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To determine the locations and predictive factors of hypertrophic pachymeningitis (HP), a serious central complication of otitis media with antineutrophil cytoplasmic antigen-associated vasculitis (OMAAV).Retrospective study.University hospital.Thirty-six patients with OMAAV underwent contrast-enhanced magnetic resonance imaging (CE-MRI) of the brain, of whom 18 and 18 had or did not have HP, respectively.The location of HP lesions, which were detected as dural thickening on CE-MRI, was reviewed. Clinical characteristics, laboratory data, and audiometric data before treatment were correlated with the occurrence of HP.HP lesions were most frequently observed in the middle cranial fossa, followed by the internal auditory meatus, tentorium cerebelli, and posterior cranial fossa, which were adjacent to the middle ear primary lesion. Headache was more frequently observed in patients with HP than without HP. The neutrophil-to-lymphocyte ratio (NLR) of the HP (+) group (median, 3.91; interquartile range, 2.50-6.06) was higher than that of the HP (-) group (median, 2.40; interquartile range, 2.01-3.03). The area under the receiver operating characteristic curve for the NLR was 0.741. An NLR of 3.46 had the highest sensitivity (61.1%) and specificity (94.4%) for predicting HP. Other markers of systemic inflammation and comorbidities of systemic diseases were not different between the groups.HP may not be a systemic manifestation of OMAAV but may be related to local lesions in the adjacent brain. A high NLR may be a predictive factor for comorbid HP. Therefore, CE-MRI should be considered for patients with a high NLR.

Objective To examine the validity of head roll-tilt subjective visual vertical (HT-SVV) in diagnosing persistent postural-perceptual dizziness (PPPD). Study design Retrospective review. Setting Tertiary referral center. Patients Sixty-one patients with PPPD, 10 with unilateral vestibular hypofunction (UVH), and 11 with psychogenic dizziness (PD), showing chronic vestibular symptoms for >3 months. Interventions Head-tilt perception gain (HTPG, i.e., mean perceptual gain [perceived/actual tilt angle]) during right or left head tilt of approximately 30° (HT-SVV) and conventional head-upright SVV (UP-SVV) were measured. Bithermal caloric testing, cervical and ocular vestibular-evoked myogenic potentials (cVEMP and oVEMP), and posturography were conducted. Main outcome measures Multiple comparisons were performed for the HT-SVV and other vestibular tests among the disease groups. A receiver operating characteristic curve was created to predict PPPD using HTPG. Results HTPG was significantly greater in the PPPD group than in the UVH and PD groups. There were no significant differences in UP-SVV, cVEMP, oVEMP, and posturography (foam ratio and Romberg ratio on foam) among the disease groups, while the UVH group had the highest canal paresis compared to the other two groups. The area under the curve of the receiver operating characteristic curve for predicting PPPD was 0.764, and the HTPG value of 1.202 had a specificity of 95.2% for diagnosing PPPD. Conclusions While conventional vestibular tests including UP-SVV, VEMPs, and posturography did not show abnormalities in PPPD, high HTPG in the HT-SVV test, an excessive perception of head tilt, can be a specific marker for discriminating PPPD from other chronic vestibular diseases.

Objective Otitis media with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV) is characterized by adult otitis media refractory to conventional treatments. OMAAV is either an aural manifestation of existing ANCA-associated vasculitis (AAV) or an initial aural manifestation of AAV. OMAAV occasionally causes an irreversible profound sensorineural hearing loss that may require a cochlear implant even in the latter case. In such a case, prompt diagnosis of OMAAV is important but sometimes difficult. When diagnosing OMAAV, repetitive otitis media with effusion (OME) in adults is the most difficult differential diagnosis. Precise evaluation of tympanic membrane (TM) findings would help to achieve a prompt diagnosis. The objective of this study was to discriminate OMAAV from adult OME based on tympanic TM findings. Methods 10 with OMAAV and 10 with adult OME were included. We established a sc oring system of O MAAV t ympanic membrane (SCOT) to evaluate TM findings of OMAAV consisted of following three characteristic findings: thickening of pars tensa, vasodilation of pars tensa, and posterior wall swelling. Each TM finding in OMAAV and OME was scored from 0 to 3 by 20 otolaryngologists who never knew the diagnosis. Reliability of the scoring system in terms of consistency between examiners was evaluated by intraclass correlation coefficients (ICC). Validity was tested by comparing the TM scores between OMAAV and OME and by the area under the curve (AUC) of receiver operating characteristic (ROC) curve to discriminate OMAAV from OME. Correlations between the TM scores and various systemic markers of OMAAV including white blood cell count, C-reactive protein, myeloperoxidase-anti-neutrophil cytoplasmic antibody, and Birmingham Vasculitis Activity Score were examined. Results The ICC of each score was over 0.95. Each of and the total TM scores were significantly higher in OMAAV than in OME. AUC of ROC curve was 0.9134. The cut-off value set at 2 points had the best combination of sensitivity (93.0%) and specificity (74.0%) to distinguish OMAAV from OME. No significant correlations were found between the total score of SCOT and systemic markers. However, the total score of SCOT significantly correlated with the average hearing level of both air (p = 0.021) and bone conductions (p = 0.032). Conclusion Reliability and validity of SCOT in discriminating OMAAV from adult OME, the most difficult differential diagnosis, were demonstrated, suggesting that SCOT would be useful to make an early diagnosis of OMAAV. Correlation of SCOT with hearing level suggests that SCOT is also useful to evaluate disease status of OMAAV.

Objective To present a case of pediatric cholesteatoma that invaded the petrous apex (PA) and discuss the usefulness of preoperative three-dimensional (3D) surgical simulation on a personal computer (PC) and patient-specific 3D printed model-assisted surgery. Patient A 5-year-old boy with congenital cholesteatoma underwent a planned two-stage canal wall up mastoidectomy. The cholesteatoma had invaded the PA from a small space anterior to the superior semicircular canal (SSCC). During the removal of this lesion in the first surgery, the tip of a 1-mm round knife broke off and fell into the PA. The surgeon could not remove it, as it was thought that opening the space might damage the SSCC and the facial nerve (FN). Intervention Before the second surgery, a preoperative 3D surgical simulation on a PC was performed, and an approach to the PA via the triangle surrounded by the SSCC, FN, and middle cranial fossa, namely, the supracochlear approach, was discovered. A patient-specific 3D-printed model, which had been drilled to make each surface of the triangle including the SSCC, FN, and middle cranial fossa visible in the PC simulation surgery, was then created and a 3D-printed model-assisted surgery was planned. Results By placing the sterilized patient-specific 3D model close to the surgical field, the cholesteatoma and iatrogenic foreign body could be successfully removed from the PA without damaging the important surrounding structures. Conclusions Preoperative 3D surgical simulations and intraoperative patient-specific 3D-printed model-assisted surgeries are new, powerful tools that aid in performing challenging surgeries on temporal bones.

OBJECTIVE To test whether the threshold of nerve integrity monitor (NIM) responses during facial nerve decompression surgery can predict the postoperative outcome. STUDY DESIGN Retrospective study. SETTING University hospital. PATIENTS Twenty peripheral facial palsy patients who underwent transmastoid decompression surgery. INTERVENTION During decompression surgery, thresholds of NIM responses were measured via direct facial nerve stimulation at three sites: the geniculate ganglion (GG), the second genu (2 G), and the stylomastoid foramen. MAIN OUTCOME MEASURES Facial nerve function was evaluated before and 6 months after surgery using the Yanagihara grading score (maximum score = 40 points). Complete recovery was defined as an improvement of the grading score to ≥ 36 points without synkinesis. Variables including age, sex, disease (Bell's palsy or Ramsay Hunt syndrome), time after onset, Yanagihara grading score, and electroneurography before surgery, and the thresholds of NIM responses during surgery were compared in the complete and incomplete recovery groups. NIM responders were defined as those exhibiting a NIM response of < 1.5 mA at any site. Postoperative Yanagihara grading scores in NIM responders and NIM nonresponders were compared. RESULTS No variables differed significantly in the complete and incomplete recovery groups before surgery. NIM response thresholds in the complete recovery group at the GG and the 2nd G were significantly lower than the corresponding thresholds in the incomplete recovery group. The postoperative Yanagihara grading scores of NIM responders were significantly better than those of NIM nonresponders. CONCLUSION NIM responses to intraoperative direct facial nerve stimulation were useful for predicting outcomes after decompression surgery.

Objective: To develop a diagnostic algorithm for chronic vestibular syndromes by determining significant items that differ among diagnoses.Methods: Two hundred thirty-one patients with chronic vestibular syndromes lasting for >3 months were included. Full vestibular tests and questionnaire surveys were performed: bithermal caloric test, cervical and ocular vestibular-evoked myogenic potential assessment, video head impulse test (vHIT), posturography, rotatory chair test, dizziness handicap inventory, hospital anxiety and depression scale (HADS), and Niigata persistent postural-perceptual dizziness (PPPD) questionnaire (NPQ). Differences in each item of the vestibular tests/questionnaires/demographic data were tested among the diagnoses. A receiver operating characteristic (ROC) curve was created for the significant items. The value that provided the best combination of sensitivity/specificity on the ROC curve was adopted as a threshold for diagnosing the targeted disease. Multiple diagnostic algorithms were proposed, and their diagnostic accuracy was calculated.Results: There were 92 patients with PPPD, 44 with chronic dizziness due to anxiety (CDA), 31 with unilateral vestibular hypofunction (UVH), 37 with undifferentiated dizziness (UD), and 27 with other conditions. The top four diagnoses accounted for 88% of all chronic vestibular syndromes. Five significant items that differed among the four diseases were identified. The visual stimulation and total NPQ scores were significantly higher in the patients with PPPD than in those with UVH and UD. The percentage of canal paresis (CP %) was significantly higher in the patients with UVH than in those with PPPD, CDA, and UD. The patients with CDA were significantly younger and had higher anxiety scores on the HADS (HADS-A) than those with UVH and UD. Moreover, catch-up saccades (CUSs) in the vHIT were more frequently seen in the patients with UVH than in those with PPPD. The most useful algorithm that tested the total and visual stimulation NPQ scores for PPPD followed by the CP%/CUSs for UVH and HADS-A score/age for CDA showed an overall diagnostic accuracy of 72.8%.Conclusions: Among the full vestibular tests and questionnaires, the items useful for differentiating chronic vestibular syndromes were identified. We proposed a diagnostic algorithm for chronic vestibular syndromes composed of these items, which could be useful in clinical settings.

Tinnitus therapies have been combined with the use of varieties of sound/noise. For masking external sounds, location of the masker in space is important; however, effects of the spatial location of the masker on tinnitus are less understood. We aimed to test whether a masking sound location would affect the perception level of simulated tinnitus. The 4 kHz simulated tinnitus was induced in the right ear of healthy volunteers through an open-type earphone. White noise was presented to the right ear using a single-sided headphone or a speaker positioned on the right side at a distance of 1.8 m for masking the simulated tinnitus. In other sessions, monaurally recorded noise localized within the head (inside-head noise) or binaurally recorded noise localized outside the head (outside-head noise) was separately presented from a dual-sided headphone. The noise presented from a distant speaker and the outside-head noise masked the simulated tinnitus in 71.1% and 77.1% of measurements at a lower intensity compared to the noise beside the ear and the inside-head noise, respectively. In conclusion, spatial information regarding the masking noise may play a role in reducing the perception level of simulated tinnitus. Binaurally recorded sounds may be beneficial for an acoustic therapy of tinnitus.

Objective Diagnostic criteria for otogenic skull base osteomyelitis (SBO) have been conflicting among researchers. We aimed to propose clinically useful diagnostic criteria and a staging system for otogenic SBO that is associated with infection control and mortality. Design The present study is designed as a retrospective one. Setting This study was conducted at the University Hospital. Participants Thirteen patients with otogenic SBO who met the novel rigorous diagnostic criteria consisted of symptomatic and radiological signs on high-resolution computed tomography (HRCT) and magnetic resonance imaging (MRI). Simple refractory external otitis was not included. A staging system according to disease extent revealed by HRCT and MRI is proposed: lesions limited to the temporal bone (stage 1), extending to less than half (stage 2), exceeding the midline (stage 3), and extending to the whole of the clivus (stage 4). All patients received long-term antibiotic therapy. Patients were divided into infection-uncontrolled or -controlled groups based on symptoms, otoscopic findings, and C-reactive protein level at the last follow-up. The mean follow-up period was 27.7 months. Main Outcome Measures Possible prognostic factors, such as immunocompromised status and symptoms, including cranial nerve palsy, pretreatment laboratory data, and treatments, were compared between the infection-uncontrolled and -controlled groups. Disease stages were correlated with infection control and mortality. Results The infection-uncontrolled rate and mortality rate were 38.5 and 23.1%, respectively. There were no significant differences in possible prognostic factors between the infection-uncontrolled and -controlled groups. HRCT-based stages significantly correlated with infection control and mortality. Conclusion We proposed here the clinically useful diagnostic criteria and staging systems that can predict infection control and prognosis of otogenic SBO.

Objective: To establish a questionnaire to diagnose and assess the severity of persistent postural-perceptual dizziness (PPPD). Study Design: Retrospective chart review. Setting: Tertiary referral center. Patients: Fifty PPPD patients and 50 consecutive control patients with other vestibular disorders. Interventions: Patients answered questions on three exacerbating factors of PPPD (upright posture/walking, movement, and visual stimulation), and each factor was evaluated using four questions scoring the severity from 0 (none) to 6 (unbearable). Somatic and psychological distress was evaluated by the Visual Analog Scale (VAS) and the Hospital Anxiety and Depression Scale (HADS), respectively. Main Outcome Measures: The questionnaire's reliability was tested by Cronbach's alpha, and it was validated by examining the differences in the questionnaire's scores between PPPD patients and controls. The area under the curve (AUC) of the receiver operating characteristic curve for each factor was calculated. Results: Cronbach's alpha coefficient was >0.8 for all factors, except the movement factor. There were no significant differences in the VAS and HADS scores between the two groups. However, the combined and individual questionnaire scores for each factor were higher in PPPD patients than in controls, indicating the questionnaire's high validity. The AUC was widest for the visual stimulation factor (0.830), and a score of 9 (full score 24) had the best sensitivity (82%) and specificity (74%) for discriminating PPPD patients from controls. Conclusions: We developed a questionnaire that exhibited high reliability and validity in evaluating PPPD severity. The visual stimulation factor may be the most characteristic among the three exacerbating factors.

Background: Persistent postural-perceptual dizziness (PPPD) is a persistent chronic vestibular syndrome exacerbated by upright posture/walking, active or passive motion, and exposure to moving or complex visual stimuli. PPPD has four precursors: phobic postural vertigo, space-motion discomfort, visual vertigo, and chronic subjective dizziness. These four diseases share clinical features that form the basis of the diagnostic criteria for PPPD. Semiological similarities do not necessarily mean that PPPD is a single entity. However, if PPPD is not a single disorder but just a composite of four precursors, it may be subdivided according to the characteristics of each precursor.Objective: To test whether PPPD is a single disorder, we attempted a subtyping of PPPD.Methods: One-hundred-eight untreated patients with PPPD were enrolled in the study, who filled out the Niigata PPPD Questionnaire (NPQ) that consists of 12 questions on exacerbating factors for PPPD. A factor analysis of the patients' answers to the NPQ and a subsequent cluster analysis of the patients with PPPD using factors revealed by the factor analysis were performed. To validate our cluster classification, cluster differences were assessed using analysis of variance. Multiple comparison analyses were performed on demographical data, precipitating diseases, the Dizziness Handicap Inventory, the Hospital Anxiety and Depression Scale, and several vestibular tests to characterize each cluster.Results: Factor analysis revealed three underlying factors among the exacerbating factors in the NPQ. Exacerbation by visual stimuli (visual factor) accounted for 47.4% of total variance in the questionnaire. Exacerbation by walking/active motion (active-motion factor) and by passive motion/standing (passive-motion/standing factor) accounted for 12.0 and 7.67% of variance, respectively. Cluster analysis revealed three clusters: the visual-dominant subtype (n = 49); the active motion-dominant subtype (n = 20); and the mixed subtype (n = 39). The patients in the active motion-dominant subtype were significantly older than those in the visual-dominant subtype. There were no significant differences among the subtypes in other demographical data or conventional vestibular tests.Conclusions: The most common main exacerbating factor of PPPD was the visual factor. PPPD may be categorized into three subtypes. Conventional vestibular tests failed to point the characteristics of each subtype.

Background: Vestibular Meniere's disease (American Academy of Ophthalmology and Otolaryngology, 1972) also known as possible Meniere's disease (American Academy of Otolaryngology Head and Neck Surgery, 1995) or vestibular type of atypical Meniere's disease (V-AMD) (Japan Society for Equilibrium Research, 2017) is characterized by an episodic vertigo without hearing loss. Though named as Meniere's disease (MD), this entity may not be caused solely by endolymphatic hydrops (EH).Objective: To estimate the role of EH in vestibular Meniere's disease in comparison with definite Meniere's disease.Methods: Thirty patients with unilateral definite MD and 16 patients with vestibular Meniere's disease were included. Those who met the criteria for definite or probable vestibular migraine were excluded. All patients underwent vestibular assessments including inner ear MRI 4 h after intravenous gadolinium injection, bithermal caloric testing, directional preponderance of vestibulo-ocular reflex in rotatory chair test, cervical- and ocular-vestibular evoked myogenic potential, stepping test, dizziness handicap inventory (DHI), and hospital anxiety and depression scale (HADS). All above tests and frequency/duration of vertigo spells were compared between vestibular Meniere's disease and MD.Results: Even in unilateral MD, cochlear and vestibular endolymphatic hydrops (c-, v-EH) were demonstrated not only in the affected side but also in the healthy side in more than half of patients. Positive rate of v-EH in vestibular Meniere's disease (68.8%) was as high as that of MD (80%). In vestibular Meniere's disease, the number of bilateral EH was higher in the vestibule (56.3%) than that in the cochlea (25.0%). There were no differences in vestibular tests and DHI between vestibular Meniere's disease and MD; however, the frequency of vertigo spells was lower in vestibular Meniere's disease (p = 0.001). The total HADS score in the MD group was significantly higher than that in the vestibular Meniere's disease group.Conclusions: MD is a systemic disease with bilateral involvement of inner ears. V-EH is a major pathophysiology of vestibular Meniere's disease, which would precede c-EH in the development of vestibular Meniere's disease, a milder subtype of MD. MRI is useful for differentiating MD from other vertigo attacks caused by different pathologies in bringing EH into evidence.

Starting from acylsufonamide HTS hit 2, a novel series of para-N-acylaminomethylbenzoic acids was identified and developed as selective prostaglandin EP4 receptor antagonists. Structural modifications on lead compound 4a were explored with the aim of improving potency, physicochemical properties, and animal PK predictive of QD (once a day) dosing regimen in human. These efforts led to the discovery of the clinical candidate AAT-008 (4j), which exhibited significantly improved pharmacological profiles over grapiprant (1).

Humans can recall various aspects of a characteristic sound as a whole when they see a visual shape stimulus that has been intimately associated with the sound. In subjects with audio-visual associative memory, auditory responses that code the associated sound may be induced in the auditory cortex in response to presentation of the associated visual shape stimulus. To test this possibility, mice were pre-exposed to a combination of an artificial sound mimicking a cat's "meow" and a visual shape stimulus of concentric circles or stars for more than two weeks, since such passive exposure is known to be sufficient for inducing audio-visual associative memory in mice. After the exposure, we anesthetized the mice, and presented them with the associated visual shape stimulus. We found that associative responses in the auditory cortex were induced in response to the visual stimulus. The associative auditory responses were observed when complex sounds such as "meow" were used for formation of audio-visual associative memory, but not when a pure tone was used. These results suggest that associative auditory responses in the auditory cortex represent the characteristics of the complex sound stimulus as a whole.

Clustered protocadherins (Pcdhs) are neuronal cell adhesion molecules characterized by homophilic adhesion between the tetramers of 58 distinct isoforms in mice. The diversity of Pcdhs and resulting highly-specific neuronal adhesion may be required for the formation of neural circuits for executing higher brain functions. However, this hypothesis remains to be tested, because knockout of Pcdh genes produces abnormalities that may interfere with higher brain functions indirectly. In Pcdh-α1,12 mice, only α1, α12 and two constitutive isoforms are expressed out of 14 isoforms. The appearance and behavior of Pcdh-α1,12 mice are similar to those of wild-type mice, and most abnormalities reported in Pcdh-α knockout mice are not present in Pcdh-α1,12 mice. We examined Pcdh-α1,12 mice in detail, and found that cortical depression induced by sensory mismatches between vision and whisker sensation in the visual cortex was impaired. Since Pcdh-α is densely distributed over the cerebral cortex, various types of higher function are likely impaired in Pcdh-α1,12 mice. As expected, visual short-term memory of space/shape was impaired in behavioral experiments using space/shape cues. Furthermore, behavioral learning based on audio-visual associative memory was also impaired. These results indicate that the molecular diversity of Pcdh-α plays essential roles for sensory integration and short-term memory.

This paper describes the design, construction, and testing of a 750-V 100-kW 20-kHz bidirectional isolated dual-active-bridge dc–dc converter using four 1.2-kV 400-A SiC-MOSFET/SBD dual modules. The maximum conversion efficiency from the dc-input to the dc-output terminals is accurately measured to be as high as 98.7% at 42-kW operation. The overall power loss at the rated-power (100 kW) operation, excluding the gate-drive and control circuit losses, is divided into the conduction and switching losses produced by the SiC modules, the iron and copper losses due to magnetic devices, and the other unknown loss. The power-loss breakdown concludes that the sum of the conduction and switching losses is about 60% of the overall power loss and that the conduction loss is nearly equal to the switching loss at the 100-kW and 20-kHz operation.

The effect of bubbles entrained in the breaker zone on air-water oxygen transfer is examined. First, the area of bubbles entrained by breakers generated on a sloping bottom in a wave tank is analyzed using a color image sensor which can count the pixel number of a specific color in a frame. It was found that the time-averaged pixel number over a wave period has a strong relationship to the energy dissipation rate per unit mass of the breaker. The time-averaged pixel number is then incorporated with some modification into an equation proposed by Eckenfelder for the calculation of the mass transfer coefficient from bubble surfaces in an aeration tank. The coefficient resulting from the modified equation shows a strong relationship between the mass transfer coefficient and the dissipation rate.

Trehalase inhibitor salbostatin has been completely synthesized by coupling of 1,5:2,3-dianhydro-D-mannitol and di- O -isopropylidene-α-valienamine followed by deprotection.

Complete synthesis of both diastereoisomeric structures, initially proposed for the trehalase inhibitor trehalostatin, and their biological assay have been carried out. The synthetic compounds were found to lack an inhibitory activity against trehalase, suggesting that the inhibitor would possess convincingly its 4′-epimeric structure later assigned for trehazolin.

Potent trehalase inhibitors 1–4 have been synthesized, thereby establishing both the structure and the absolute configuration of the known inhibitor trehazolin 2. Compound 1, previously proposed as the structure of trehalostatin, and its diastereoisomer 3, have been shown not to possess any observable inhibitor activity against trehalase. These results indicate that the initial structure assigned for trehalostatin is incorrect, and that its structure is identical with that of trehazolin 2.

In order to elucidate structure–activity relationships of the trehalase inhibitor trehazolin 1, three analogues: deoxytrehazolin D-2, and de(hydroxymethyl)trehazolin D-3 and its diastereoisomer L-3 were synthesized by coupling of the sugar isothiocyanate 18 with the newly prepared aminocyclopentanetetraols D-10, D-26 and L-26, followed by cyclisation to give the isourea, and deprotection. In addition, an attempt was made to synthesize the analogue 4, the aminocyclitol moiety being replaced with the 5a-carba sugar, validamine. A biological assay showed that enantiomers D-3 and L-3 are strong inhibitors of trehalase, and, interestingly, the latter isomer, having the unnatural-type structure, is ∼ 50 times more potent.

The total synthesis of trehalase inhibitor salbostatin (1), recently discovered as a novel metabolite of Streptomyces albus species, has been achieved starting from the major product (58 % yield) from the coupling of the amine di-O-isopropylidene-α-valienamine and the electrophile 1,5 : 2,3-dianhydro-D-mannitol in 2-propanol. Deprotection with aqueous acetic acid and subsequent purification on a column of acidic resin afforded 1, which showed inhibitory activity (IC50 = 8.3 μML−1) against silkworm trehalase.

A novel central nervous system (CNS) selective neurokinin-1 (NK(1)) receptor antagonist, (2S,3S)-3-[(1R)-6-methoxy-1-methyl-1-trifluoromethylisochroman-7-yl]-methylamino-2-phenylpiperidine 'CJ-17,493' (compound (+)-1), was synthesized stereoselectively using a kinetic resolution by lipase-PS as a key step. Compound (+)-1 displayed high and selective affinity (K(i)=0.2 nM) for the human NK(1) receptor in IM-9 cells, potent activity in the [Sar(9), Met(O(2))(11)]SP-induced gerbil tapping model (ED(50)=0.04 mg/kg, s.c.) and in the ferret cisplatin (10mg/kg, i.p.)-induced anti-emetic activity model (vomiting: ED(90)=0.07 mg/kg, s.c.), all levels of activity comparable with those of CP-122,721. In addition, compound (+)-1 exhibited linear pharmacokinetics rather than the super dose-proportionality of CP-122,721 and this result provides a potential solution for the clinical issue observed with CP-122,721.

The total synthesis of trehalase inhibitor salbostatin (1), recently discovered as a novel metabolite of Streptomyces albus species, has been achieved starting from the major product (58 % yield) from the coupling of the amine di-O-isopropylidene-α-valienamine and the electrophile 1,5 : 2,3-dianhydro-D-mannitol in 2-propanol. Deprotection with aqueous acetic acid and subsequent purification on a column of acidic resin afforded 1, which showed inhibitory activity (IC50 = 8.3 μML−1) against silkworm trehalase.

Eight analogues of trehazolin were synthesized and tested for trehalase inhibitors. Deoxygenation of the cyclopentanepolyol moiety all decreased the inhibitory activity. Epimerization at the branching point of the cyclopentane ring did not so affect the potency. The cyclic isourea part was shown to be replaced with guanidine structure with a considerable decrease of activity. The 6′-fluoro-6′-deoxy derivative was still a strong inhibitor. It seems that trehazolin strictly mimics the substrate α,α-trehalose and any structural change and/or removal of the hydroxyl functions appreciably influence its potency. The present results led to finding 5-aminocyclopentane-1,2,3,4-tetraols to be new lead compounds for glycohydrolase inhibitors.

In order to elucidate structure–activity relationships of the trehalase inhibitor trehazolin 1, three analogues: deoxytrehazolin D-2, and de(hydroxymethyl)trehazolin D-3 and its diastereoisomer L-3 were synthesized by coupling of the sugar isothiocyanate 18 with the newly prepared aminocyclopentanetetraols D-10, D-26 and L-26, followed by cyclisation to give the isourea, and deprotection. In addition, an attempt was made to synthesize the analogue 4, the aminocyclitol moiety being replaced with the 5a-carba sugar, validamine. A biological assay showed that enantiomers D-3 and L-3 are strong inhibitors of trehalase, and, interestingly, the latter isomer, having the unnatural-type structure, is ∼ 50 times more potent.