmacologically active drug. This is illustrated by the anticoagulant drug warfarin, which has a low therapeutic index and is 9899% protein-bound. Aspirin and other non-steroidal inflammatory drugs are also extensively protein-bound. If aspirin is given to a patient on warfarin, then more of the anticoagulant will be displaced from the binding site, causing an increase in the free, pharmacologically active warfarin. The result of such an interaction is an increase in the patients INR and a serious haematological risk (see later). This type of drug interaction is illustrated in Figure 2.

The problem with warfarin is compounded by its low therapeutic index. Warfarin is 99% protein-bound, with only 1% available to affect blood coagulation. If a further drug is administered that reduces warfarin binding from 9998%, then the amount of free or active warfarin increases from 12%. This is a 100% increase in the amount of pharmacologically active warfarin, which will raise the patients INR.

All drugs which exhibit more than 90% protein binding are at a significant risk from drug interactions. Within this category are, in addition

Figure 2. (a) Aspirin and warfarin in terms of protein binding. (b) Diagram to show the interaction between aspirin and warfarin in terms of competition for protein-binding sites.

a

b


DentalPharmacology


to warfarin, oral anti-diabetic drugs (chlorpropamide and other sulphonylureas), and the anti-epileptic drug, phenytoin.

Drug metabolism

Many drugs are metabolized (biotransformed) in the liver, rendering the drug inactive, or changing its physico-chemical properties to make it easier to excrete. The liver also biotransforms inert pro-drugs to more active metabolites. This is the case with codeine, the metabolite morphine being more pharmacologically active than the parent drug.

Drugs biotransformed in the liver by enzymes are collectively known as drug metabolizing enzymes (DME). Of the various DMEs, the ones most frequently the target of drug interactions are the cytochrome P450 isoenzyme system.4 The cytochrome P450 nomenclature is as follows: CYP stands for cytochrome P. This is followed by a number representing the subfamily and then another number representing the individual gene. The cytochrome enzymes most frequently involved in drug interaction include CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4.

These CYP45O enzymes can be induced or inhibited by drugs. For example, although not particularly relevant to dentistry, the anti-tuberculosis drug rifampicin induces the CYP450 enzyme that metabolizes the oral contraceptive, leading to pill failure.5

By contrast, the antibiotic erythromycin is an enzyme inhibitor for CYP3A4, which includes the enzyme responsible for the biotransformation of simvastatin and atorvastatin.6 This interaction can potentially increase the risk of statin-induced myopathy (Figure 3).

It should also be recognized that other substances, which may not be regarded by patients as drugs, can also have an effect on the cytochrome P450 group of enzymes. Alcohol, smoking, various recreational drugs and even char-grilled meats have been identified as enzyme inducers. Grapefruit juice has been shown to be an enzyme inhibitor. Grapefruit juice consumption prior to oral midazolam sedation could be problematic. Taking 200 ml of grapefruit juice two hours before oral midazolam can double the plasma concentration of this benzodiazepine.7 Whilst such high levels of midazolam should not present a serious problem in an otherwise

healthy adult, this could be problematic in a child or a medically compromised patient.

Drug excretion

The kidney is the main site of drug excretion. Renal excretion of drugs often involves an energy-dependent, multi-drug efflux pump known as P-glycoprotein. As with drug metabolizing enzymes, certain drugs can induce or inhibit P-glycoprotein. An inducer of P-glycoprotein will result in more drug excretion, whilst the converse will apply to an inhibitor. The latter will raise serum concentration and increase the risk of toxic effects.

Of dental relevance under this category is the ability of non-steroidal anti-inflammatory drugs, such as ibuprofen or diclofenac, to inhibit the renal excretion of lithium.8 Lithium has a narrow therapeutic index and a raised serum concentration can lead to severe renal and CNS toxicity.

Competitive inhibition is a further process of drug interactions involving excretion. Weak acids, such as the penicillins, may compete with methotrexate in the renal tubules for excretion, so that there is an increase in serum methotrexate and increased toxicity. NSAIDs inhibit the synthesis of prostaglandins, which results in a fall in renal

Figure 3. Schematic diagram to illustrate the effect of drug interactions involving hepatic drug metabolizing enzymes (DMEs).

Erythromycin(enzyme inhibitor)

Rifampicin(enzyme inducer)

LIVER DMEs

SimvastatinContraceptive pill

Increased risk ofsimvastatin-induced

myopathy

Reduced plasma concentration

of the contraceptive pill, increasing the risk of pill

failure



DentalPharmacology

perfusion. This could lead to a rise in serum methotrexate level and likewise increased toxicity.

Pharmacodynamic drug interactions

Pharmacodynamic interactions

are those where the action of one drug is enhanced by the action of another. These actions may be additive or synergistic, where the pharmacological effect is greater than the simple sum of either drug alone. Pharmacodynamic interactions occur at the site of drug action, often at receptor level. Examples of pharmacodynamic drug

interactions include the antiplatelet action of aspirin and the anticoagulant effect of warfarin, atropine and tricyclic antidepressants (antimuscarinic effect), and opioid analgesics and alcohol (sedative CNS effect). More recent evidence has shown that non-steroidal anti-inflammatory drugs, such as ibuprofen and diclofenac, interact with selective serotonin

Antibiotic Interacting drug Mechanism Outcomes and recommendations

Erythromycin Theophylline, aminophyline Inhibition of CYP3A4 Increase in plasma concentrations of theophylline(systemic broncho-dilator) leading to tachycardia, dysrythmias, tremors-

seizure. Avoid prescribing erythromycin.

Erythromycin Simvastatin Inhibition of CYP3A4 Increase in plasma concentration of simvastatin leading to increased risk of myalgias, rhabdomyolysis and renal failure. Avoid prescribing erythromycin or, if the antibiotic is essential , then stop taking simvastatin.

Erythromycin Ciclosporin and tacrolimus Inhibition of CYP3A4 Increase in plasma levels of both immunosuppressives leading to excessive immunosuppression and increased risk of renal toxicity. Avoid prescribing erythromycin if possible.

Erythromycin Warfarin Inhibition of CYP3A4 Increase in plasma concentrations of warfarin leading to a raised INR and increased risk of bleeding.

Concurrent use need not be avoided as erythromycin-induced inhibition of CY3PA4 is somewhat unpredictable.

Erythromycin Carbamazepine Inhibition of CYP3A4 Increase in levels of carbamazepine leading to increased risk of drowsiness, ataxia and confusion. Avoid erythromycin.

Erythromycin Midazolam Inhibition of CYP3A4 Increase in plasma concentration of midazolam leading to excessive and prolonged sedation. Avoid erythromycin for some 12 hours before iv sedation with midazolam.

Metronidazole Alcohol Blocks enzyme Increase in levels of acetaldehyde which producesacetaldehyde flushing, headache, nausea and palpitations. Avoiddehydrogenase which alcohol consumption during metronidazole therapyconverts acetaldehyde and for at least 2-3 days after completing course.to acetic acid

Metronidazole Warfarin Inhibition of CYP3A4 Increase in plasma concentrations of warfarin leading to a raised INR and increased risk of bleeding. Avoid metronidazole.

Erythromycin Calcium channel blocks, Inhibition of CYP3A4 Increase in plasma concentration of nifedipineeg nifedipine resulting in severe risk of hypotension and oedema

formula. Avoid erythromycin.

Table 1. Possible drug interactions arising from antibiotic prescribing.


DentalPharmacology


reuptake inhibitors (eg Prozac). As both drugs have an effect on platelet aggregation, this interaction increases the risk of a NSAID-induced gastrointestinal bleed.9

Drug interactions that are significant in dental practice

Dental practitioners prescribe relatively few categories of drugs and this section will focus only on three widely used categories: Antibiotics; Analgesics; and Local anaesthetic solutions.

Drug interactions involving antibiotics

A synopsis of possible drug interactions relating to antibiotic prescription is shown in Table 1.

Some of the drug interactions involving antibiotics are worth highlighting.

Metronidazole, erythromycin and warfarin

Both antimicrobials inhibit liver enzymes CYP2C9 (metronidazole) and CYP3A4 (erythromycin). These enzymes are involved in the metabolism of warfarin (especially CYP2C9) and their inhibition will lead to an increase in plasma concentrations of warfarin, leading to an increased INR and risk of bleeding.10 If either antibiotic is essential in the management of a patients infection, then control of the infection should take precedent. It would be worthwhile informing the patients physician before prescribing metronidazole. An antibiotic-induced change in hepatic metabolism of warfarin, and hence an increase in INR, is likely to be of short duration. Despite this, it is essential to check the patients INR if he/she has recently (within two to three days) completed a course of either metronidazole or erythromycin.

Bactericidal and bacteriostatic antibiotics

Antibiotics have two modes of action against bacteria; they either destroy them (bactericidal) or stop them dividing (bacteriostatic). Table 2 provides a list of antibiotics used in dentistry categorized according to their mode of action. Bactericidal antibiotics are more effective if the bacteria that they are targeting are dividing. Theoretically, therefore, administration of a bacteriostatic agent will reduce significantly

the efficacy of the bactericidal drug. For example, tetracycline or erythromycin should not be prescribed to a patient taking penicillin or metronidazole. However, clinical evidence to support this is not strong. There is no rationale for using such a combination in dentistry for the management of odontogenic infections.

Antibiotics and oral contraceptives

An oral contraceptive pill contains a combination of oestrogen and progestogen (combined oral contraceptive, COC) or progestogen alone (progestogen only pill, POP). There are two ways in which oral contraceptives can be affected by antibiotics: first, their metabolism can be induced leading to lower levels of the circulating hormones and thus failure of effect. This can occur with the antibiotic rifampicin; secondly, by their effect on the gut flora, eg amoxicillin,

erythromycin and the tetracyclines. Antibiotics used in dentistry will affect the gut flora.

Although numerous case reports have appeared in the literature indicating that systemic antibiotic therapy has resulted in pill failure, evidence from controlled trials are lacking. Following initial absorption of the oestrogen component of a COC, it undergoes conjugation with glucuronic acid in the liver. Once conjugated, the oestrogen is pharmacologically inactive and is excreted via the bile into the gut. In normal circumstances, the conjugate is hydrolysed by colonic bacteria, which releases the oestrogen to be reabsorbed for the suppression of ovulation. This process is illustrated in Figure 4. Thus a viable gut flora is thought to be necessary for oestrogen metabolism and pill efficacy. As progestogen does not undergo enterohepatic recycling, POPs are not affected by antibiotics. Many antibiotics reduce the gut flora and thereby there is, in theory, an increased risk of pill failure. As there is no easy way of determining the effect of the gut flora in reducing circulating levels of oestrogen, all women taking the COC pill should be considered at risk from pill failure if prescribed systemic antibiotics. The overall failure rate of oral contraceptives in women taking systemic antibiotics may be no greater

Bacteriostatic BactericidalTetracyclines PenicillinsErythromycin CephalosporinsClindamycin Metronidazole

Table 2. Classification of antibiotics used in den-tistry by their mode of action.

Figure 4. Interaction between broad spectrum antibiotics and COC.



DentalPharmacology

than when taking oral contraceptives alone. It is recommended that all female patients taking the pill are warned of the risk of pill failure if prescribed systemic antibiotics and to use additional methods of contraception during the antibiotic therapy, and for at least one week after the last antibiotic dose.11 If these seven days run beyond the end of a packet, the next packet should be started immediately without a break.

Drug interactions involving analgesic agents

In dental practice, analgesics are frequently prescribed as short 35 day courses for the management of post-operative pain after a dental or oral surgical procedure. Drug interactions involving analgesics are summarized in Table 3.

Combinations of non-steroidal anti-inflammatory drugs (NSAIDs) to control post-operative pain will not result in additional analgesia, however, it will increase the risk of adverse effects. For example, using both aspirin and ibuprofen to treat post-operative pain increases the risk of gastro-intestinal problems and ulceration. There is also an interaction between ibuprofen or other NSAIDs and low dose aspirin taken for vascular and cerebrovascular protection.12 A single dose of ibuprofen 400 mg, when taken before aspirin, has been shown to reduce aspirins antiplatelet effect by up to 50%. If ibuprofen is taken after aspirin, the effect on aspirin-induced antiplatelet activity is minimal. If ibuprofen or other NSAIDs are prescribed to a patient taking low dose aspirin, then the patient should be advised to take the aspirin before the NSAID.13

NSAIDs, aspirin and selective serotonin re-uptake inhibitors (SSRIs) can interact to increase the risk of bleeding. SSRIs, eg fluoxetine (Prozac), citalopram, paroxetine, and sertraline also inhibit serotonin re-uptake in platelets. Serotonin is normally released from platelets as a response to injury and has an important role in regulating the haemostatic response by potentiating platelet aggregation. NSAIDs and aspirin also affect platelet aggregation by blocking thromboxane synthesis and release. This interaction is illustrated in Figure 5. The major significant risk from this interaction is a gastro-intestinal bleed; when both drugs are used concurrently the risk of a bleed increases 1516 fold.14 This increased risk of a GIT bleed

Figure 5. Schematic diagram to illustrate interaction between aspirin and NSAIDs with SSRIs leading to an increased risk of bleeding.


DentalPharmacology


should be compared with a 45 fold increase when NSAIDs are used alone. In view of the significance of this interaction, NSAIDs should be prescribed with caution to patients taking SSRI. The addition of a gastroprotective agent, eg a proton pump inhibitor (omeprazole), should be considered if this combination is essential. Paracetamol can be used as an alternative.

Drug interactions involving local anaesthetic agents

The three main local anaesthetic drugs used in dental practice are lidocaine, prilocaine and articaine. All are amide agents and, when used at normal doses, have

an excellent safety record. Most of the concerns with local anaesthetic agents and drug interactions reside with the vasoconstrictor component, in particular, adrenaline. This vasoconstrictor is an agonist at both A-1 and B2 adrenergic receptors. A-1 stimulation causes vasoconstriction in the skin and mucous membranes, whilst B2 activity results in vasodilatation in skeletal muscles. These actions of adrenaline are short lived owing to its short half-life in the bloodstream.

A considerable amount of conjecture has surrounded many possible drug interactions involving adrenaline and related compounds and these will be discussed below.

Adrenaline and B-adrenoreceptor blockers (Beta -blockers)

Beta-blockers are widely used for the treatment of a range of cardiovascular problems, in particular hypertension, angina and disorders of cardiac rhythm. They are categorized as being either selective (block B1 receptors only) or non-selective, blocking both B1and B2 receptors. Potential interactions between adrenaline and beta-blockers depend upon the type of beta-blocker and the systemic absorption of adrenaline. For example, an intravenous infusion of adrenaline (0.0160.032 g), when given to hypertensive patients on propanolol therapy (a non-selective beta-blocker),

Analgesic Interacting drug Outcome and recommendation

Paracetamol Alcohol Increased risk of paracetamol toxicity and liver damage. Daily(acetaminophen) dose of paracetamol should not exceed 4000 g (8 tablets) and

for alcoholics this should not exceed 2000 g (4 tablets).

Aspirin and other non-selective Alcohol Increased risk of gastro-intestinal toxicity. Analgesic intake andcyclo-oxygenase inhibitors, eg alcohol consumption should be separated by 12 hours.ibuprofen

Non-steroidal anti-inflammatory Antihypertensive drugs, NSAIDs can affect renal function and causes salt and waterdrugs, eg ibuprofen especially beta-blockers retention which can antagonize antihypertensive drugs. This

(atenolol), ACE inhibitors only becomes a clinical problem if such analgesics are(lisinopril) and diuretics prescribed for more than 5 days. Limit analgesic usage to this

timeframe for patients on antihypertensives.

NSAIDs, eg ibuprofen Methotrexate The effects of NSAIDs on renal perfusion are described above. This increases the risk of methotrexate toxicity. Avoid NSAIDs whenever possible in patients taking methotrexate.

NSAIDs, aspirin Selective serotonin Both drugs affect platelet function and increase the risk of post-reuptake inhibitors, eg operative bleeding and bleeding from the gastro-intestinal tract.fluoxetine Avoid concomitant use.

Aspirin Warfarin Increased risk of bleeding: displacement of warfarin from protein-binding sites and both drugs affect haemostasis. Avoid aspirin in patients taking warfarin.

Aspirin Clopidogrel Both drugs affect platelet function and therefore increase risk of bleeding. Avoid analgesic doses of aspirin.

Aspirin, NSAIDs Systemic corticosteroids Both categories of drugs are ulcerogenic and increase the risk of gastro-intestinal bleeding. Avoid aspirin and NSAIDs in patients on systemic corticosteroids unless they are taking anti- ulcer drugs.

Table 3. Synopsis of drug interactions with commonly prescribed analgesics.



DentalPharmacology

cause a significant rise in both systolic and diastolic blood pressure.15 The dose of adrenaline used in this study is equivalent to 12 cartridges of adrenaline-containing local anaesthetic solution (2550 g). By contrast, when the same group of patients were treated with a cardio-selective beta-blocker (atenolol), there was only a slight rise in blood pressure.

Whilst these findings were in hypertensive patients, similar observations have been found in health volunteers; selective beta-blockers, such as atenolol, metoprolol, and acebutolol, can block an adrenaline-stimulated increase in blood pressure.16

The interaction between adrenaline and non-selective beta-blockers (eg propanolol, nadolol, sotalol) is potentially serious, but is dose-related and will be more pronounced if adrenaline is given, inadvertently, intravenously.15 Some authors recommend that patients on non-selective beta-blockers are given a test dose of 1 cartridge of an adrenaline-containing local anaesthetic solution. If there is no significant increase in blood pressure, then it is safe to give up to two cartridges of this anaesthetic agent. A 25% increase in either systolic or diastolic blood pressure would be considered significant.17

Whilst caution should always be exhibited when giving local anaesthetics, it is important to ensure adequate analgesia for the dental procedure to be undertaken. Inadequate pain control can bring about a significant increase in endogenous adrenaline production.

An adrenaline-containing retraction cord should be completely avoided in patients taking non-selective beta-blockers. Such a cord can contain as much as 0.5 mg of adrenaline, equivalent to 0.2 mg/cm.18

Adrenaline and tricyclic antidepressants

Tricyclic antidepressants produce their therapeutic effect by blocking the reuptake of noradrenaline at central synapse. The excess of noradrenaline in the synapse means that administration of adrenaline can

have a significant effect, notably in the cardiovascular system, leading to an increase in blood pressure.

Animal experiments have shown that such an interaction can occur, but only if the adrenaline dose exceeds the equivalent of seven cartridges of local anaesthetic solution.19 It is recommended that no more than three cartridges of adrenaline-containing local anaesthetic solution should be given at any one time to patients on tricyclic antidepressants.20

There is also a suggestion that chronic dosing of tricyclic antidepressants can result in desensitization in response to adrenaline as a consequence of down regulation of post synaptic receptors.21

Atomoxetine is used in the management of attention deficit hyperactivity disorder. It has a similar mode of action to the tricyclic antidepressants and the same caution, with respect to the number of cartridges of adrenaline-containing local anaesthetic solution used, should also apply to patients on this medication.

Adrenaline and non-potassium sparing

diuretics

Adrenaline has an impact upon metabolism and, in particular, causes a decrease in plasma potassium levels.22 Such fluctuations in potassium levels may be significant in those patients taking non-potassium sparing diuretics. Such diuretics include the thiazide group, eg bendroflumethiazide, and loop diuretics, eg furosemide. Adrenaline-containing local anaesthetics are likely to cause disorders of cardiac rhythm in patients taking these diuretics and the recommendation is not to exceed three cartridges of anaesthetic solution in those patients.23

ConclusionsDrug interactions are

important and can lead to significant morbidity and even mortality. Fortunately, the latter is a rare occurrence in connection with dental prescribing. Dentists prescribe a limited range of drugs and, for the most part, these are safe. However, interactions can occur and it is essential to take a full drug history from

patients at every visit. Many patients know their drugs only by the trade name and it must then be checked in the Formulary. If in doubt, contact the patients general medical practitioner. There are certain categories of drugs that are more likely to be involved in drug interactions, notably those that are extensively protein-bound, those with a low therapeutic index, and those drugs metabolized by the CYP450 enzymes. Drug interactions can be minimized in the dental setting by taking a full drug history and using alternative drugs where indicated, or dose reductions.

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clinical patients. J Prosthet Dent 1992; 68:761765.

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