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News 09/09/2544


CLINICAL SIGNIFICANCE OF ANTIRETROVIRAL DRUG LEVELS
The present approach of administering a standard fixed dose of an antiretroviral drug to all adults is not likely to ensure the optimal anti-HIV response, and strategies that integrate pharmacologic knowledge into the design of dosing regimens warrant careful evaluation

ORAL CARE AND DENTINAL HYPERSENSITIVITY
In a typical workday, the retail pharmacist may field several questions about oral care and oral discomfort. Patients may complain about one or more teeth that are intermittently painful.

ULTRA-LOW-DOSE ORAL CONTRACEPTIVE EFFECTIVELY TREATS ACNE
An ultra-low-dose oral contraceptive has been shown to be just as effective in treating acne as pills with higher doses of estrogen.

AS A CLASS, HIGHER-PRICED NEW DRUGS REDUCE NEED FOR HOSPITALIZATION
Despite carrying a higher price tag, newer brand-name medications reduce overall health spending more than older, lower-priced drugs.


Clinical Significance of Antiretroviral Drug Levels

Courtney V. Fletcher, PharmD.

[Medscape HIV/AIDS: Annual Update 2001. © 2001 by iMedOptions, LLC.]


Introduction

The use of highly potent combination antiretroviral regimens has achieved a reduction in the morbidity and mortality associated with HIV-1 infection.[1] This success is tempered by rates of virologic failure that have ranged from 20% to 67% among therapy-naive persons receiving these potent drug combinations in clinical trials and in clinical practice.[2-6] Variability in the response to antiretroviral agents has been attributed to pharmacokinetic, virologic, immunologic, and behavioral differences between patients.[7-9] All antiretroviral agents currently used for the treatment of HIV infection share certain properties. Interpatient variability in pharmacokinetic disposition is uniformly present; consequently, the current practice of administering the same dose to all patients produces different systemic and intracellular concentrations. The anti-HIV effect of these drugs is related to the concentration in the body. Therefore, subtherapeutic drug concentrations contribute to variability in virologic response. A series of recent publications has noted the ability of drug-sensitive HIV to replicate despite ongoing therapy with 3 or 4 antiretroviral drugs.[10-12] An International AIDS Society-USA consensus statement warned that the presence of suboptimal drug concentrations "will permit ongoing viral replication and favor emergence of resistant virus over time."[9] The current approach of a standard fixed dose for all adults represents a significant gap in the application of pharmacologic principles to antiretroviral therapy, and will likely result in certain patients not deriving the maximum therapeutic benefit from these agents.

Concentration and Effect Relationships

A general principle of pharmacology is that the intensity and duration of drug effect are related to the dose administered, the concentration of the drug in the body, or both.[13] This principle is underscored by the common use of dose escalation studies early in the drug development process, to identify doses that have acceptable safety and tolerance and achieve the desired pharmacologic effect. Concentration-effect relationships are less commonly sought, which is unfortunate because relationships between drug dose and effect that are not apparent may be revealed when drug concentrations are examined.

Figure 1 is a conceptual model of the continuum of antiretroviral therapy: After a dose is taken, a certain concentration of the compound is achieved in plasma and subsequently at the pharmacologic site of action inside the infected cell, which results in inhibition of viral replication, leading to a decrease in the HIV-1 RNA level in plasma and an increase in the CD4+ cell count.

figure 1


Figure 1. Continuum of Antiretroviral Therapy
Each box in Figure 1 highlights a source of variability that contributes to individual differences observed in the response to antiretroviral therapy. For example, a patient's adherence to the prescribed regimen directly affects the amount of drug that is available for absorption. The actual dose administered is also important; in antiretroviral therapy, there have been several cases in which suboptimal dosing regimens of potent agents have been demonstrated to be associated with worse outcomes (eg, the poorer results seen with saquinavir hard-gel vs saquinavir soft-gel, or with indinavir administered twice-daily vs 3-times-daily). The pharmacokinetic processes of absorption, distribution, metabolism, excretion, and protein-binding subsequently govern the amount of drug that is present in the systemic circulation and at the site of action. Considering drug metabolism solely, at least a 20- to greater than 1000-fold range in the amount of various cytochrome P450 isoforms has been demonstrated.[14,15] This provides a physiologic basis for variability in systemic concentrations for drugs that are substrates for cytochrome P450-catalyzed oxidative metabolism, such as HIV protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). PIs and NNRTIs are highly bound to plasma proteins, and differences in binding also contribute to variability in concentrations at the pharmacologic site of action; for example, the investigational protease inhibitor SC-52151 was orally absorbed and achieved plasma levels expected to be therapeutic, but its development was halted by the discovery that it was highly (70%) bound to alpha1 acid glycoprotein and plasma proteins, severely reducing cellular uptake, which explained the lack of any clinical anti-HIV effect.[16,17]

Drug-drug and drug-food interactions and concomitant disease states further accentuate pharmacokinetic variability. It is important to keep in mind that many HIV-infected patients take herbal products which may also have significant interactions with prescribed medications. For example, the effect of garlic supplements on the pharmacokinetics of saquinavir was recently determined in 10 healthy volunteers.[18] In the presence of the garlic supplement, mean trough concentrations of saquinavir decreased 49% from 108 to 55 ng/mL (range, -82% to +33%; P = .002), AUC decreased 51% from 3382 to 1673 ng*h/mL (range, -84% to +12%, P = .007), and Cmax decreased 54% from 1190 to 543 ng/mL (range, -88% to +30%, P = .006). After a 10-day washout, the trough, AUC, and Cmax had only returned to 60% to 70% of baseline values. These data, like previous studies of the effects of St. John's wort,[19] indicate that commonly used herbal products can have significant adverse interactions with PIs.

The active moiety of nucleoside reverse transcriptase inhibitors (NRTIs) is not the parent compound, but rather the triphosphate anabolite formed intracellularly. The amount of triphosphate formed is the aggregate of several processes.[20,21] NRTI agents have differing anti-HIV activity in stimulated and resting cells, relationships between systemic concentrations of the parent drug and the intracellular triphosphate are complex and multifactorial, and variability in plasma concentrations contributes to variability in intracellular concentrations.

Recent studies have provided evidence that genetic variability in drug transport proteins and drug-metabolizing enzymes may influence the differences in plasma drug concentrations among patients. Allelic variations in P-glycoprotein and CYP2D6 were analyzed in 63 white patients with plasma HIV-1 RNA levels less than 400 copies/mL receiving PI- or efavirenz-containing regimens.[22] Multivariate logistic regression found that the patients with high drug concentrations had a greater likelihood of having a CC allele (Pgp) and/or a poor metabolizer genotype for CYP2D6 (odds ratio [OR], 2.2; 95%CI, 1.5-3.4). Patients with low drug concentrations were more likely to have a TT allele (Pgp) and/or an ultra-fast metabolizer genotype for CYP2D6 (OR, 8.4; 95%CI, 2.0-35.4). In another study of 49 patients, those individuals who overexpressed MDR-1, the gene that encodes for P-glycoprotein, had significantly lower trough intracellular concentrations or penetration of PIs.[23]

Collectively, interpatient differences in pharmacokinetic characteristics will result in different systemic and intracellular concentrations among patients taking the same dose. For example, zidovudine concentrations in the plasma 1 hour after an observed 100-mg dose ranged 6-fold (from 0.54 to 3.07 mcM) in 30 HIV-infected persons,[24] and trough concentrations of indinavir in 43 subjects following an observed 800-mg oral dose ranged 85-fold (from 0.02 to 1.7 mg/L).[25]

Relationships Between Drug Concentrations and Anti-HIV Effect

Relationships have been described for all 3 classes of antiretroviral agents between the amount of drug on the body and anti-HIV effect.[8,26]

Nucleoside Reverse Transcriptase Inhibitors. In a randomized, cross-over study of concentration-controlled zidovudine monotherapy compared with standard-dose (500 mg/day) zidovudine monotherapy, the CD4+ cell counts of subjects assigned initially to receive the concentration-controlled regimen remained above baseline for significantly longer than those of subjects who initially received standard therapy (median, 21 weeks vs 14 weeks; P = .01).[20] Intracellular concentrations of zidovudine-triphosphate (ZDV-TP) in peripheral blood mononuclear cells (PBMCs) were determined in 16 persons enrolled in this study. The average intracellular concentration of ZDV-TP achieved with concentration-controlled therapy was 160 fmol/106 PBMCs, which was significantly greater than the 92 fmol/106 PBMCs obtained with standard therapy (P = .012). Intracellular ZDV-TP concentrations were significantly higher in patients with a CD4+ cell count response than in nonresponders (160 vs 69 fmol/106 PBMCs). Thus, this study demonstrated that higher plasma concentrations of zidovudine resulted in higher intracellular ZDV-TP concentrations, and that the higher concentrations were associated with a significantly improved CD4+ cell count response.

Nonnucleoside Reverse Transcriptase Inhibitors and Protease Inhibitors. Trough concentrations of the NNRTI agents, nevirapine and efavirenz, have been related to anti-HIV effect.[27,28] For example, among 419 participants in phase 2 studies of efavirenz, treatment failure was 3-fold more common in patients with trough efavirenz concentrations below 1.1 mg/L compared with those who had higher trough concentrations.[28] Likewise, several investigations with PIs -- including studies using dual-PI combinations -- have related trough concentrations of ritonavir, indinavir, nelfinavir, and saquinavir to the degree of plasma HIV-1 RNA suppression.[29-35]

Pharmacodynamic data also provide evidence for exposure-response relationships between PI concentrations and the emergence of viral resistance. For example, the frequency of ritonavir resistance mutations was shown to be lower in patients who had higher ritonavir 12-hour areas-under-the-curve (AUCs) and trough concentrations.[36] The resistance pathways taken by HIV during therapy with amprenavir were analyzed according to amprenavir dose and plasma concentration.[37] Individuals who developed the I50V mutation pathway had significantly higher amprenavir trough concentrations than did subjects who developed the I54L/M mutation. The I50V mutation appears to confer the greatest reduction in amprenavir susceptibility; thus, prevention of this mutation would be an important therapeutic objective. These findings provide a strong rationale to determine whether a safe and tolerable pharmacologic threshold that prevents the emergence of resistant strains can be identified for antiretroviral agents.

Two recent studies illustrate the clinical importance of antiretroviral drug concentrations. The Viradapt study[38] randomized individuals who had failed combination NRTI and PI therapy to receive a subsequent regimen guided by either a genotypic resistance test or by a standard-of-care approach (ie, treatment history without a resistance test). In an analysis of pharmacologic data from 81 participants in this study, PI concentrations in plasma were determined, and classified as optimal or suboptimal if they were higher or lower than 2 times the IC95, respectively. Multivariate analyses showed that PI concentrations were an important predictor of plasma HIV-1 RNA response. For example, no patient in the standard-of-care group who also had suboptimal PI concentrations achieved a plasma HIV-1 RNA level less than 200 copies/mL at 6 months, compared with 39.4% of those who received genotype-guided therapy and had optimal PI concentrations (Figure 2).

figure 2


Figure 2. Proportions of Patients in the Viradapt Study Who Achieved Plasma HIV-1 RNA Level Less Than 200 Copies/mL, Analyzed By Study Arm and PI Concentrations*
* Modified from Durant and colleagues[38]
AIDS Clinical Trials Group (ACTG) study 359 compared the antiretroviral activity of 6 salvage regimens in subjects with plasma HIV-1 RNA levels between 2000 and 200,000 copies/mL who had received at least 6 months of prior therapy with indinavir.[39] A total of 277 individuals were randomized to receive saquinavir with ritonavir or nelfinavir, in addition to delavirdine, adefovir, or both. Participants were NNRTI- and adefovir-naive. Overall, one third of patients achieved virologic suppression to less than 500 copies/mL at week 16. Subjects who received delavirdine had a greater virologic response than did those who received adefovir (40% vs 18%). There was no difference between the delavirdine compared with delavirdine-plus-adefovir groups (40% vs 33%). This finding was surprising, as additive-to-synergistic activity was expected with the combination of delavirdine and adefovir, given the different mechanisms of action of these 2 drugs and given that subjects had not previously received either an NNRTI or adefovir. A companion study to ACTG 359, ACTG 884 was a pharmacokinetic evaluation of the concentrations of the agents in the 6 treatment regimens.[40] ACTG 884 found that saquinavir concentrations were 50% lower in the arms containing the combination of delavirdine plus adefovir compared with those receiving delavirdine alone. In addition, delavirdine concentrations were reduced by approximately 50% in the delavirdine-plus-adefovir arms compared with the delavirdine arms. These unexpected drug-drug interactions provide the most plausible explanation for the unexpected findings in ACTG 359 -- namely, why subjects in the delavirdine-plus-adefovir arm did no better than those who received delavirdine. As such, this study illustrates the clinical consequences of adverse drug-drug interactions that lower antiretroviral drug concentrations.

A recent abstract has indicated that current regimens are not producing maximal anti-HIV potency. The combination of lopinavir/ritonavir, efavirenz, tenofovir, and lamivudine appeared to produce a faster initial rate of decline in plasma HIV-1 RNA levels than commonly used 3-drug regimens.[41] The authors suggested that the antiretroviral regimens in common use today might be about 20% less potent than the drug combination they studied.

Recent evidence indicates that the integration of virologic and pharmacologic characteristics is likely to provide a better predictor of virologic response than either characteristic alone. In an analysis of 37 patients who had plasma HIV-1 RNA levels between 50 and 50,000 copies/mL on a stable 3-times-daily indinavir regimen and were switched to twice-daily indinavir/ritonavir (400 mg of each), the virtual phenotype (vPT) and virtual inhibitory quotient (vIQ) were examined as predictors of response.[42] The vPT is a probabilistic estimate of the real phenotype, derived by taking a patient's genotype and matching it (with respect to important drug resistance mutations) with genotypes in the Virco database. The phenotypes that correspond to the matching genotypes are summed to give an average phenotype (ie, average fold change in susceptibility compared with a reference strain) for each of the drugs. The patient's vIQ for indinavir was determined by multiplying the vPT by the serum-adjusted IC50 for wild-type HIV, and dividing the trough concentration of indinavir by the result (ie, vIQ = Cmin/vPT x IC50 for wild-type HIV). At week 24, virologic response was observed in 5 of 13 patients with a baseline vPT, indicating less than 6-fold resistance to indinavir, compared with 3 of 13 patients with greater than 6-fold baseline vPT for indinavir (P < .05). With regard to the vIQ, 11 of 17 patients with a vIQ greater than 2 were virologic responders at week 24, compared with none of 8 patients with a vIQ less than 2 (P < .003).

In aggregate, the data from these studies reaffirm a general principle of pharmacology -- that the intensity and duration of the anti-HIV effect of antiretroviral agents are related to the concentration of the drug in the body. Thus, when considering the elements that contribute to therapeutic success, pharmacologic factors should be considered alongside virologic and immunologic factors (Table 1).

Strategies to Integrate Pharmacologic Knowledge Into Dosage Regimen Design

Pharmacokinetic information on antiretroviral agents thus has a potentially very important role to play as a tool to optimize HIV therapeutics. The existence of concentration-response relationships for virologic response to therapy, drug toxicity, or both should make it possible to define the therapeutic window for a drug, ie, a target concentration range in which there is an optimal likelihood of achieving a virologic response without incurring treatment-limiting toxicity.

For example, 17 Thai patients receiving indinavir (800 mg) plus ritonavir (100 mg) every 12 hours underwent a pharmacokinetic study after 4 weeks of therapy in order to investigate relationships between pharmacokinetic parameters, virologic response, and tolerance.[43] The pharmacokinetic characteristics in the Thai patients did not appear to differ from those in whites. Indinavir pharmacokinetic parameters significantly associated with virologic failure were the 12-hour AUC, </= 42 mg*h/L; and, Cmin, </= 0.25 mg/L. Indinavir parameters associated with nephrotoxicity were the 12-hour AUC, >/= 60 mg*h/L; and, Cmax, >/= 13 mg/L. With regard to efavirenz, Marzolini and colleagues[44] recently studied the predictive value of plasma concentrations for viral suppression and central nervous system adverse effects, and proposed that 1000-4000 mg/L at mid-dosing interval represents the optimal target range for dose individualization.

With regard to drug development, there are several reasons to prefer a concentration-targeted study design rather than a traditional dose-ranging study design. In the latter, a number of different dosing regimens are studied, but interpatient variability means that the drug concentrations achieved will vary from subject to subject within a single dose group -- ie, patients receiving the same dose will not have the same systemic concentrations. By contrast, in a concentration-targeted study the investigators select the range of drug concentrations that they wish to evaluate, then dose as needed to achieve those concentrations. This approach allows the investigators to select for further development the dose that is required to achieve drug levels within the desired range in the majority of patients treated.

Pediatric AIDS Clinical Trials Group (PACTG) study 382, a phase 1/2 study of efavirenz and nelfinavir in HIV-infected children, illustrates an innovative trial design that employed an AUC-controlled strategy in individual patients for both efavirenz and nelfinavir. In this case, the AUC-controlled approach was designed to efficiently find a dose of efavirenz for initial use in children in the absence of prior pediatric pharmacokinetic data and to avoid underdosing of both efavirenz and nelfinavir. Each subject had an intensive pharmacokinetic study obtained at weeks 2 and 6 of therapy. Dose adjustments were made at week 4, and again at week 8 if necessary to achieve the target AUC. The clinical results of the 57 children enrolled in PACTG 382 trial demonstrated a high degree of anti-HIV efficacy, superior to that of any previously published clinical trial in children.[45] This improved response can be attributed, at least in part, to the strategy of identifying children with inadequate drug levels and adjusting the doses administered, thereby preventing underdosing.

Prospective Studies of Therapeutic Drug Monitoring of Indinavir and Nelfinavir

Therapeutic drug monitoring (TDM) is a potentially attractive approach to addressing the pharmacologic individualization of therapy with selected drugs in certain patient groups. The characteristics of drugs to which TDM may be applicable, and an evaluation of whether antiretroviral agents currently meet these criteria, are outlined in Table 2.

ATHENA is a prospective study of TDM being conducted in The Netherlands. Preliminary 1-year results of TDM in antiretroviral-naive patients initiating therapy with either an indinavir- or a nelfinavir-based regimen are now available. PI levels were measured on a number of occasions in TDM recipients, and the PI dose was either increased or decreased as needed to try to achieve plasma concentrations within a target range. For indinavir, 55 antiretroviral-naive patients were randomized to the TDM arm or to a control arm. In an ITT analysis in which noncompleters were treated as failures (ITT, NC=F), the proportion of patients with plasma HIV-1 RNA levels less than 500 copies/mL after 1 year was higher among TDM recipients compared with control patients (75.0% vs 48.1%, P = .04).[46] This response appeared to be driven primarily by a lower rate of treatment discontinuations for toxicity in the TDM group. For nelfinavir, 92 antiretroviral-naive patients taking nelfinavir at a dose of 1250 mg twice daily were randomized to TDM or control (1250 mg twice daily).[47] In an ITT NC=F analysis, after 1 year of therapy a higher proportion of the TDM recipients had plasma HIV-1 RNA levels less than 500 copies/mL compared with the control arm (80.5% vs 58.8%, P = .03).

These analyses of a prospective study of TDM indicate that this intervention improved patient outcome, with a lower rate of toxicity for indinavir and an improved virologic response rate for nelfinavir. While there remains significant work to be done before TDM can be adopted as the standard of care for the use of these agents, these data provide a strong basis for the application of TDM into the pharmacotherapy of HIV infection.

Conclusions

Therapy of the HIV-infected person is a challenging, long-term undertaking. Optimizing the pharmacologic determinants of response alone will not provide absolute certainty of achieving the desired therapeutic goal, because other determinants of response such as virologic, immunologic, and behavioral characteristics also play a fundamental role. However, as has been shown in other diseases, when pharmacologic considerations have been applied to drug dosing, an improved outcome was achieved. For example, adjusting the dose of methotrexate to achieve a target plasma concentration was shown to improve the 5-year rate of continuous complete remission in children with B-lineage acute lymphoblastic leukemia.[48] Therefore, integration of pharmacologic considerations into drug and dose selection for antiretroviral agents should facilitate the healthcare provider in translating the therapeutic principles for treatment of HIV infection into clinical reality.

Summary -- Implications for Clinical Practice

Table 1. Elements of Therapeutic Success

Virologic Immunologic Pharmacologic
  • Initial viral load

  • Nadir of viral load reduction; time to nadir; decay rate constant

  • Virus genotype and phenotype
  • Cellular
    • CD4+ function
    • Cytotoxic T lymphocytes


  • Humoral

  • Chemokine
    • CCR5
    • CCR2b
    • CXCR4
  • Pharmacokinetic and pharmacodynamic properties

  • Antiretroviral regimen
    • Potency
    • Simplicity
    • Tolerance
    • Optimal doses


  • Adherence

Table 2. Characteristics of Drugs Applicable for Therapeutic Drug Monitoring

Criteria Met/unmet for antiretrovirals?
Pharmacologic Pharmacokinetic drug data are available Met
Significant interpatient pharmacokinetic variability exists Met
The drug has a narrow therapeutic index Met for some agents
The pharmacologic effect observed persists for a relatively long period of time Met
The pharmacologic effect is related to the drug concentration Met
Clinical Clinical studies have documented the therapeutic range of the drug Unmet, although progress is being made with certain agents
Plasma concentration reflects the concentration at the site of action Met
Lack of effect is detrimental to the patient Met
Analytical The drug assay is accurate, precise and specific, requires a small sample volume, yields results quickly, and is relatively inexpensive Met, although availability of antiretroviral assays is not widespread

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  44. Marzolini C, Telenti A, Decosterd LA, Greub G, Biollaz J, Buclin T. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS. 2001;15:71-75.
  45. Starr SE, Fletcher CV, Spector SA, et al. Combination therapy with efavirenz, nelfinavir, and nucleoside reverse transcriptase inhibitors in children infected with human immunodeficiency virus type 1. N Engl J Med. 1999;341:1874-1881.
  46. Burger D, Hugen PWH, Droste J, Huitema ADR, for the Athena study group. Therapeutic drug monitoring of indinavir in treatment-naive patients improves therapeutic outcome after 1 year: Results from ATHENA. Program and abstracts of the 2nd Workshop on Clinical Pharmacology of HIV Therapy; April 2-4, 2001; Noordwijk, The Netherlands. Abstract 6.2a.
  47. Burger D, Hugen PWH, Droste J, Huitema ADR, for the Athena study group. Therapeutic drug monitoring of nelfinavir 1250 mg BID in treatment-naive patients improves therapeutic outcome after 1 year: Results from ATHENA. Program and abstracts of the 2nd Workshop on Clinical Pharmacology of HIV Therapy; April 2-4, 2001; Noordwijk, The Netherlands. Abstract 6.2b.
  48. Evans W, Relling M, Rodman J, et al. Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia. N Engl J Med. 1998;338:499-505.
Courtney V. Fletcher, PharmD, is a Professor in the Department of Experimental and Clinical Pharmacology at the University of Minnesota in Minneapolis, MN.


Oral Care and Dentinal Hypersensitivity

W. Steven Pray, Ph.D., R.Ph., Professor of Nonprescription Products and Devices, School of Pharmacy, Southwestern Oklahoma State University, Weatherford, OK

[U.S. Pharmacist 2609 2001. © 2001 Jobson Publishing Corp.]


Introduction

In a typical workday, the retail pharmacist may field several questions about oral care and oral discomfort. Patients may complain about one or more teeth that are intermittently painful. The pain is invariably triggered by actions such as drinking a hot or cold beverage, eating a sweet or sour food, or dental manipulations such as touching the tooth or directing an air blast on it.

The patient may have concern that the tooth requires a filling or that it may need to be extracted. However, the problem, known as dentinal hypersensitivity, may be a relatively simple one to treat.

fig1

Figure 1. When a tooth's protective covering is absent, dentin is exposed. Dentinal tubules are open at the surface of the dentin, allowing a direct channel to the nerve pulp.


Dental Anatomy

The crown is the section of tooth normally exposed to the interior of the mouth; the section below the gingival line, buried in alveolar bone, is the root. The crown is covered with enamel, the hardest substance in the human body. Enamel is 96% to 97% inorganic.[1] The root is covered with a softer substance known as cementum. Cementum resembles bone in that it is composed of 45% to 50% organic material. Beneath the enamel and cementum is a material known as dentin, which encloses the tooth's sensory mechanisms, such as the dental pulp or nerve root. Dentin is 70% inorganic material, 18% organic material, and 12% water. Dentin is riddled with thousands of small channels known as dentinal tubules. Dentinal tubules contain odontoblastic processes (portions of the dentin-producing cells, also known as Tomes' fibers), tissue fluids that bathe the processes and fill the tubules, and minerals.

Prevalence

A significant portion of the aged population is edentulous (lacking natural teeth). Prior to the advent of fluoridated water, it was expected that people would begin a pernicious process of tooth loss as they reached the age of 30. This loss usually accelerated during the patient's thirties and forties until a full set of dentures was required to masticate food. Widescale fluoridation, which was first introduced in the baby boomer generation, dramatically reduced the incidence of edentulousness; thus people have kept their natural teeth for longer periods than before.[2] However, cumulative damage from years of exposure to mechanical and environ- mental insults increases the incidence of problems peculiar to aged teeth. Recent reports place the prevalence of dentinal sensitivity at 40% to 45%, a figure that is certain to rise as the average age of the population increases.

Hydrodynamic Theory

Why should certain teeth in certain people become hypersensitive? This question was elegantly answered by a set of facts and suppositions that collectively became known as "the hydrodynamic theory."[3] While this theory is not yet regarded by all as completely factual, it explains most of the available clinical observations and anatomical realities.

The first component of the theory is the observation that dentin is normally covered by cementum or enamel. When this covering is in place, the teeth are not hypersensitive. However, when cementum or enamel are absent due to erosion, abrasion, dental manipulation or a tooth defect, dentin is exposed.[4]

The second part of the theory focuses on the dentinal tubules, which are open at the surface of the dentin, allowing a direct channel to the nerve pulp. Supposedly, any of the abrasive or erosive forces that expose dentin also open these tubules to the oral interior.[5] When any trigger is present, the tissue fluids inside the tubules move slightly inward or outward.[6] Cold causes the tissue fluid volume to shrink slightly, and heat causes it to expand. Strongly osmotic sugar or sour solutions cause fluid to be drawn out of the tubules. An air blast on the tooth (by a dental instrument) dries a tiny portion of fluid at the distal end of the tubule, causing a significant outer flow of fluid in the tubule. Touching the tooth with a dental instrument or periodontal cleansing aid forces a small amount of fluid into the tubule. Intratubular fluid shifts are interpreted as pain by the Tomes' fibers and/or central nerve root of the tooth.

Causes of Dentinal Hypersensitivity

The hydrodynamic theory also explains many of the epidemiological observations on the causes of dentinal hypersensitivity.

Brushing Habits

Sustained and overzealous brushing (especially with harder-bristled brushes) is known to thin enamel and cause gingiva to recede, exposing the softer subgingival cementum, which is also damaged by brushing.[7,8] Right-handed people tend to brush their left teeth more zealously and vice versa, which results in hypersensitivity in those teeth. Also, since people tend to brush the front teeth and outer tooth surfaces more zealously, those areas are more likely to be sensitive than back teeth and inner surfaces, mirroring the incomplete brushing habits of most people.

Tooth Grinding

Patients who grind their teeth experience a higher incidence of dentinal hypersensitivity. This action wears down the enamel on teeth, exposing the dentin.

Gender

Women are more prone to dentinal hypersensitivity. This is because women of any age, generally speaking, are more attentive to basic hygiene than an age-matched group of males. Since this includes dental care, female teeth are more likely to have exposed dentinal tubules as a result.

Age

There is also an age link to dentinal hypersensitivity. The problem does not occur in most people until they reach their late twenties, thirties or forties because overzealous brushing and other factors begin to take their toll at this time.[3,9]

Diet

Habitual ingestion of acidic substances causes erosion of enamel and dentin, subsequently opening dentinal tubules. The citric acid in citrus fruits (e.g., lemons) dissolves enamel. Similarly, ingestion of other acidic foods and beverages (e.g., ginger ale, which has the lowest pH of any drink commonly available) discussed in this month's patient information should be avoided whenever possible, since they effectively strip away the tooth's protective smear layer (a layer of dead organic material that occludes the dentinal tubules, preventing the outward flow of tubular solution). Further, brushing directly after ingestion of these substances causes direct damage to enamel and must be avoided.

Smokeless Tobacco

Users of smokeless tobacco more frequently experience dentinal hypersensitivity.[9] The "quid" of smokeless tobacco placed between the gum and cheek is a well-known cause of gingival recession. As the gingiva recede in response to this noxious chemical, softer subgingival cementum is exposed. Continual brushing erodes the cementum, opening the dentinal tubules.

Disease

There is an increased risk of dentinal hypersensitivity in bulimics and those afflicted with gastroesophageal reflux disease. Both conditions increase intraoral acidity, subsequently causing the type of enamel erosion that leads to dentinal hypersensitivity.

Periodontal disease and gum disease may also result in dentinal sensitivity. With these conditions, the tooth's root surface is exposed through recession of the gums or loss of supporting ligaments.

Treatment of Dentinal Hypersensitivity

Several approaches have been investigated for treating dentinal hypersensitivity. One option is simply to occlude the dentinal tubules through the use of a particulate toothpaste ingredient, such as abrasive silica. Hypothetically, even partial tubule occlusion could be of great benefit, since Poiseuille's law holds that reducing the tubule radius by 50% reduces the flow through the tubule to 6.25% of its original value. However, the use of toothpastes containing silica particles is widespread, and does not appear to have substantially affected the prevalence of dentinal hypersensitivity. Therefore, any special toothpaste ingredient must demonstrate the ability to desensitize teeth to a statistically greater extent than the toothpaste alone. To date, only potassium nitrate has met this requirement. It is thought to act directly on the pulpal sensory nerves. After an initial depolarization of sensory nerve fiber membranes, excess potassium halts repolarization.[10] Thus, the ability of potassium nitrate to quell dentinal hypersensitivity may be due to an irreversible depolarization.

Many products are available to treat dentinal hypersensitivity. Potassium nitrate-containing toothpastes include Aqua-fresh Sensitive, Colgate Sensitive, Crest Sensitivity Protection, Dental Care Sensitive Formula, Sensodyne Extra Whitening, and Sensodyne Fresh Mint. One toothpaste, Sensodyne Tartar Control Plus Whitening, also contains tartar control and whitening ingredients. Other products for sensitive teeth are Protect Sensitive Teeth Gel Toothpaste, Rembrandt Whitening Toothpaste for Sensitive Teeth, and Orajel Sensitive Pain Relieving Toothpaste for Adults. All of these toothpastes contain fluoride to strengthen dental enamel and protect against cavity formation.[11]

A dentist can relieve dentinal hypersensitivity by applying fluoride paste, bonding agents or dentin sealer to the exposed root surface.

References

  1. Over-the-counter oral health care and discomfort drugs; establishment of a monograph. Fed Reg 1982;47(101):22712-22930.
  2. Wathen WF. The dentulous, aging patient: What should we do? Quintessence Int 1997;28(4):225.
  3. Lavigne SE, Gutenkurst LS, Williams KB. Effects of tartar-control dentifrice on tooth sensitivity: A pilot study. J Dent Hyg 1997;71(3): 105-111.
  4. Irwin CR, McCusker P. Prevalence of dentine hypersensitivity in a general dental population. J Ir Dent Assoc 1997;43(1):7-9.
  5. Seltzer S, Boston D. Hypersensitivity and pain induced by operative procedures and the "cracked tooth" syndrome. Gen Dent 1997;45(2): 148-159.
  6. Gaffar A. Treating hypersensitivity with fluoride varnish. Compend Contin Educ Dent 1999;20(1 Spec No):27-33.
  7. Gillam DG, Seo HS, Bulman JS, et al. Perceptions of dentine hypersensitivity in a general practice population. J Oral Rehabil 1999;26(9):710-714.
  8. Touyz LZ, Stern J. Hypersensitive dentinal pain attenuation with potassium nitrate. Gen Dent 1999;47(1):42-45.
  9. Carlson-Mann LD. Dentin hypersensitivity. Probe 1995;29(6):226-227.
  10. Schiff T, Dos Santos M, Laffi S, et al. Efficacy of a dentifrice containing 5% potassium nitrate and 1500 PPM sodium monofluorophosphate in a precipitated calcium carbonate base on dentinal hypersensitivity. J Clin Dent 1998;9(1):22-25.
  11. Mandel ID. The new toothpastes. J Calif Dent Assoc 1998;26(3): 186-190.


The Dos and Don'ts of Brushing

DO



DON'T:



For more information, patients can log on to the American Dental Association website: http://www.ada.org/.

Patient Information

Help For Hypersensitive Teeth

Many people notice a painful sensation when they consume a food or beverage that is hot, cold, sweet or sour, or when brushing their teeth, or when a dentist cleans or dries the tooth with an air blast. The teeth may not hurt at any other time. This condition is dentinal hypersensitivity.


Treatment

If you already have dentinal hypersensitivity, you may find relief in any of several brands of toothpastes for sensitive teeth. They contain potassium nitrate plus a fluoride. Potassium nitrate is the only ingredient presently proven to be effective for the problem. To use the toothpaste, you should choose the softest bristle brush you can find (this is also the best advice for patients without dentinal hypersensitivity, unless advised otherwise by a dentist). Place a one-inch strip of toothpaste on the brush and brush for at least one minute twice daily, morning and evening. Make sure that you allow the toothpaste to come into all areas where you noted dental pain. Brush no more than twice daily. Avoid excessive force when brushing.

Do not use these toothpastes for more than four weeks without a diagnosis of dentinal hypersensitivity from a dentist. The reason is that your tooth pain may be due to a much more serious problem, such as a chipped tooth, a cracked filling, erosion underneath a dental filling, bruxism (i.e., tooth grinding), or damage from malocclusion (i.e., an uneven bite). Once a dentist has ruled out these serious problems, you may continue to use the toothpastes for as long as hypersensitivity is present.

Prevention

It is best to avoid causes of dentinal hypersensitivity. Acidic food and drinks can damage tooth enamel. From most acidic to least, some of the foods and drinks to use cautiously include ginger ale, limes/lemons and their juices, wine, cranberry sauce, coffee, vinegar, pickles, cola and citrus-based drinks, apples, rhubarb, raspberries, root beer, relish, strawberries, fruit jams/jellies, peaches, sauerkraut, blueberries, pineapples/pineapple juice, cherries and grapes. It is especially important not to brush right after ingesting these foods, because they strip away the tooth's protective layer, and you will be brushing naked enamel, which is more prone to damage. Never suck directly on limes/lemons or allow these to be placed into a baby bottle given at night. This permits them to be in prolonged contact with the teeth, causing "nursing bottle mouth" (i.e., there are severe cavities in the section of the mouth bathed by the milk).

Avoid buying small packets of sour, acidic powders or candies coated in them. Their acidity is too high for tooth health.

Do not use smokeless tobacco. Constantly exposing the gums to this toxic substance causes them to recede, exposing the softer tooth sections below the gumline. They are then more prone to damage during brushing.

Follow proper oral hygiene and see your dentist regularly for evaluation and professional care.

Remember, if you have questions, Consult Your Pharmacist.


Ultra-Low-Dose Oral Contraceptive Effectively Treats Acne


New York - An ultra-low-dose oral contraceptive has been shown to be just as effective in treating acne as pills with higher doses of estrogen, according to a study published in the September issue of Fertility and Sterility.

"Our study confirms that an oral contraceptive containing only 20 micrograms of estrogen — the lowest dose on the market today — is effective in suppressing androgen production and reducing acne lesions," said Diane Thiboutot, MD, lead study investigator and associate professor of medicine at Penn State College of Medicine in Hershey, Pennsylvania.

The double-blind, placebo-controlled, randomized clinical trial examined 350 healthy women with regular menstrual cycles and moderate facial acne. By random selection, half the women took a 20-microgram pill containing ethinyl estradiol and the progestin levonorgestrel (Alesse; Wyeth-Ayerst Pharmaceuticals), and the other half received a placebo. After 6 cycles of treatment, there were a significantly lower number of acne lesions in the treated group compared with placebo, and changes in weight were similar in both groups.

"This clinical trial is good news for women because it shows that we now have more birth control choices that are not only 99% effective in preventing pregnancy, and offer numerous other health benefits, but can also treat acne lesions without causing a change in weight — a common estrogen-related side effect," said Dr. Thiboutot.

"In addition, the choice of a low-dose contraceptive resulted in a low occurrence of estrogen-related side effects like nausea, headaches, and breast tenderness, in addition to weight gain," she added. "If women experience fewer side effects and can treat their acne, they may be less likely to discontinue pill use, to switch to a less effective method of birth control, or to use no birth control at all."

Fertil Steril. 2001;76(3):461-468


As a Class, Higher-Priced New Drugs Reduce Need for Hospitalization


NEW YORK (Reuters Health) Sept 06 - Despite carrying a higher price tag, newer brand-name medications reduce overall health spending more than older, lower-priced drugs, according to study results released Thursday.

Frank Lichtenberg, a business professor at New York's Columbia University, examined federal data on a random sample of the US population and determined that people taking more recently approved medications had a longer lifespan and lower health costs, largely because they had fewer hospital stays.

"People who are taking newer drugs are significantly less likely to be hospitalized than those taking older drugs," Lichtenberg told Reuters Health. "On average, newer drugs are better than older drugs, and are worth the money." Lichtenberg's report appears in the September/October issue of Health Affairs.

Overall, taking new therapies resulted in a reduction in non-drug spending of $71.09, which far outweighs the average $18 increase in money spent on those new drugs, said Lichtenberg. The absolute benefit was better for people over age 65 than for younger individuals, but overall spending is also higher for the older age group, he noted.

Lichtenberg cautioned against using his study to support conclusions about specific drugs, noting that the numbers of patients he studied with any particular condition were relatively small.

He used the Agency for Health Care Research and Quality's Medical Expenditure Panel Survey (MEPS) for 1996 to make his calculations. That database holds information about prescriptions, physician office visits, hospitalizations and home healthcare on 23,230 people who took slightly more than 170,000 medications for multiple different conditions.

In the study, "new" drugs were defined as those approved by the US Food and Drug Administration in the years just prior to 1996. Only about 17% of the drugs taken by patients in the MEPS database were approved in the 1990s, while more than half were approved before 1980 and one-fourth were approved before 1950.

With use of the new drugs, the likelihood of being hospitalized went down by 0.5%, Lichtenberg found. Given that hospital stays average $8,000, expected hospital costs would decrease by $40 to $50, he said.

The study did have limitations, Lichtenberg acknowledged. The only measure of drug quality was how recently it had been approved by the FDA. Also, the database could not account for whether a drug taken for one condition might affect the outcomes or spending for another.

But, he concluded, "If there was little therapeutic benefit from new drugs, you would not see any benefit, and we're seeing that the average benefit is quite high."

Lichtenberg's study was funded by the National Pharmaceutical Council, a non-profit group that is supported by pharmaceutical companies.


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