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The purpose of this study is to propose a new benefit segmentation method based on customer reviews existing on the web. With the diversification in customer needs, it is difficult to accurately identify the needs of customers with market segmentation using demographic information. Therefore, it is important in marketing to segment the customer market based on the benefits that customers receive for products or services. In this research, we use the random forest algorithm for benefit segmentation, as this algorithm identifies training data with high accuracy even if noise and outliers exist, and it is widely used for analysis of text data. In our experiment, we analyzed customer reviews for hotels. We treated the reason for using hotels as the benefit, and analyzed topics based on word frequency in the text data as explanatory variables. We extracted factors that influenced each benefit to determine customer needs.

We describe a design and a construction of a TW-class 12-fs Ti:sapphire chirped-pulse amplification system. We developed a broadband pulse stretcher, a broadband gain-narrowing compensator, broadband high-energy mirrors, high-energy dichroic chirped mirrors, a dispersion compensator, and a broadband pulse compressor for /spl sim/10-fs pulse generation. Utilizing these optical devices, we demonstrated a generation of 12-fs pulses from a 10-Hz-repetition-rate Ti:sapphire chirped-pulse multipass amplifier system and a 1-kHz-repetition-rate Ti:sapphire chirped-pulse regenerative amplifier system. Optimized designs of broadband Ti:sapphire amplifiers with multilayer gain-narrowing compensators and an adaptive dispersion compensator with a spatial light modulator contribute to the shorter pulse amplification.

Kerr-lens mode-locked Cr:LiSrAlF/sub 6/ lasers are demonstrated with various prism pairs based on a recalculation of the condition for compensating the intracavity dispersion. The minimum pulse duration is 9.9 fs, which is the limit for ordinary nonchirped dielectric mirrors. To develop an efficient diode-pumped Kerr-lens mode-locked Cr:LiSAF laser, diode-pumping geometry is also discussed.

The high pressure effect on resistance of the LB film of ditetradecyldimethylammonium-Au(dmit)2 [2C14N+Me2-Au(dmit)2] salt has been investigated; the measurements were performed down to 0.8 K and pressures up to 1.03 GPa using a clamptype pressure cell. The resistance gradually decreases with increasing pressure reaching a 57% smaller value at 1.03 GPa compared to the ambient one. The resistance increases with decreasing temperature for three different conditions of the measurement: at 0 GPa and under pressure (clamped at 0.80 GPa and 1.03 GPa) in the temperature range of 18−295 K. Over the whole temperature range, the higher the pressure is, the lower the sheet resistance is, indicating that the application of pressure is effective to reduce the sheet resistance. Although we have already reported the magnetic anomaly suggesting the Meissner state in the LB film below 3.9 K, no resistance drop is observed even if the resistance was measured down to 0.8 K.

We report a broadband high-energy mirror for TW-class chirped-pulse amplification of ≈10-fs pulses. This mirror consists of broadband coatings and optimized high-damage-threshold coatings for decreasing the intensity on the broadband coatings. It is important to optimize the number of high-damage-threshold coatings so that high damage-threshold and relatively low dispersion are traded off against each other. The bandwidth of this mirror (Δλ≈200 nm at λ0≈800 nm) is almost equivalent to that of a commercial broadband mirror, and the damage threshold of this mirror is almost equivalent to that of a commercial high-energy mirror. This mirror can withstand chirped pulse laser beam‘s with high fluence (>1 J/cm2) and wide spectra (153 nm FWHM) in practice.

The rotating dilution refrigerator has been built up and tested to study topology and dynamics of vortices in thin helium films in porous glasses. The torsional oscillator method is considered as the basic technique to be used. We are able to rotate the cryostat with angular velocity Ω up to 6.3 rad/s and resolve changes of about 0.3 mrad/s. The 40mK minimum temperature of the cryostat does not change up to the highest angular velocities.

Very dilute3He-4He solutions provide a model system for the study of the effects of magnetic polarisation. It was proposed by the Lancaster group1 that a “pumping” effect of3He should be observed under appropriate conditions in these solutions. In a strong magnetic field gradient, the3He should be pumped from the low field region towards the high field region, in which the3He is polarised. We have now observed this effect in 0.1% and 0.06% solutions, using a vibrating wire resonator in the low field region as the concentration indicator. The concentration change of a few percent under our present experimental conditions (9T maximum field, 10 mK) is of the expected magnitude so that development of the technique can now be considered.

Effects of a kampo (Japanese herbal) medicine "kami-untan-to (KUT)" on central cholinergic neurons were examined in vitro and in vivo. When rat embryo septal cells were cultured in the presence of KUT (50-500 μg/ml) for 3 days, significant increase of choline acetyltransferase (ChAT) activity was observed. However, KUT had no significant effect on nerve growth factor (NGF)-induced ChAT activity in basal forebrain cultures. When KUT was orally administered to the ibotenic acid-induced forebrain lesioned rats, mean latency was significantly increased on passive avoidance of step through type and ChAT activity in cerebral cortex was also increased. These results indicate that KUT is a neurotrophic-like agents which is effective to the cholinergic nervous system and may be useful as a potential therapeutic agent in diseases exhibiting cholinergic deficit.

Observations and applications of nonlinear acoustic phenomena in superfluid3He-B are reported. Two-phonon absorption (TPA) by the real squashing (rsq) mode has been detected under several experimental conditions below p = 3.5 bar, using two coincident sound pulses. The attenuation peak height has been investigated as a function of the energy densities of the two sound waves. We discovered the five-fold Zeeman splitting of TPA by parallel sound pulses in an applied magnetic field and the two-fold dispersion splitting due to the finite wave vector of the mode when the two sound pulses are mutually perpendicular. The dispersion relation of the real squashing mode has been investigated at zero pressure and in zero magnetic field by exciting the mode with two parallel, perpendicular, or antiparallel sound waves. Experimental values for the parameters that determine the collective-mode velocities have been extracted from the positions of the observed attenuation maxima. An anomalous structure has been observed in the attenuation and phase velocity spectra of a single high-intensity sound wave near the threshold for pair breaking by two phonons; in an applied magnetic field the phase velocity anomaly splits into a triplet.

The excitation gas in superfluid 3He at low temperatures shows a number of remarkable dynamical properties arising from the unusual dispersion curve. The existence of an energy gap leads to many of the observed properties varying rapidly with temperature, since the excitation density is dominated by the gap Boltzmann factor exp(—Δ/kT). But also, the fact that the minimum energy lies at finite momentum gives rise to Andreev scattering processes, in which the velocity of the excitation is reversed but the momentum left virtually unchanged. Since the dispersion curve looks different to a moving observer, there is the possibility of the free production of quasiparticle-quasihole pairs at a Landau critical velocity. At low temperatures the mean free path becomes much larger than any experimental size. Using vibrating wire resonators as universal probes, we can monitor the temperature, measure the Kapitza resistance, examine the nonlinear regime beyond the two-fluid model, observe the Landau velocity, create and detect thermal beams of excitation with black-body radiators, observe Andreev reflection directly and probe A-phase textures (in which the gas is one-dimensional). Future possibilities are discussed.

We describe the first direct measurement of the Andreev reflection of a beam of quasiparticle excitations in the B phase of superfluid 3 He in the ballistic regime (T/T c ≤0.2). The beam is generated by a blackbody radiator. The changing effective excitation gap which gives rise to the Andreev reflection is provided by a superflow gradient along the direction or the beam induced by a moving paddle. The component or the beam reflected by Andreev processes is observed via the retroreflective nature or the process which returns the reflected excitations to the blackbody and thereby increases its temperature over the value observed with no superflow

We report ultrasonic measurements on rotating 3He-A at 26.7 bar pressure and at magnetic fields below 12.0 mT. We observed two distinct types of vortices: the attenuation of zero sound by vortices which were created at small fields is higher than the attenuation by vortices created at high fields. The first order transition between the two vortex states was observed at Hc∼HD ({all equal to}3 mT). The low field structure can be identified with type-I vortices proposed by Fujita et al. and the high field one with that of Seppälä and Volovik and initially discovered in NMR experiments. The structural change may be viewed as a topological transition, because the d̂-vector distribution is different for the dipole-locked vortices in low fields from that for the dipole-unlocked vortices in high fields. In addition, a continuous change between coreless vortices and vortices with a well-defined core was observed at low enough fields H′ ≪ Hc. The vortices in 3He-A can, therefore, be characterized by three magnetic fields: H′, Hc, and Hcl. The last is the catastrophe field at which the dipole-locked vortices become unstable.

We report on investigations of a nonlinear parametric excitation of the real squashing (RSQ) collective mode in superfluid 3He-B. Two-phonon absorption (TPA) at fs + fp = frsq has been observed by two coincident zero sound pulses, with the signal and the pump wave frequencies at fs and fp, respectively. We have also discovered and studied the Zeeman splitting of TPA in a magnetic field, which is a characteristic feature of the J = 2+ mode in the linear response regime. The dependence of the mode frequency on the magnitude of the wave vector has been investigated; this can be done easily in parametric measurements only. In our earlier, preliminary observations, the coupling of the RSQ mode by TPA was weaker than theory predicted; the discrepancy has now been systematically studied and clarified.

A wave-acoustics theory has been developed to describe the propagation of zero sound parallel to vortex lines in rotating 3 He-A. We show that a diffraction «shadow» is formed in which the wave amplitude is suppressed by interference around vortices. This phenomenon contributes to the experimentally observed effect of rotation on the sound amplitude and exceeds the attenuation at large core radii. The dependence of the diffraction contribution on the angular velocity changes drastically at the transition from vortices with a finite core to foreless vortices when the magnetic field is decreased to zero

We have observed in superfluid {sup 3}He-{ital B} two-phonon absorption, which is one of the nonlinear effects recently predicted by McKenzie and Sauls. The {ital J}=2{sup +} real squashing mode was excited with two coincident sound pulses at the temperature {ital T}{sup +}, f{sub signal}+{ital f}{sub pump}={ital f}{sub rsq}({ital T}{sup +}), under 0, 2.7, and 3.5 bars pressure. The heights of the attenuation peaks scale almost linearly with the energy of the higher-intensity wave, in qualitative agreement with the theory. Furthermore, a satellite peak appears even in zero magnetic field, which originates from the reflected wave.

An ultrashort-pulses mode-locked ytterbium-doped fiber laser has been developed with 28.3 fs duration at 80 MHz. The dispersion was compensated by a grating pair inside the cavity and a prism pair outside the cavity.

Vortices in {sup 3}He-{ital A} in low magnetic fields ({ital H}{le}20 mT) have been studied by ultrasonics. A first-order phase change between two vortex types, with dissimilar sound absorption, has been found. The magnetic field at the transition is on the order of the dipolar field {ital H}{sub {ital d}}. The observed change occurs between continuous vortex textures with different topological charges in the {bold {cflx d}} field (where {bold {cflx d}} is the magnetic anisotropy vector).

Zero sound experiments on superfluid 3He-A at low pressures (< 3 bar) and in strong magnetic fields (>0.3T) show an increase in the attenuation at low temperatures (6 0.4 mK) which has been a puzzle until the present experiment. Coupling of the re-entrant normal flapping (NFL) mode to zero sound in a geometry where sound propagates in the direction of the magnetic field is shown to arise from a boundary layer at the walls whose thickness is about the dipolar coherence length D, of 3He-A. We estimate the value oft; at low temperatures and at low and intermediate pressures. We have also studied the nonlinearity of sound propagation near the NFL mode and found a reversal of it when passing the mode.

Two experimental studies are presented illustrating applications of organic materials of high nonlinear refractive index to femtosecond light-pulse technology. One is intracavity pulse-compression of a colliding-pulse mode-locked dye laser with the addition of nonlinear organic materials into a saturable absorber solution. Another is femtosecond pulse compression external to the laser using nonlinear organic fibers. On the basis of the experimental results, the present problems and the optical properties that nonlinear organic materials should satisfy are discussed.

Zero sound attenuation at 8.9 and 26.8 MHz in {sup 3}He-{ital B} shows an extremum at {ital T}{sub {ital AB}} in a field of {approx}2 kG at low pressures, both in the stationary and in the rotating superfluid. This is in accordance with the prediction that a critical magnetic field separates two types of {ital B} phases at the {ital AB} transition line, with and without nodes in the energy gap, respectively, and with a change in the nature of the transition. The {ital AB} phase transition takes place via an intermediate state, possibly a new phase, characterized by excess sound attenuation.

summary This study evaluated the fracture loads of three-unit all-ceramic bridges on implants; the core frameworks of the bridges were made of zirconium oxide. Three core framework designs were fabricated according to the design of the bars between the retainers: (i) straight, (ii) curved in the occlusal direction, or (iii) curved in the gingival direction. A static load was applied at the centre of the pontic, and the mean initial crack and final fracture loads were measured and compared. The core framework curved in the occlusal direction had the highest final fracture loads; there were significant differences (P

Summary from only given. We succeed to improve the pulse duration of a diode-pumped KLM Cr:LiSrAlF/sub 6/ (Cr:LiSAF) laser using broadband chirped mirrors. Moreover, we apply the laser configuration for a Cr:LiSGaF laser to generate 10-fs pulses. These are, to our knowledge, the shortest pulses ever produced from Cr:LiSAF and Cr:LiSrGaF/sub 6/ (Cr:LiSGaF) lasers.

Summary form only given. The control of CEP-slip of mode-locked laser oscillators has been demonstrated recently. To use the amplified high-intensity pulses, however, measurement of the CEP on a single-shot basis is preferable. Here, we propose a method for the single-shot measurement of the CEP by observing the electron angular distribution generated by ionization by a time-dependent polarization (TDP) pulse. Some important points such as the broadening of the distribution, Gouy phase shift, phase difference between the two components, and the asymmetric pulse shape, are discussed. This method is robust against intensity fluctuation because the positions of the peaks depend only on the CEP and the relative heights of the peaks depend on the peak intensity.

We present the results of investigations on the thermal effects in the Ti:sapphire multipass amplifier. The thermal lensing in the amplifier was evaluated by measuring the optical path difference (OPD). The OPD denotes the optical path difference of the Ti:sapphire gain medium in the amplifier with and without thermal loading of the pumping.

Summary form only given. Mode-locked Cr:LiSAF lasers are attractive femtosecond (fs)-pulse sources which can directly be pumped by compact diode lasers. Although 14.8-fs pulses were generated using Kr-ion laser as a pumping source, the pulse durations from all-solid-state Cr:LiSAF lasers have been no shorter than 18 fs. In this letter we present what we believe to be the first generation of 12-fs pulses from an all-solid-state femtosecond Cr:LiSAF laser.

Mode-locked Cr:LiSAF lasers are attractive femtosecond (fs)-pulse sources which can directly be pumped by compact diode lasers. Although 14.8-fs pulses were generated using Kr-ion laser as a pumping source, the pulse durations from all-solid-state Cr:LiSAF lasers have been no shorter than 18 fs. In the report we analyze intracavity dispersions of the all-solid-state femtosecond Cr:LiSAF laser which produces 12-fs pulses, This is to our knowledge the shortest pulses ever produced from a mode-locked Cr:LiSAF laser.

A novel phase-locked loop was developed for synchronization between two mode-locked lasers. The up-converted signal was used to detect phase difference. The relative timing jitter was reduced to less than 500 fs for 30 minutes.

We design and fabricate a chirped mirror for a sub-10-fs Ti:sapphire oscillator, which has the layers with optical thickness of more than 100 nm.

In-situ feedback controlled pulse shaping has demonstrated when a pulse shaping apparatus is placed before the amplifier. For the efficient and rapid control, we evaluated optimization algorithms and parameters.

Summary form only given. Fourier-transform synthesis of femtosecond laser pulses is opening up new application fields including mode-selective excitation of coherent phonons and generation of THz radiation from a semiconductor quantum well. Some applications, such as the coherent control of chemical reactions and the efficient generation of electrons in an RF-gun, need amplified and arbitrarily shaped femtosecond laser pulses. When we want such pulses, we should place a pulse shaping apparatus, which consists of a modulating devise, a grating pair, and a lens pair, between an oscillator and an amplifier to avoid damages to a modulation device. In order to obtain arbitrarily shaped femtosecond laser pulses, we may use amplitude-phase filters or a phase-only filter. Amplitude modulation of laser pulses before the chirped pulse amplification may cause damages of optical elements in a regenerative amplifier especially for a longer shaped pulse. Hence, in this presentation, we show the results with a phase-only filter, which does not cause damages in a process of the chirped pulse amplification.

Summary form only given. A high brightness femtosecond X-ray pulse can be obtained by the laser Compton scattering process. In our plan, a 1 ps single electron bunch, which is generated from an RF photocathode and accelerated by a Microtron accelerator, is collided with a 100 fs high power laser pulse. One of the key technologies of this X-ray pulse generation technique is the synchronization of the laser pulses with the electron bunches. Therefore, it is extremely important to manage the shot-to-shot timing fluctuation in femtosecond optical pulse sources.Recently, we proposed a new method of shot-to-shot timing error measurement for low-repetition rate high-energy ultrafast pulses by means of the spectral-resolved cross-correlation technique, and applied the method to a conventional kHz Ti:sapphire regenerative amplifier. In this report, we demonstrate the active stabilization of amplified pulse timing for a kHz regenerative amplifier based on our monitoring method.

Summary form only given.We have developed a subharmonic generator by using the femtosecond optical parametric oscillator (OPO) and observed phase relation between three pulses. Wavelengths of the pump, signal and the idler are 850 nm (3w), 1275 nm (2w) and 2550 nm (w), respectively by using KTiOPO/sub 4/ (KTP) with a 71.5 deg. phase matching angle.

A Phase 2 multicenter trial of 123I-IBF, (S)-5-iodo-7-N-[(1-ethyl-2- pyrrolidinyl)methyl]carboxamido-2,3-dihydrobenzofuran, was conducted to evaluate its clinical efficacy and safety in 158 patients with Parkinson's disease (PD) or Parkinson syndromes (PS). SPECT data were acquired at two hours (2H-SPECT), after intravenous injection of 123I-IBF (167 MBq). Additional SPECT scan at three hours (3H-SPECT) and dynamic SPECT scan at most until one hour were performed when possible. No severe side effects due to 123I-IBF injection were observed. The sensitivity, specificity and accuracy for discriminating PS from PD using the striatal specific binding count-to-frontal cortex count ratio (St/Fc-1) in 3H-SPECT were 72.7%, 81.0% and 78.1% in 64 clinically definite cases (i.e., typical cases), respectively. The putamen-to-caudate ratios were significantly lower in striatonigral degeneration compared with those in PD. The contralateral-to-ipsilateral ratios against the symptomatic side of tremor and/or rigidity in the patients with PD (HoehnYahr I) were significantly higher than the left-to-right ratios in the normal controls. St/Fc-1 in 3H-SPECT was significantly lower in the patients showing a poor response to levodopa than in those showing a good response. The dopamine D2 receptor binding potential (k3/k4), obtained by dynamic SPECT based on compartment model analysis, correlated well with the striatal specific binding count-to-occipital cortex count ratio. These results suggest that 123I-IBF is a promising agent for differential diagnosis and pathophysiological evaluation of PD and PS.

In this age of "Medical Imaging", Nuclear Medicine has occupied a preeminent position, heralded by the following four points: the development of novel radio-nuclides containing compounds (radio-diagnostic and radio-therapeutic agents), the power of extremely sensitive new measuring devices, the highly reliable quantification of physio-pathological changes occurring in disease and the guidance to medical diagnosis. On those four points, Nuclear Medicine will continue to spread, but new frontiers are emerging, and it is challenged to provide measurements of consistently reliable accuracy to guide various forms of treatment and radiotherapy requiring a high standard of competence.

The phase III clinical trial of strontium-89 chloride agent (SMS.2P) was performed in 90 patients with painful bone metastases secondary to prostate (53), breast (18) and other types of cancer (19). Some patients experienced a transient increase in pain or nausea and vomiting. However both symptoms subsided and serious side effects were not observed in any of the patients. As reported, we confirmed some abnormal changes in peripheral blood picture. A decrease in the number of white blood cells and platelets was considered to be partly a result of bone marrow suppression due to 89Sr irradiation. Pain was substantially improved after 89Sr therapy in 58% of the patients and there was some alleviation in 12%. The release from pain was accompanied by an improved quality of life for these patients including sleep patterns and morbidity. Some patients were able to resume their former life styles. Most of the improved patients experienced pain relief from days to one week following 89Sr therapy and in half cases, this remained effective for 2 or 3 months. There were even cases in which the pain relief continued over an observation period of time of clinical study.

Serum tissue polypeptide antigen (TPA) was measured using a newly developed Prolifigen TPA-M "Daiichi" kit in 1,236 healthy subjects, 2,867 patients with malignant tumors, and 901 with benign diseases. Because 94.0% of healthy subjects had serum TPA under 70 U/l, the cut-off value was set at 70 U/l. Serum TPA was elevated in more than 50% of patients with head and neck cancer, lung cancer, liver cancer, gallbladder or bile duct cancer, pancreatic cancer, colorectal cancer, ovarian cancer, and prostate cancer. The overall positive rate in malignant tumors was 55.5%. Serum TPA was higher in advanced cancer than in earlier stage cancer, and decreased after the resection of the tumor. The false positive rate in benign diseases was 31.3%. ROC analysis revealed the usefulness of TPA as a tumor marker in many cancers. The correlation coefficient between TPA and CYFRA 21-1, and between TPA and TPSA, was 0.747 and 0.694, respectively. In conclusion, measurement of serum TPA using the new kit is useful in the management of patients with various malignant tumors.

Single photon emission computed tomography (SPECT) using 123I-Iomanzenil (IMZ), a tracer which binds specifically to central-type benzodiazepine receptors, was performed in patients with cerebrovascular diseases (CVD) to determine the clinical signicigance of IMZ SPECT studies in evaluating the pathophysiology of CVD. IMZ SPECT images obtained three hours after administration of the tracer were compared with the images of cerebral blood flow (CBF) studies in 206 cases. In regions with decreased CBF, the uptake of IMZ was relatively preserved in patients with cerebral thrombosis in comparison with cerebral embolism, and in those with perforator branch infarction in comparison with cortical infarction. The uptake of IMZ decreased as a function of both the severity of the decrease in the CBF and the duration of illness in regions with a significantly decreased perfusion reserve. These results suggest that decreased IMZ binding in ischemic stroke reflects the neuronal damage caused by the cerebral ischemia. On the other hand, in patients with intracerebral hemorrhage, the cortical uptake of IMZ was relatively well-preserved in regions with decreased CBF, and the decrease in the uptake of IMZ was more profound as a function of the decrease in the CBF, especially in cases of putaminal hemorrhage. These results also suggest that the decreased cortical CBF is a remote effect caused by a neuronal disconnection, and neuronal damage may occur in regions with severely impaired CBF.

Iomazenil (IMZ) is a partial inverse agonist of central-type benzodiazepine receptors (BZR) which binds specifically to BZR with high affinity. The safety and clinical effectiveness of 123I-IMZ SPECT in the diagnosis of brain diseases were evaluated in 655 patients with various brain diseases, such as epilepsy, cerebrovascular diseases, degenerative diseases and mental disorders relating to BZR. This was a Phase 3 study conducted as a multicenter trial at 52 collaborating institutions. There was no significant adverse reactions in the clinical symptoms or abnormal laboratory test values. The investigators judged 123I-IMZ SPECT to be effective in 95% of 638 analyzed cases. The injected dose did not correlate with the image quality or the clinical effectiveness of 123I-IMZ SPECT, suggesting that these items depend largely on the characteristics of the apparatus used, the disease or pathology of the patients, rather than the dose. We conclude that 123I-IMZ imaging is safe and provides effective information based on BZR binding which is useful in the diagnosis of various brain diseases.

A Phase 3 clinical trial of 123I-Iomazenil (IMZ), a tracer which binds specifically to central-type benzodiazepine receptors (BZR), was performed, and the clinical usefulness of IMZ was evaluated in 121 patients with epilepsy (106 cases with partial epilepsy and 15 cases with generalized epilepsy). A regional abnormality in the BZR distribution was detected in late IMZ images in 20 of 24 cases without abnormal MRI and/or X-ray CT findings. Moreover, only 16 of these 20 cases showed abnormal findings in the cerebral blood flow (CBF) images. In partial epilepsy, abnormal regions in late IMZ images agreed or partially agreed with epileptic foci estimated from the clinical symptoms of epileptic seizures, interictal EEG, and MRI and/or X-ray CT findings in 76%, 70% and 96% of the cases detected. These regions also agreed or partially agreed with the estimated epileptic foci in 92% of the cases with foci estimated by combination of those three methods and in 72% of those estimated by ictal EEG. The agreement or partial agreement rates of late IMZ images with each of the other methods were higher than those of CBF images, although the differences were not significant. For surgically-proven epileptic foci without any abnormality in the CBF image, abnormal regions were detected in late IMZ images. These findings suggest that IMZ SPECT is a useful new tool for detecting epileptic foci based on the distribution of BZR in the brain.

Iomazenil (IMZ) is a partial inverse agonist of central-type benzodiazepine receptors (BZR) which binds specifically to BZR with high affinity. A multi-center Phase 3 clinical study was performed to evaluate the clinical usefulness of 123I-IMZ-SPECT in the diagnosis of brain disorders in 169 patients with degenerative neurological diseases and 37 patients with mental disorders such as neurotic, stress-related and somatoform disorders. In dementia, the decrease in activity in late images, obtained three hours after administration of 123I-IMZ, correlated negatively with the dementia score. In Parkinson's disease and spinocerebellar degeneration. 123I-IMZ showed a more profound decrease in uptake in late images than seen in the cerebral blood flow (CBF) images, and this decrease was in proportion to the duration and severity of the illness. In mental disorders, the ratio of the late to early image counts showed a negative correlation with Hamilton's anxiety scale in all regions in the brain cortices. In panic disorders, the ratio of the cerebral count to the cerebellar count in the late images correlated negatively with the severity of the attack in the frontal, temporal and parietal cortices. These results suggest that 123I-IMZ-SPECT enables us to evaluate the neuronal damage in degenerative diseases and the decrease in the BZR binding potential in mental disorders.

A phase 2 study of 123I-Iomazenil (IMZ) was performed to evaluate its clinical usefulness in SPECT imaging of central-type benzodiazepine receptors (BZR). A total of 246 patients with various central nervous system disorders [82 with epilepsy, 94 with cerebrovascular disease (CVD), 47 with degenerative disorders, 14 with mental disorders relating to BZR and 9 with other diseases] were intravenously injected with 111-222 MBq of IMZ. Early and late images were obtained 15 min and 180 min after injection as the mid-scan time, respectively. In comparison with regional cerebral blood flow (rCBF) images, the uptake of IMZ in the late images, which reflect the regional distribution of BZR, was relatively preserved compared to the uptake of CBF tracers in most of the patients with CVD. In the area of hyperperfusion in the subacute phase of cerebral infarction, however, the defects of IMZ uptake were accompanied by increased uptake of the CBF tracers. On the other hand, late IMZ uptake in most of the patients with the other diseases was decreased more significantly than the uptake of the CBF tracers, suggesting that cortical neuronal damage is more prominent than rCBF in these diseases compared to the vascular perfusional state. No adverse reactions were recognized relating to the IMZ administration. These results suggest that IMZ may provide us with valuable information for assessing pathophysiological state in the brain, which are difficult to achieve with other imaging modalities.

A phase 2 clinical study of 123I-iomazenil (IMZ) was performed to evaluate its clinical usefulness as central-type benzodiazepine receptor imaging agent in 81 cases with epilepsy, 82 cases with cerebrovascular diseases (CVD), 35 cases with degenerative disorders and 14 cases with mental disorders. In epilepsy, IMZ SPECT images for detection of epileptic foci showed relatively high specificity compared with EEG recording in not only interictal but also ictal state, in spite of the fact that IMZ SPECT images was performed during interictally. It was surmised that IMZ SPECT provides valuable clinical information for detection of epileptic foci which are hard to be diagnosed by EEG. The frequency of abnormal findings by IMZ late images was higher than that by interictal blood flow images and comparable to that by ictal blood flow images. In patients with CVD, different observations were obtained between IMZ late images and blood flow images; for example, in regions of hemodynamic cerebral ischemia, postischemic reperfusion and other pathological perfusion, IMZ late images seemed to reflect the degree of cortical neuronal loss. In patients with degenerative disorders, the binding potential (calculated by a simple quantitative method for IMZ) and other parameters correlated with the dementia score. While the number of examined cases with mental disorders was limited, the frequency of abnormal findings with IMZ imaging was higher than that with morphological imaging.

The biodistribution, metabolism and excretion of 123I-iomazenil have been studied in rats, rabbits and humans following i.v. administration. In all the species, 123I-iomazenil was rapidly metabolized and more than 90% of the administrated radioactivity was excreted within the first 24 hr. Dominant metabolites were acid metabolite (R-COOH), glucuronide of the acid (R-COOH-Glc) and free iodide (I-) in rats and humans. On the other hand, R-COOH, oxidative metabolite (R'-CH2COOH) and I- were found in rabbits. Thus, the possible metabolic pathways of iomazenil were hydrolysis, oxidation, conjugation and deiodination. The radioactivity was excreted into both urine and feces in rats, while primary route of excretion in rabbits and humans was from the kidneys. At 3 hr after injection, more than 97% of the radioactivity in rat brain was found in the form of the parent compound. This result indicates that metabolites of 123I-iomazenil do not cross the blood-brain barrier.

A Phase 1 clinical study of 123I-iomazenil (IMZ), a new radiopharmaceutical developed for evaluation of central-type benzodiazepine receptor (BZR) with SPECT, was performed to examine its safety and biodistribution in six healthy volunteers. The brain uptake of 123I-IMZ reached a maximum value of 11.7 +/- 1.6% of the injected dose at 10-20 min after i.v. administration, and then decreased slowly. The regional tracer distribution immediately after injection (0-10 min) was considered to be a reflection of the cerebral blood flow. From 2 to 3 hours post-injection, washout of the radioactivity from the deep gray matter was observed, resulting in the distribution reflecting the reported distribution of BZR. No significant accumulation was seen in any organ other than the brain. The estimated absorbed dose of 123I-IMZ calculated by the MIRD method was comparable to that of 123I-N-isopropyl-p-iodoamphetamine. Neither adverse reactions nor abnormal clinical laboratory findings due to the drug administration were observed. These results suggest that 123I-IMZ is a safe and promising agent for evaluating the function of central-type BZR.