Differences in nonclinical pharmacokinetics between species and prediction of human pharmacokinetics of TAK-272 (SCO-272), a novel orally active renin inhibitor.

In the search for orally available drugs, the prediction of human pharmacokinetics (PK) is essential for successfully selecting compounds that will be clinically useful. This report describes the selection of TAK-272 (SCO-272), a novel orally active renin inhibitor, as a clinical candidate via the detailed investigation of nonclinical PK data and human PK prediction. The bioavailability (BA) of TAK-272 after oral administration to rats and monkeys was low, especially in fasted monkeys, and the systemic exposure of TAK-272 was highly variable in monkeys. The results of mass balance studies in animals suggested that the absorbed TAK-272 was largely eliminated by metabolism. In vitro studies revealed that TAK-272 was mainly metabolized by CYP3A4/5 in humans, and it was a P-glycoprotein substrate. PK analysis suggested that the factors responsible for the low BA were different in rats and monkeys. First-pass hepatic extraction was high in rats, while the fraction absorbed from the gastrointestinal tract (Fa * Fg ) was low in monkeys. It was predicted that humans would have a higher BA and a longer half-life in the plasma compared with the animals by a simple calculation using intrinsic hepatic clearance in monkeys, which correlates well with human values for CYP3A4 substrates, and Fa * Fg in rats, which correlates relatively well with human values. TAK-272 was finally selected as a clinical candidate based on the result of human PK prediction. The actual human PK after oral administration of TAK-272 was comparable to the predicted profile and was preferable for clinical usage.

Pre-clinical Characterization of Absorption, Distribution, Metabolism and Excretion Properties of TAK-063.

TAK-063 is currently being developed to treat schizophrenia. In this study, we investigated the absorption, distribution, metabolism and excretion (ADME) properties of TAK-063 using several paradigms. Following oral administration of TAK-063 at 0.3 mg/kg, bioavailability of TAK-063 was 27.4% in rats and 49.5% in dogs with elimination half-lives of 3.1 hr in rats and 3.7 hr in dogs. TAK-063 is a highly permeable compound without P-glycoprotein (P-gp) or breast cancer resistance protein substrate liability and can be readily absorbed into systemic circulation via the intestine. TAK-063 can also cross the blood-brain barrier. TAK-063 was metabolized mainly by CYP2C8 and CYP3A4/5, while incubation with human liver microsomes produced the major human metabolite, M-I as well as several unknown minor metabolites. Metabolism of TAK-063 to M-I occurs through hydroxylation of the mono-substituted pyrazole moiety. In vitro, TAK-063 was observed to inhibit CYP2C8, CYP2C19 and P-gp with IC50 values of 8.4, 12 and 7.13 µM, respectively. TAK-063 was primarily excreted in the faeces in rats and dogs with M-I as a predominant component. The pre-clinical data from these ADME studies demonstrate a favourable pharmacokinetic profile for TAK-063 with good brain distribution supporting the feasibility of targeting central nervous system regions involved in schizophrenia pathophysiology. TAK-063 has recently been investigated in a phase 2 clinical trial (NCT02477020).

Long-Term Stability of Cryopreserved Human Hepatocytes: Evaluation of Phase I and II Drug-Metabolizing Enzyme Activities and CYP3A4/5 Induction for More than a Decade.

We evaluated the long-term stability of hepatocytes stored in the vapor phase of liquid nitrogen for their viability, cytochrome P450 (CYP) 1A2 activity, CYP3A4/5 activity, uridine diphosphate-glucuronosyl transferase (UGT) activity, sulfotransferase (SULT) activity, and CYP3A4/5 induction during 14 years of preservation. No substantial degradation of viability, CYP1A2 activity, UGT activity, or CYP3A4/5 induction was observed. CYP3A4/5 activity showed a slight decrease after 7 years of storage, and SULT activity gradually decreased during storage, although substantial activities remained even after 14 years. These results indicate that cryopreserved human hepatocytes can be stored stably for more than a decade with little or no change in viability, activity of drug-metabolizing enzymes, or CYP3A4/5 induction, and can be widely applicable to qualitative research in drug metabolism.

In vitro metabolism of TAK-438, vonoprazan fumarate, a novel potassium-competitive acid blocker.

1. TAK-438, vonoprazan fumarate, is a novel orally active potassium-competitive acid blocker, developed as an antisecretory drug. In this study, we investigated the in vitro metabolism of 14C-labeled TAK-438. In human hepatocytes, M-I, M-II, M-III and M-IV-Sul were mainly formed, and these were also detected in clinical studies. N-demethylated TAK-438 was also formed as an in vitro specific metabolite. Furthermore, CYP3A4 mainly contributed to the metabolism of TAK-438 to M-I, M-III, and N-demethylated TAK-438, and CYP2B6, CYP2C19 and CYP2D6 partly catalyzed the metabolism of TAK-438. The sulfate conjugation by SULT2A1 also contributed to the metabolism of TAK-438 to form TAK-438 N-sulfate, and CYP2C9 mediated the formation of M-IV-Sul from TAK-438 N-sulfate. The metabolite M-IV, which could be another possible intermediate in the formation of M-IV-Sul, was not observed as a primary metabolite of TAK-438 in any of the in vitro studies. 2. In conclusion, TAK-438 was primarily metabolized by multiple metabolizing enzymes including CYP3A4, CYP2B6, CYP2C19, CYP2D6, and a non-CYP enzyme SULT2A1, and the influence of the CYP2C19 genotype status on gastric acid suppression post TAK-438 dosing could be small. The multiple metabolic pathways could also minimize the effects of co-administrated CYP inhibitors or inducers on the pharmacokinetics of TAK-438.

Species differences and substrate specificity of CYP3A heteroactivation by efavirenz.

1. The purpose of this study was to clarify species differences in the heteroactivation of CYP3A substrates by efavirenz, which is known from clinical studies to activate midazolam 1'-hydroxylation, and to assess the feasibility of an animal model. 2. In monkey and human liver microsomes, efavirenz activated CYP3A-mediated midazolam 1'-hydroxylation, but had no effect in rat liver microsomes. The activating effect of efavirenz was also observed with recombinant human CYP3A4 and CYP3A5. Midazolam 4-hydroxylation, testosterone 6ß-hydroxylation and the oxidation of nifedipine were not activated by efavirenz in any of the microsomes. 3. In an in vivo study using monkeys, the AUC ratio of midazolam/1'-hydroxymidazolam was reduced from 0.85 to 0.30 by efavirenz treatment, which was comparable to that obtained in clinical studies. However, the AUC changes of midazolam caused by efavirenz were smaller than those observed in clinical results, therefore the effect of efavirenz on monkeys was not completely consistent with that seen in humans. 4. In conclusion, this is the first report that efavirenz specifically activates midazolam 1'-hydroxylation only in monkey and human liver microsomes, revealing marked species differences and high substrate specificity in the heteroactivation. A further study is required to clarify whether this in vitro result reflects the in vivo situation.

UDP-glucuronosyltransferase 2B15 (UGT2B15) is the major enzyme responsible for sipoglitazar glucuronidation in humans: retrospective identification of the UGT isoform by in vitro analysis and the effect of UGT2B15*2 mutation.

Recently, genotyping in clinical studies has revealed that UGT2B15 genetic polymorphism has an influence on the clinical pharmacokinetics of sipoglitazar. In this study, the UGT responsible for sipoglitazar was retrospectively identified by in vitro analysis. A study using UGT-expressing supersomes revealed that sipoglitazar glucuronidation was more extensively catalyzed by UGT1A1, 1A3, 1A6, 2B4, and 2B15 than by other UGTs. Enzyme kinetic studies for sipoglitazar glucuronidation and recent findings related to mRNA expression analysis of UGTs narrowed the involved isoforms down to UGT1A1 and UGT2B15 among these five human UGTs. In a correlation study between sipoglitazar glucuronidation and UGT isoform-specific activities, the glucuronidation of S-oxazepam, a specific substrate for UGT2B15, strongly correlated with that of sipoglitazar, as compared with that of ß-estradiol, a representative UGT1A1 substrate. The analysis of the species difference strengthens the possibility of UGT2B15 rather than that of UGT1A1. These in vitro findings indicate that UGT2B15 is principally responsible for sipoglitazar glucuronidation. Moreover, the UGT2B15*2 mutation significantly increased the Km value of sipoglitazar in the kinetic analysis using recombinant His-tag UGT2B15*1- or *2-membrane fractions. These results show that sipoglitazar is a good example to elucidate the relationship between phenotype and genotype for UGT2B15 from in vitro analysis.

Absorption of TAK-491, a new angiotensin II receptor antagonist, in animals.

The absorption process in animals of TAK-491, designed as ester-based prodrug with medoxomil moiety, was evaluated. In the plasma of rats and dogs, TAK-536, the pharmacologically active metabolite, was present as the main component with hardly detectable concentrations of TAK-491 after oral administration of TAK-491. In the rat portal plasma, TAK-536 was also present as the main component with hardly detectable concentrations of TAK-491 after jejunal loop injection of TAK-491, suggesting TAK-491 was absorbed from small intestine and hydrolyzed almost completely during absorption. Caco-2 study indicated the permeability of TAK-491 was improved by prodrug modification and the compound could be mainly transferred as TAK-491. This is well consistent with the facts that the AUC and T(max) of TAK-536 after oral administration of TAK-491 were higher and shorter than those after oral administration of TAK-536 in dogs Hydrolysis of TAK-491 is observed not only by the intestinal and hepatic S9 fraction, but also by plasma and human serum albumin. However, medoxomil alcohol wasn't detected during the hydrolysis of TAK-491. These metabolic features of TAK-491 were similar to olmesartan medoxomil, suggesting the hydrolytic pathway and enzymes for TAK-491 when catalyzing to TAK-536 would be the same as olmesartan medoxomil.

Orteronel (TAK-700), a novel non-steroidal 17,20-lyase inhibitor: effects on steroid synthesis in human and monkey adrenal cells and serum steroid levels in cynomolgus monkeys.

Surgical or pharmacologic methods to control gonadal androgen biosynthesis are effective approaches in the treatment of a variety of non-neoplastic and neoplastic diseases. For example, androgen ablation and its consequent reduction in circulating levels of testosterone is an effective therapy for advanced prostate cancers. Unfortunately, the therapeutic effectiveness of this approach is often temporary because of disease progression to the 'castration resistant' (CRPC) state, a situation for which there are limited treatment options. One mechanism thought to be responsible for the development of CRPC is extra-gonadal androgen synthesis and the resulting impact of these residual extra-gonadal androgens on prostate tumor cell proliferation. An important enzyme responsible for the synthesis of extra-gonadal androgens is CYP17A1 which possesses both 17,20-lyase and 17-hydroxylase catalytic activities with the 17,20-lyase activity being key in the androgen biosynthetic process. Orteronel (TAK-700), a novel, selective, and potent inhibitor of 17,20-lyase is under development as a drug to inhibit androgen synthesis. In this study, we quantified the inhibitory activity and specificity of orteronel for testicular and adrenal androgen production by evaluating its effects on CYP17A1 enzymatic activity, steroid production in monkey adrenal cells and human adrenal tumor cells, and serum levels of dehydroepiandrosterone (DHEA), cortisol, and testosterone after oral dosing in castrated and intact male cynomolgus monkeys. We report that orteronel potently suppresses androgen production in monkey adrenal cells but only weakly suppresses corticosterone and aldosterone production; the IC(50) value of orteronel for cortisol was ~3-fold higher than that for DHEA. After single oral dosing, serum levels of DHEA, cortisol, and testosterone were rapidly suppressed in intact cynomolgus monkeys. In castrated monkeys treated twice daily with orteronel, suppression of DHEA and testosterone persisted throughout the treatment period. In both in vivo models and in agreement with our in vitro data, suppression of serum cortisol levels following oral dosing was less than that seen for DHEA. In terms of human CYP17A1 and human adrenal tumor cells, orteronel inhibited 17,20-lyase activity 5.4 times more potently than 17-hydroxylase activity in cell-free enzyme assays and DHEA production 27 times more potently than cortisol production in human adrenal tumor cells, suggesting greater specificity of inhibition between 17,20-lyase and 17-hydroxylase activities in humans vs monkeys. In summary, orteronel potently inhibited the 17,20-lyase activity of monkey and human CYP17A1 and reduced serum androgen levels in vivo in monkeys. These findings suggest that orteronel may be an effective therapeutic option for diseases where androgen suppression is critical, such as androgen sensitive and CRPC.

Metabolic fate of sipoglitazar, a novel oral PPAR agonist with activities for PPAR-γ, -α and -δ, in rats and monkeys and comparison with humans in vitro.

Sipoglitazar is a novel anti-diabetic agent with triple agonistic activities on the human peroxisome proliferator-activated receptors, hPPAR-γ, -α, and -δ. The bioavailability for sipoglitazar was 95.0% and 72.6% in rats and monkeys respectively and sipoglitazar is hardly subject to first pass metabolism in either species. Following oral administration of [¹4C]sipoglitazar to rats, sipoglitazar and its metabolites were distributed to the rat tissues with relatively high concentrations in the liver and also to the target tissue, the adipose tissue. The major component was sipoglitazar in the plasma of rats and monkeys. In rats, sipoglitazar was mainly excreted into the feces via biliary excretion as sipoglitazar-G, while the major component was M-I-G in the urine and M-I in the feces of monkeys. In hepatocytes, the metabolism was not extensively advanced in rats and the main metabolites were M-I and sipoglitazar-G in humans, similar to the metabolic profile in monkeys. There was no metabolite specific for humans in vitro. In conclusion, the formation of M-I, M-I-G and sipoglitazar-G is considered to be crucial and sipoglitazar is presumed to be cleared primarily by oxidation and glucuronidation in humans, when examined in vivo and in vitro.

An unusual metabolic pathway of sipoglitazar, a novel antidiabetic agent: cytochrome P450-catalyzed oxidation of sipoglitazar acyl glucuronide.

Animal pharmacokinetic studies of sipoglitazar, a novel antidiabetic agent, showed that the deethylated metabolite (M-I) and the glucuronide conjugate of sipoglitazar (sipoglitazar-G) appeared to be the key metabolites in the elimination process. M-I was also measured as the main metabolite in the plasma of humans administered sipoglitazar. In vitro metabolic studies were performed to investigate the metabolic pathways from sipoglitazar to M-I in humans. The metabolic profile with human hepatocytes and hepatic microsomes indicated that M-I was not formed directly from sipoglitazar and that sipoglitazar-G was involved in the metabolism from sipoglitazar to M-I. Further studies of the metabolism of sipoglitazar-G revealed that the properties of the glucuronide conjugate and its metabolism are as follows: high-performance liquid chromatography, liquid chromatography-tandem mass spectrometry, and NMR analyses showed that sipoglitazar-G was composed of two glucuronides, sipoglitazar-G1, a ß-1-O-acyl glucuronide, and sipoglitazar-G2, an α-2-O-acyl glucuronide. The stability study of these glucuronides suggested that sipoglitazar-G1 could be converted to sipoglitazar-G2 and sipoglitazar, but sipoglitazar-G2 could not be converted to sipoglitazar-G1. The oxidative metabolic study of sipoglitazar-G1 and -G2 with human hepatic microsomes and cytochrome P450-expressing microsomes revealed that M-I was formed only from sipoglitazar-G1, not from sipoglitazar-G2, and that CYP2C8 was mainly involved in this process. From these results, it is shown that the metabolic pathway from sipoglitazar to M-I is an unusual one, in which sipoglitazar is initially metabolized to sipoglitazar-G1 by UDP-glucuronosyltransferase and then sipoglitazar-G1 is metabolized to M-I by O-dealkylation by CYP2C8 and deconjugation. Sipoglitazar-G2 is sequentially formed by the migration of the ß-site of sipoglitazar-G1.

Metal artifacts in MRI from non-magnetic dental alloy and its FEM analysis.

Artifacts in MR(Magnetic Resonance) images of oral cavity produced from non-magnetic metal restorations was verified by measuring the image of index finger and a cylinder of fat test piece with a type 4 gold alloy ring using a compact MRI equipment. In the images of finger, portion around the ring disappeared. However, it was nearly restored with a cut ring. In the cylinder of fat test piece, obvious artifacts appeared when circumferential surface of the ring was placed perpendicular to RF(Radio Frequency) field of MRI equipment's excitation/detection coil. However, in other directions or with a cut ring, artifact disappeared. The cause was simulated with FEM(Finite Element Method) electromagnetic field analysis, and alternating magnetic field was shown to induce surface current on the continuous gold ring. Magnetic field produced by that current interfered with the field from excitation coil. This demonstrated the characteristics and cause of artifacts by non-magnetic dental metals.

Transformation of 3DP gypsum model to HA by treating in ammonium phosphate solution.

Three-dimensional printing (3DP) is a CAD/CAM built-up using ink-jet printing technique. Commercially available 3DP system can form only gypsum model and not for bioceramics. On the other hand, transformation of hardened gypsum into hydroxyapatite (HA) by treatment in ammonium phosphate solution was found lately. In the present study, transformation of the 3DP gypsum block to HA was attempted. However, the fabricated 3DP block was soluble in water. To insolubilize, it was heated at 300 degrees C for 10 min, and then, gypsum was transformed to calcium sulfate hemihydrate, CaSO(4) x 0.5H(2)O. The 3D block was immersed in 1M (NH(4))(3)PO(4) x 3H(2)O solution at 80 degrees C for 1-24 h, and the transformation into HA within 4 h was ascertained. A heat-treated plaster of Paris (POP) block was also investigated for comparison. The unheated POP block consisting of gypsum dihydrate took 24 h to complete the transformation, while the heat-treated POP consisting calcium sulfate hemihydrate promoted the transformation into HA; but the transformed thickness in the block was less than the 3DP block. This is probably due to higher solubility of the hemihydrate than gypsum dihydrate. Accelerated transformation of the 3DP block was also caused by its porous structure, which enabled an easy penetration of the phosphate solution. With the present method, it is possible to transform the fabricated gypsum by 3D printing that is adaptive to the osseous defect into HA prostheses or scaffold.

Role of acidic amino acid for regulating hydroxyapatite crystal growth.

Non-collagenous proteins in hard tissue matrix are thought to play a pivotal role in regulating the crystal growth of hydroxyapatite (HAp). As most non-collagenous proteins are acidic proteins containing acidic amino acid-rich sequences, we examined the growth of HAp crystals from HAp seed crystals in the presence/absence of acidic amino acid. New HAp formation generally started from the P-surface of HAp. However, in the presence of acidic amino acid, new HAp formation was observed on both P-surface and C-surface of HAp seed crystals. Furthermore, newly formed HAp showed specific orientation along the long-axis direction of HAp seed crystals. In terms of crystallinity, HAp formed in the presence of acidic amino acid showed low crystallinity. These results suggested that, in biomineralization, the adsorbed or free state of acidic amino acid would influence crystal formation and orientation as follows: 1) If free in solution, acidic amino acid would inhibit HAp crystal growth; 2) If adsorbed or immobilized on matrix, acidic amino acid would become HAp nucleation site and regulate the orientation of HAp crystals.

Improvement of cell adhesion on poly(L-lactide) by atmospheric plasma treatment.

The purpose of this study is to elucidate the interaction between the cell and the surface of poly(L-lactide) (PLLA) samples, which were modified using a low-temperature plasma treatment apparatus at atmospheric pressure. The plasma treatments were carried out in the atmospheres of air, carbon dioxide (CO2), and perfluoro propane (C3F8) gas. The PLLA samples before and after the plasma treatment were analyzed by XPS and their contact angles with water. Furthermore, the cell adhesion capability and cell mass culturing tests on the PLLA samples were carried out using MC3T3-E1 cells. The results showed that the contact angle of the samples, which was plasma treated in air or in CO2 gas, decreased compared with that of the untreated samples. On the other hand, the contact angle of the samples, which was plasma treated in the C3F8 gas, increased compared with the untreated plasma samples. The cell response on the PLLA samples plasma treated in air or in the CO2 gas were significantly superior to that of the PLLA samples, which was plasma treated in the C3F8 gas.

New evaluation method by microfocus radiograph CT for 3D assessment of internal adaptation of all-ceramic crowns.

The aim of this study was to evaluate the effectiveness of the microfocus radiograph CT system in examining the adaptation of all-ceramic crowns three-dimensionally and non-destructively. The computed tomograms of the crown and abutment model were filmed by microfocus radiograph CT. Using a volumetric rendering software, images of gaps were extracted and reconstructed three-dimensionally, and their volume data analyzed. In order to compare this method with the conventional method, fitness test silicone paste was sandwiched between the abutment and all-ceramic crown. Adaptation of the crown on the abutment model was then observed non-destructively and three-dimensionally. Furthermore, the gaps could be analyzed in any arbitrary position. Concerning mean gap thickness, there was significant differences between the two measurement methods. However, it was very slight. We therefore concluded that the microfocus radiograph CT system is well positioned to be an extremely effective method in examining the adaptation of all-ceramic crowns.

A novel method of removing artifacts because of metallic dental restorations in 3-D CT images of jaw bone.

CT images, especially in a three-dimensional (3-D) mode, give valuable information for oral implant surgery. However, image quality is often severely compromised by artifacts originating from metallic dental restorations, and an effective solution for artifacts is being sought. This study attempts to substitute the damaged areas of the jaw bone images with dental cast model images obtained by CT. The position of the dental cast images was registered to that of the jaw bone images using a devised interface that is composed of an occlusal bite made of self-curing acrylic resin and a marker plate made of gypsum. The patient adapted this interface, and CT images of the stomatognathic system were filmed. On the other hand, this interface was placed between the upper and lower cast models and filmed by CT together with the cast models. The position of the marker plate imaged with the dental casts was registered to those adapted by the patient. The error of registration was examined to be 0.25 mm, which was satisfactory for clinical application. The damaged region in the cranial bone images as an obstacle for implant surgery was removed and substituted with the trimmed images of the dental cast. In the method developed here, the images around the metallic compounds severely damaged by artifacts were successfully reconstructed, and the stomatognathic system images became clear, and this is useful for implant surgery.

Surface modification of pure titanium by plasma exposure and its bonding to resin.

The purpose of this study was to investigate the effects on shear bond strength to resin after pure titanium (Ti) was exposed to plasma under different kinds of gas atmosphere. Polished Ti samples were treated using a plasma exposure apparatus in gas atmospheres of air, CO2, and C3F8. Surface analysis of Ti exposed to plasma was achieved through surface free energy and XPS measurements. The Ti sample was bonded with adhesive resin (4-META, MAC-10, HEMA, MDP, VBATDT) to a stainless steel piece. After which, shearing adhesion test was done. It was observed that plasma exposure in a specific gas atmosphere in regulated the bonding strength of titanium surface to resin. Based on the results of this study, we concluded that plasma exposure was a useful surface treatment method for dental practices.

Fabrication of porous particulate for the scaffold by applying solution spraying method.

A simple and novel method--in the form of solution spraying--was developed to fabricate biodegradable, porous poly(L-lactic acid) (PLLA) particulates for scaffold. PLLA pellets were dissolved in an organic solvent. Then, 5 % PLLA-dioxane solution was sprayed using an air-assisted atomizer with a nozzle diameter of 2.5 mm at an air flow rate of 15 L/min. After the sprayed solution solidified in liquid nitrogen, spherical particulates with median diameter of 225microm were obtained. Morphology of sprayed products could be altered by varying the fabrication conditions. When nozzle diameter was reduced to 1.5 mm, sprayed products became fibrous. When the concentration of PLLA-dioxane solution was increased, the diameter of particulates increased too. On the other hand, when air flow rate was increased, the diameter of particulates decreased. Likewise, solidification conditions also affected the morphology of sprayed products, such that they were either thin film-like or in particulate form. Based on the results of the present study, we concluded that PLLA particulates of varying morphologies could be obtained by adjusting the fabrication conditions.

Advantages of TOF-SIMS analysis of hydroxyapatite and fluorapatite in comparison with XRD, HR-TEM and FT-IR.

The chemical analysis of hydroxyapatite and fluorapatite was carried out using time-of-flight secondary ion mass spectrometry (TOF-SIMS). Hydroxyapatite and fluorapatite were synthesized at 80 +/- 1 degrees C and pH 7.4 +/- 0.2. Fluorapatite was better crystallized, with its (300) reflection shifted to a slightly higher angle. High-resolution transmission electron microscopy clearly revealed a typical, regular hexagonal cross section perpendicular to the c-axis for fluorapatite and a flattened hexagonal cross section for hydroxyapatite. FT-IR spectra of fluorapatite confirmed the absence of OH absorption peak--which was seen in hydroxyapatite at about 3570 cm(-1). TOF-SIMS mass spectra showed a peak at 40 amu due to calcium. In addition, a peak at 19 amu due to fluorine could be clearly seen, although the intensities of PO, PO2, and PO3 were very low. It was confirmed that TOF-SIMS clearly showed the differences between positive and negative mass spectra of hydroxyapatite and fluorapatite, especially for F-. We concluded that TOF-SIMS exhibited distinct advantages compared with other methods of analysis.

Measurement of masticatory movement by a new jaw tracking system using a home digital camcorder.

The aim of this study was to confirm the precision of our simple and inexpensive jaw tracking system which combined the use of a digital camcorder and a motion capture software developed lately. A marker was attached to the mandibular incisors of the subject, and a mirror was assembled beside the subject's face to detect antero-posterior movement during chewing. Jaw movements, including the mirror images, were recorded by a digital camcorder. The movements were traced by a motion capture software and translated into 3D data using original handmade software. To confirm the beneficial performance of our system in measuring masticatory movement, the masticatory movements of five subjects were simultaneously recorded together with a conventional jaw tracking system. Trajectories obtained from both systems were similar, and the correlation coefficient values by simple regression analysis between both trajectories were 0.9 or higher for all subjects. It was confirmed that our system could record masticatory movement with sufficient precision equivalent to that of a conventional jaw tracking system.