A phase I, randomized, placebo-controlled study of molnupiravir in healthy Japanese to support special approval in Japan to treat COVID-19.

Molnupiravir (MK-4482) is an oral prodrug of the antiviral ribonucleoside analog, N-hydroxycytidine (NHC), which has activity against RNA viruses, including severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). We conducted a phase I safety and pharmacokinetic study of molnupiravir in healthy Japanese adult participants. A sample size larger than typically used in pharmacokinetic studies was implemented to collect additional safety data in the Japanese population to support special approval for emergency use in Japan. Single doses of molnupiravir up to 1600 mg and multiple doses of 400 and 800 mg administered every 12 h (q12h) for 5.5 days were generally well-tolerated. NHC appeared rapidly in plasma and reached maximum concentration (Cmax ), with a median time to Cmax (Tmax ) between 1.00 and 2.00 h. Area under the concentration versus time curve from zero to infinity (AUC0-inf ), area under the concentration versus time curve from zero to 12 h (AUC0-12 ), and Cmax of plasma NHC increased approximately dose proportionally. With q12h dosing, the geometric mean (GM) accumulation ratios for NHC AUC0-12 and Cmax were ~1 for 400 and 800 mg. Pharmacokinetics of NHC triphosphate (NHC-TP), the active metabolite of NHC was assessed in peripheral blood mononuclear cells and also demonstrated roughly dose proportional pharmacokinetics. The GM accumulation ratios for NHC-TP AUC0-12 and Cmax were ~2.5 for 400 and 800 mg. Following administration with food, only a modest reduction (24%) in plasma NHC Cmax with comparable AUC0-inf was seen, supporting administration without regard to food.

Evaluation of the safety, tolerability, and pharmacokinetics of a single bolus injection of daptomycin in healthy Japanese subjects.

UNLABELLED: This was a phase I double-blind, randomized, placebo-controlled, 2-period, single-dose, crossover study in healthy Japanese subjects to evaluate the safety, tolerability, and pharmacokinetics of a single bolus injection of daptomycin. Twenty healthy subjects were randomized; 16 received a single intravenous (IV) administration of 6 mg/kg of daptomycin and 4 received a single intravenous administration of placebo (0.9% sodium chloride) by either bolus injection (10 s) or infusion (30 min) following an overnight fast in Periods 1 or 2. There was a minimum 5-day washout period from the administration in Period 1 to the administration in Period 2. Administration of a single bolus injection of daptomycin 6 mg/kg was generally well tolerated. The geometric mean ratios (GMRs) (90% confidence intervals [CIs]) for AUC0-∞, AUC0-24 h, Cmax, and C24 h of daptomycin in plasma following bolus injection over 10 s relative to IV infusion over 30 min were 1.01 (1.00, 1.03), 1.02 (1.00, 1.03), 1.50 (1.41, 1.60) and 1.05 (1.02, 1.08), respectively. Because no existing studies of this nature were available, Cmax following daptomycin 6 mg/kg/10 s multiple-dose bolus injections was simulated. It was estimated at 178 µg/mL (upper limit) and was expected to be equal to or less than the confirmed Cmax in Japanese or non-Japanese healthy subjects following single- or multiple-dose IV infusion over 30 min. From the results of this study, daptomycin multiple-dose bolus injections over 10 s are expected well tolerated and to have similar Cmax values as IV infusion over 30 min, thus offering potential clinical benefit. TRIAL REGISTRATION: Because this was a phase I trial in healthy subjects, the trial was not registered.

Influence of respiration on cerebrospinal fluid movement using magnetic resonance spin labeling.

BACKGROUND: Magnetic resonance imaging (MRI) cardiac gated phase contrast (PC) cine techniques have non-invasively shown the effect of the cardiac pulse on cerebrospinal fluid (CSF) movement. Echo planar imaging (EPI) has shown CSF movement as influenced by both cardiac pulsation and respiration. Previously, it has not been possible to visualize CSF movement in response to respiration non-invasively. The present study was undertaken to do so. METHODS: The effect of respiration on CSF movement was investigated using a non-contrast time-spatial labeling inversion pulse (Time-SLIP) with balanced steady-state free precession (bSSFP) readout. CSF movement was observed in the intracranial compartment in response to respirations in ten normal volunteers. To elucidate the respiration effect, the acquisition was triggered at the beginning of deep inhalation, deep exhalation and breath holding. RESULTS: By employing this respiration-induced spin labeling bSSFP cine method, we were able to visualize CSF movement induced by respiratory excursions. CSF moved cephalad (16.4 ± 7.7 mm) during deep inhalation and caudad (11.6 ± 3.0 mm) during deep exhalation in the prepontine cisternal area. Small but rapid cephalad (3.0 ± 0.4 mm) and caudad (3.0 ± 0.5 mm) movement was observed in the same region during breath holding and is thought to reflect cardiac pulsations. CONCLUSIONS: The Time-SLIP bSSFP cine technique allows for non-invasive visualization of CSF movement associated with respiration to a degree not previously reported.

Computed diffusion-weighted imaging using 3-T magnetic resonance imaging for prostate cancer diagnosis.

OBJECTIVE: To assess the efficacy of computed diffusion-weighted images (cDWIs) of b = 2000 s/mm(2) (cDWI2000) generated from DWIs of b = 0 and 1000 for prostate cancer (PCa) diagnosis in comparison with that of measured original DWIs of b = 1000 (mDWI1000) and b = 2000(mDWI2000) using 3-T MRI. METHODS: Eighty patients who underwent a preoperative MRI examination, including T2WI and DWI (b = 0, 1000, 2000 s/mm(2)), were enrolled in this study. Four combinations of images, protocol A (T2WI alone), B (T2WI + mDWI1000), C (T2WI + mDWI2000) and D (T2WI + cDWI2000), were assessed for their diagnostic capability. Areas under the receiver operating characteristic curve (Az) and diagnostic performance were evaluated, as well as contrast ratios (CR) between cancerous and non-cancerous lesions for each DWI. RESULTS: The highest CR was obtained with cDWI2000 (0.29 ± 0.16). Sensitivity, specificity, accuracy, and Az of the protocols were: A: 66.3 %, 59.4 %, 63.0 %, 0.67; B: 82.6 %, 62.0 %, 72.5 %, 0.80; C: 84.1 %, 66.5 %, 75.5 %, 0.86; D: 83.2 %, 70.0 %, 76.6 %, and 0.84, respectively The specificities and accuracies of protocol C and D were significantly higher than those of protocol B (P < 0.05). CONCLUSION: cDWI2000 appears to be more effective than mDWI1000, and at least as effective as mDWI2000 for PCa diagnosis.

Contralateral and ipsilateral responses in primary somatosensory cortex following electrical median nerve stimulation--an fMRI study.

OBJECTIVE: Ten healthy adult subjects were examined using functional magnetic resonance imaging (fMRI) to investigate responses in the contralateral and ipsilateral primary somatosensory cortex (SI) following electrical stimulation of the median nerve. METHODS: The right and left median nerves were stimulated alternately at the wrist in the different sessions. First, the location of the response in contralateral SI was identified following median nerve stimulation, and then, a spherical search volume with a 10mm radius centered on the region of the contralateral response was determined. Whether or not fMRI activation occurred within this sphere following ipsilateral stimulation was examined using a 3T MR imager. RESULTS: A response in contralateral SI was observed in 8 of the 10 subjects in right and left hemisphere. Responses in ipsilateral SI were observed in 6 of 8 subjects in right hemisphere, and the region of the response tended to be posterior to the contralateral region. On the other hand, in left hemisphere, the ipsilateral responses were found in three. CONCLUSIONS: In the present study, not only contralateral SI but also ipsilateral SI was activated following median nerve. The location of the ipsilateral activation was significantly more posterior than the contralateral one in right hemisphere. SIGNIFICANCE: The region of activation in ipsilateral SI was located in the posterior portion of post central gyrus, corresponding to around BA2 and 5 in human.

Diffusion-weighted imaging of the liver: technical challenges and prospects for the future.

Diffusion-weighted imaging (DWI) has recently been attempted in the abdominal region. We review diffusion-weighted images of the liver, especially from the technical point of view. We discuss selection of pulse sequence parameters, effects of anti-breathing motion technique, tips for measuring apparent diffusion coefficient (ADC), and utility of superparamagnetic iron oxide (SPIO), showing clinical cases, including those at 3T. Our current trial of new pulse sequencing, such as SPIO-mediated breath-holding black-blood fluid-attenuated inversion recovery (BH-BB-FLAIR), imaging is shown. Some prospects for the future in DWI of the liver are also stated.

Flow ghost artifact in slice-encoding direction mimicking vestibular schwannoma in contrast-enhanced 3D spoiled gradient-echo sequence.

The value of MR imaging by post-contrast T1-weighted 3D spoiled gradient-echo (3D SPGR) is well established for the detection of small vestibular schwannomas in the cerebellopontine angle region. We describe a case in which a flow ghost artifact in the slice-encoding direction mimicked a vestibular schwannoma and heavily T2-weighted MR cisternography and multiplanar reconstruction images helped us to reach the correct diagnosis. In addition, we conducted a volunteer study to demonstrate that changing the k-space trajectory can reduce this artifact in post-contrast 3D SPGR images.

Pre-surgical mapping of primary motor cortex by functional MRI at 3 T: effects of intravenous administration of Gd-DTPA.

The functional magnetic resonance imaging (fMRI) is often performed at the end of a routine MRI examination during which, dependent on the clinical indication, contrast agent has been administered; however, the effects of Gd-DTPA injection on the results of blood oxygenation level dependent (BOLD)-fMRI remain unknown. The present study was conducted to investigate the effects of the intravenous administration of Gd-DTPA on the results of pre-surgical localization of the primary motor cortex by BOLD-fMRI at 3 T. Eight normal subjects were included in this study. After the anatomical scans, pre- and post-contrast fMRI scanning was performed. The number of significantly activated voxels and the mean percentage signal change were compared. The mean number of significantly activated voxels was 115.0+/-27.0 in pre-contrast runs and 90.8+/-27.1 in post-contrast runs (mean value of all 8 volunteers+/-standard deviation; p<0.05). The mean mean percentage signal change was 4.07+/-0.39 in pre-contrast runs and 3.86+/-1.91 in post-contrast runs ( p=0.16). Pre-surgical localization of the motor area by BOLD-fMRI should be performed before the administration of Gd contrast material.

High-resolution T1-weighted 3D real IR imaging of the temporal bone using triple-dose contrast material.

The small structures in the temporal bone are surrounded by bone and air. The objectives of this study were (a) to compare contrast-enhanced T1-weighted images acquired by fast spin-echo-based three-dimensional real inversion recovery (3D rIR) against those acquired by gradient echo-based 3D SPGR in the visualization of the enhancement of small structures in the temporal bone, and (b) to determine whether either 3D rIR or 3D SPGR is useful for visualizing enhancement of the cochlear lymph fluid. Seven healthy men (age range 27-46 years) volunteered to participate in this study. All MR imaging was performed using a dedicated bilateral quadrature surface phased-array coil for temporal bone imaging at 1.5 T (Visart EX, Toshiba, Tokyo, Japan). The 3D rIR images (TR/TE/TI: 1800 ms/10 ms/500 ms) and flow-compensated 3D SPGR images (TR/TE/FA: 23 ms/10 ms/25 degrees) were obtained with a reconstructed voxel size of 0.6 x 0.7 x 0.8 mm3. Images were acquired before and 1, 90, 180, and 270 min after the administration of triple-dose Gd-DTPA-BMA (0.3 mmol/kg). In post-contrast MR images, the degree of enhancement of the cochlear aqueduct, endolymphatic sac, subarcuate artery, geniculate ganglion of the facial nerve, and cochlear lymph fluid space was assessed by two radiologists. The degree of enhancement was scored as follows: 0 (no enhancement); 1 (slight enhancement); 2 (intermediate between 1 and 3); and 3 (enhancement similar to that of vessels). Enhancement scores for the endolymphatic sac, subarcuate artery, and geniculate ganglion were higher in 3D rIR than in 3D SPGR. Washout of enhancement in the endolymphatic sac appeared to be delayed compared with that in the subarcuate artery, suggesting that the enhancement in the endolymphatic sac may have been due in part to non-vascular tissue enhancement. Enhancement of the cochlear lymph space was not observed in any of the subjects in 3D rIR and 3D SPGR. The 3D rIR sequence may be more sensitive than the 3D SPGR sequence in visualizing the enhancement of small structures in the temporal bone; however, enhancement of the cochlear fluid space could not be visualized even with 3D rIR, triple-dose contrast, and dedicated coils at 1.5 T.

Pseudostenosis of the internal carotid artery in 3D time-of-flight MR angiography: effects of a magnetization transfer contrast pulse and metallic material.

Pseudostenosis or pseudoocclusion of the internal carotid artery in 3D time-of-flight MR angiography has been reported to be caused by susceptibility artifacts due to the presence of a metallic foreign body in the subject's neck. We experimentally demonstrate that the use of a non-slice-selective magnetization transfer contrast (MTC) pulse increases the degree of pseudostenosis, whereas slice-selective MTC does not. Selective MR angiography demonstrating this phenomenon was also performed. We then report a case that exhibited this phenomenon. We conclude that the magnetic field inhomogeneity induced by metallic material causes the non-slice-selective MTC pulse to act as a local presaturation pulse. Selective MR angiography using this phenomenon can be applied on varieties of MR scanners from different vendors.

The subtypes of muscarinic receptors for neurogenic bladder contraction in rats.

We evaluated in vivo functional selectivity profiles for muscarinic M(2) and M(3) subtypes of four muscarinic antagonists: Compound A (a novel muscarinic receptor antagonist with M(2)-sparing antagonistic activity), darifenacin, (a muscarinic M(3) receptor antagonist); methoctramine (a muscarinic M(2) receptor antagonist) and tolterodine (a nonselective muscarinic receptor antagonist), and compared the inhibition potency on distention-induced bladder contraction in rats. In an in vivo functional study, Compound A (0.03-10 mg/kg, i.v.) showed antimuscarinic activity with high selectivity for M(3) (salivation) over M(2) (bradycardia) (>100-fold). Darifenacin (0.01-0.3 mg/kg, i.v.) showed only slight selectivity for M(3) over M(2) (3.7-fold). Methoctramine (0.003-1 mg/kg, i.v.) showed the reverse selectivity profile (0.077-fold). Tolterodine (0.003-0.3 mg/kg, i.v.) showed less selectivity (1.2-fold). Compound A at M(3) inhibitory doses (0.1 and 0.3 mg/kg, i.v.) showed inhibition in a distention-induced neurogenic bladder contraction model, and its maximal inhibitory effects were about 60% at an even higher dose (3 mg/kg). Methoctramine at M(2) inhibitory doses (0.03 and 0.1 mg/kg, i.v.) did not significantly affect distention-induced bladder contraction. When tolterodine and darifenacin caused inhibition of distention-induced bladder contraction, its maximal inhibitory effects were similar to that of Compound A. Therefore, these findings suggest that Compound A would be an excellent pharmacological tool to give a better understanding of which subtypes of muscarinic receptors act in bladder function so far, and muscarinic M(3), but not M(2), receptors mainly mediate the cholinergic component of distention-induced bladder contraction.

High-spatial-resolution MR cisternography of the cerebellopontine angle in 90 seconds with a zero-fill interpolated fast recovery 3D fast asymmetric spin-echo sequence.

BACKGROUND AND PURPOSE: Although the 12-minute 3D fast asymmetric spin-echo (FASE) protocol for imaging the inner ear has been satisfactory, reducing imaging time to minimize patient discomfort and maximize system throughput is desirable. We therefore evaluated the performance of a zero-fill interpolated (ZIP) fast recovery 3D FASE sequence in screening for cerebellopontine (CP) angle lesions in 90 seconds. METHODS: Thirty consecutive patients known or suspected to have CP angle lesions underwent MR imaging at 1.5 T with use of bilateral quadrature phased-array coils designed for examination of the CP angle. Conventional 3D FASE images (4000/240/1 [TR/TE/NEX]) were obtained in 11 minutes 48 seconds with a field of view (FOV) of 16 cm, matrix of 512 x 512 x 40, section thickness of 0.8 mm, and echo train length of 80. Then, ZIP fast recovery 3D FASE images (2000/240/1) were obtained in 90 seconds by using the same FOV. Contrast-enhanced T1-weighted 3D spoiled gradient-echo (SPGR) images were obtained as the reference standard. Three radiologists evaluated the images independently. Conventional 3D FASE and ZIP fast recovery 3D FASE images were reviewed at separate sessions. RESULTS: On 3D SPGR images, 10 tumors were detected in 10 of the 30 patients. All lesions were depicted with both 3D FASE protocols. There were no false-positive results with either 3D FASE protocol. Both protocols showed 100% sensitivity and 100% specificity for all three reviewers. CONCLUSION: High-spatial-resolution MR cisternography with the ZIP fast recovery 3D FASE protocol in 90 seconds results in a substantial reduction (by a factor of about eight) in the time required for screening for CP angle lesions compared with the previously reported conventional 3D FASE protocol, while maintaining high sensitivity and specificity.

Fast recovery 3D fast spin-echo MR imaging of the inner ear at 3 T.

High-resolution MR imaging of the inner ear with a heavily T2-weighted 3D fast spin-echo sequence has been performed successfully at 1.5 T. However, at 3 T, the longer T1 time of CSF necessitates a longer TR, resulting in significantly prolonged imaging times. In this study, the fast recovery 3D fast spin-echo sequence, which permits the TR to be reduced while maintaining T2 contrast, was optimized at 3 T for imaging of the inner ear. The optimized sequence parameters are as follows: 1500/294 (TR/TE); echo spacing, 18.1 ms; bandwidth, 38 kHz at 512 readout; and imaging time, 13 minutes.