Whole body physiologically based modelling of ß-blockers in the rat: events in tissues and plasma following an i.v. bolus dose.

BACKGROUND AND PURPOSE: Whole body physiologically based pharmacokinetic (PBPK) models have been increasingly applied in drug development to describe kinetic events of therapeutic agents in animals and humans. The advantage of such modelling is the ability to incorporate vast amounts of physiological information, such as organ blood flow and volume, to ensure that the model is as close to reality as possible. EXPERIMENTAL APPROACH: Previous PBPK model development of enantiomers of a series of seven racemic ß-blockers, namely, acebutolol, betaxolol, bisoprolol, metoprolol, oxprenolol, pindolol and propranolol, together with S-timolol in rat was based on tissue and blood concentration data at steady state. Compounds were administered in several cassettes with the composition mix and blood and tissue sampling times determined using a D-optimal design. KEY RESULTS: Closed-loop PBPK models were developed initially based on the application of open loop forcing function models to individual tissues and compounds. For the majority of compounds and tissues, distribution kinetics was adequately characterized by perfusion rate-limited models. For some compounds in the testes and gut, a permeability rate-limited distribution model was required to best fit the data. Parameter estimates of the tissue-to-blood partition coefficient through fitting of individual enantiomers and of racemic pair were generally in agreement and also concur with those from previous steady-state experiments. CONCLUSIONS AND IMPLICATIONS: PBPK modelling is a very powerful tool to aid drug discovery and development of therapeutic agents in animals and humans. However, careful consideration of the assumptions made during the modelling exercise is essential.

A six-year evaluation of methadone prescribing practices at a substance misuse treatment centre in the UK.

OBJECTIVES: To document changes in prescribing practice at a specialized substance misuse service in the UK occurring since the introduction of the 1999 UK National Guidelines on the management of drug misuse, and to explore a possible link between the length of time spent in methadone maintenance therapy (MMT) and the dosage prescribed. METHODS: A retrospective analysis of a computerized prescription database between 1996 and 2002 obtained from Sheffield Care Trust Substance Misuse Service was performed. The relationship between various measures of dosage and the length of time spent in MMT was investigated. RESULTS: In accordance with the 1999 UK National Guidelines, the proportion of injectable methadone prescribed decreased from 22% to 16%. This was offset by an increase in the prescribing of methadone elixir from 74% to 79%. The 'maximum dose' of methadone prescribed correlated significantly with patient retention, explaining 14% of the variation in time spent in MMT. CONCLUSIONS: Our findings indicate that publication of the UK National Guidelines had a measurable effect on prescribing practice at the Service. We found that a higher methadone dose is associated with increased patient retention in MMT. However, as only a maximum of 14% of the variation in the length of stay is related to methadone dose, the importance of other aspects of treatment such as counselling and rehabilitation programmes, should be considered for the successful treatment of opioid abusers.

Assessing dentin color changes from nightguard vital bleaching.

BACKGROUND: At-home bleaching with 10 percent carbamide peroxide in a custom-fitted tray has been reported to change the color of dentin. The purpose of this study was to validate the color change of dentin and to determine whether the color change was uniform or occurred from the outside (the dentinoenamel junction) to the inside (the pulpal wall). METHODS: The authors sectioned 10 extracted human teeth incisogingivally through the midfacial long axis, and sealed their cut surface against glass microscope slides. Identifying marks were placed on the glass over the tooth sections to serve as a color control and in the dentinal areas closest to the dentinoenamel junction and the pulpal wall. Teeth were bleached for 10 days with 10 percent carbamide peroxide. Photographs were taken from the glass-covered side of the teeth, digitized and converted to gray-scale levels (consisting of 256 shades of gray ranging from black to white). Marked areas were measured with a National Institutes of Health Image software program and analyzed statistically for changes in lightness between the control marks and the inner and outer dentinal marks over time. RESULTS: Paired t-tests and analysis of variance indicated a significant increase in lightness (P = .01) for the inner and outer dentinal areas during bleaching compared with the control areas. No significant differences were found in the rate of change for the inner and outer dentinal areas (P = .89). CONCLUSIONS: The increase in lightness confirms that a significant color change occurred in the dentin during bleaching with 10 percent carbamide peroxide. This change occurred throughout the dentin at a uniform rate, rather than from the outside inward. CLINICAL IMPLICATIONS: The results of this study show that at-home bleaching with 10 percent carbamide peroxide can change the color of dentin, which is important to treat intrinsic stains from tetracycline treatment, trauma and aging or inherited discolorations. The bleaching material easily penetrates the tooth to change the dentin color at the same rate throughout, indicating that the type of stain may be the important factor in determining bleaching success.

Clinical study of tooth shade lightening from dentist-supervised, patient-applied treatment with two 10% carbamide peroxide gels.

PURPOSE: Prescribed, patient-applied tooth lightening agents, or nightguard vital bleaching, typically utilizes a 10% carbamide peroxide agent applied during nocturnal hours. The purpose of this randomized double-blind study was to compare the amount of tooth color change in two groups of subjects using dentist-supervised, patient-applied 10% carbamide peroxide gel. MATERIALS AND METHODS: One group used Opalescence (Ultradent Products Inc., South Jordan, Utah) and the other NiteWhite Excel (Discus Dental, Inc., Los Angeles, California). Evaluation of tooth color for the six maxillary anterior teeth was done using a Vita shade guide at baseline, 1, 2, and 4 weeks. Subjects were instructed to apply the gel nocturnally using a custom-made soft tray 8 hours per day for 2 weeks. The 16 tabs of the shade guide were ranked according to value from darkest to lightest. The number (1-16) that correlated to the shade tab selected as the match for each tooth was the outcome variable. A Kruskal-Wallis one way analysis of variance on ranks was used. RESULTS: The test revealed no statistically significant difference between Opalescence and NiteWhite Excel for lightening the teeth (p = .807). The color change was still significant after 2 weeks without further bleaching activity. The baseline evaluation of the maxillary incisors and canines for all subjects, regardless of group, demonstrated a significant shade difference, with the canines being darker. This difference was not seen after 2 weeks of active bleaching or at the 4-week evaluation. CLINICAL SIGNIFICANCE: In this study comparing bleaching products, patients using Opalescence and NiteWhite Excel experienced a significant change in the color of their teeth relative to baseline values after 2 weeks of active treatment.

Assessing the effects of 10 percent carbamide peroxide on oral soft tissues.

To examine the effects of a 10 percent carbamide peroxide bleaching gel on the oral soft tissues, the authors conducted a prospective, double-blind, placebo-controlled clinical investigation. Fifty-two patients completed a two-week treatment regimen, applying either a placebo or a 10 percent carbamide peroxide gel in a soft tray for eight hours a day. Clinicians examined the participants' oral soft tissues at baseline and one week, two weeks and six weeks after the first treatment. The examiners recorded the Silness and Löe plaque and gingival indexes, nonmarginal gingival index and nongingival oral mucosal index at each examination. The data collected at these intervals did not indicate that any soft tissue damage had occurred as a result of the bleaching regimen.

Effect of a silica-containing etchant on shear bond strength to dentin.

The viscosity of phosphoric acid etchants for enamel and dentin may be increased by the addition of silica. This in vitro study investigated the effect of a silica-containing 10% phosphoric acid gel on the bond strength of composite resin to dentin as compared to a 10% phosphoric acid gel without silica, using 20 extracted human molars. The results indicated that the etchant containing submicron silica provided higher bond strengths than the etchant without a silica constituent. The learning objective of this article is to provide the findings of the study for the clinicians.

Pit and fissure sealant application using a drying agent.

This clinical investigation assessed the retention of pit and fissure sealants with and without the use of a post-etching drying agent in pediatric dental patients. Twenty eight healthy patients with four fully erupted, non-carious first permanent molars participated. Sixteen males and 12 females, 5-12 years of age, each received four sealants, two with and two without a drying agent. Sealants were placed by three dental operators. Assignment for sealant application (with and without drying agent) was based on a computer-generated randomization table. Sealant application involved cleansing of the teeth with a non-fluoridated prophylaxis paste followed by rinsing 60 seconds with air/water spray, enamel conditioning with 40% phosphoric acid for 60 seconds, rinsing with air/water spray for 60 seconds, application of drying agent for 5 seconds, application of sealant material, and light curing for 60 seconds. Modified USPHS (Ryge) criteria were used to evaluate interfacial staining, secondary caries, marginal integrity, and surface texture. Sealant retention was evaluated as fully retained or lost (failed). All 28 participants returned for the 12-month recall visit. Four evaluators reported a 91% overall retention rate. Of the 56 teeth sealed without a drying agent, there was a 13% (n = 7) failure rate compared to 5% (n = 3) failure rate for the 56 teeth sealed with a drying agent. These results were not statistically significant (P > 0.05) based on the log-rank test.

Assessing the long-term effect of a surface penetrating sealant.

Small defects are commonly found on the surfaces of composite restorations--especially in stress-bearing areas. Sealant application may reduce the wear rates of these restorations. This five-year study assesses the effect of sealant application on interfacial staining, clinical wear, marginal integrity and surface texture.

Dye ingress in molars: furcation to chamber floor.

An in vitro dye leakage study was performed to determine the incidence of patent furcal accessory canals following exposure of the pulp chamber to 5.25% sodium hypochlorite. One hundred extracted molars were labeled, endodontically opened, and irrigated for 1 h at 5-min intervals. The external furcations were exposed to 0.5% basic fuchsin for 24 h. Patency was determined by dye presence on the chamber floor. Statistical analysis revealed that first and second molars, regardless of arch position or location, demonstrated a patent accessory canal at a rate of 57% +/- 19.6% in the furcal area. It was concluded that accessory canal exposure to 5.25% sodium hypochlorite in the furcal area of molars produced patency which was demonstrable via passive methods--no vacuum or injection pressures were utilized.

Clinical evaluation of a highly wear resistant composite.

The purpose of this clinical study was to determine the long-term potential of a resin composite restorative material. A total of 62 restorations of a modified Herculite Incisal formulation were inserted into Class I and Class II preparations. A control group of the conventional Herculite formulation was also placed into Class I and Class II cavity preparations at an earlier date. The cavity preparations for both formulations were standardized to conform to that of conventional conservative amalgams. Deep portions of the preparations were lined with calcium hydroxide. The enamel margins were etched per manufacturers' directions followed by a dentin bonding agent. After application of the appropriate matrix, the restorations were placed incrementally. Each restoration was independently evaluated by two clinicians at baseline, 6-months, 1, 2 and 3 years in accordance with the USPHS criteria. In addition, all restorations were evaluated for wear using a series of optical standards (M-L). The color matching ability of the material never fell below 96%. The percent of restorations exhibiting a surface texture similar to enamel never fell below 90% Alfa. At the end of 3 years, the total average loss of material was only 28 microns. No clinical evidence of bulk fracture was detected with the modified Herculite formulation at 3 years. The wear rate of the modified formulation of Herculite was essentially one-half that of conventional Herculite XR. Marginal ditching, which is characteristic of most posterior resin composites in which the filler particle is 1 micron or less, was exhibited.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of thermocycling in microleakage analysis.

The purpose of this study was to evaluate the effect of thermocycling on dye penetration during in vitro microleakage analysis of composites. Fifty non-carious human molars, stored in 75% ethanol, were divided into five groups (N = 10). Each tooth was prepared for a MOD slot preparation using a high speed handpiece and water, one proximal cervical margin in cementum, the other in enamel. The enamel margins were etched, rinsed, dried, and the composite inserted and cured in multiple increments. Group A was not thermocycled (TC) and was immersed in 0.5% basic fuchsin dye for 24 h at 37 degrees +/- 1 degrees C. Group A' was not TC and was immersed in 0.5% basic fuchsin dye for 4 h at 37 degrees +/- 1 degree C. Group B was TC in a water bath and immersed in dye as with Group A, Group B' was TC and immersed in dye as in Group A'. Group C was TC, as in Group B, but in a basic fuchsin dye bath. Thermocycling consisted of 250 cycles, 15 s dwell time each in 5 degrees C and 50 degrees C bath. The teeth were mounted in acrylic, and multiple cross-sections of all surfaces were prepared. Dye penetration was read on a scale of 0 (no leakage) to 4 (leakage to the pulpal floor) and means calculated for each surface and tooth. There was no significant increase of microleakage in restorations when thermocycling was used to simulate temperature extremes, either in dye or water baths, as opposed to restorations which were not thermocycled.

Comparison of shear bond strengths of some third-generation dentin bonding agents.

Recently a series of new dentin bonding systems has been introduced to the dental profession. These agents are the third generation of systems that have been developed over the past two decades. Some dentin bonding agents are easily applied, clinically, while others are complicated, multi-step procedures. A comparison of the shear bond strengths of five of these systems was made at 15 minutes and after 24 hours stored in water at 37 degrees C.

Effect of surface penetrating sealant on wear rate of posterior composite resins.

Although posterior composite resins have been improved considerably, secondary caries and wear continue to be a major concern. Recent studies suggested that microstructural defects such as voids and microcracks contribute to a weakened surface. The purpose of this study was to evaluate the effect of an experimental surface-penetrating sealant on the wear resistance of a posterior composite resin. At the end of 1 year, the rate of wear of the treated restorations was one-half of those not receiving the surface penetrating sealant.

Exercise therapy for Parkinson's disease.

The outcomes of two different 12-week exercise programs were assessed by machine measurements of motor signs, tests of grip strength, motor coordination and speed, and neurophysiologic determinations of long-latency stretch responses in two groups of Parkinson patients matched for age, sex and stage of disease. The programs tested included an exercise program developed by the United Parkinson Foundation and a program of upper body karate training. Outcomes of these programs were similar. The majority of patients in both groups showed improvements in gait, tremor, grip strength and motor coordination on tasks requiring fine control. In one task involving whole body coordination there was a decline in function, while muscle rigidity was unchanged. The findings suggest that exercise is a useful adjunct to pharmacologic therapy.