Pharmacokinetics of Edaravone Oral Suspension in Patients With Amyotrophic Lateral Sclerosis.

PURPOSE: Edaravone is a neuroprotective agent approved as an intravenous treatment for amyotrophic lateral sclerosis (ALS). The intravenous administration of edaravone places a burden on patients and there is a clinical need for oral agents for the treatment of ALS. This report aimed to assess the pharmacokinetics and safety of an edaravone oral suspension in patients with ALS after oral and percutaneous endoscopic gastrostomy (PEG) tube administration. METHODS: Two single-dose, open-label phase 1 clinical studies were conducted. Edaravone oral suspension (105 mg of edaravone in 5 mL aqueous suspension) was administered orally and via PEG tube to 9 and 6 Japanese patients with ALS, respectively. Plasma and urinary pharmacokinetics of unchanged edaravone and its metabolites (sulfate and glucuronide conjugates) were determined. Safety was also evaluated. FINDINGS: After reaching maximum plasma concentration, the mean plasma concentration-time of unchanged edaravone showed a triphasic elimination. Mean plasma concentration-time profiles of the metabolites were higher than those of unchanged edaravone. The mean urinary excretion ratios were higher for the glucuronide conjugate than for either unchanged edaravone or the sulfate conjugate. In patients administered edaravone orally, a single adverse event occurred (blood urine present), which was mild and improved without medical intervention. No adverse drug reactions or serious adverse events were reported. In patients administered edaravone via PEG tube, 5 treatment-emergent adverse events were reported in 3 patients; none were related to the study drug. No adverse drug reactions were reported. IMPLICATIONS: In patients with ALS, a single dose of edaravone oral suspension was well absorbed and mainly eliminated in urine as the glucuronide conjugate. No safety concerns emerged. Pharmacokinetics were similar to those previously reported in healthy participants following oral administration. This indicates that effective drug concentrations were achieved and edaravone can be successfully administered both orally and via a PEG tube in patients with ALS. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04176224 (oral administration) and NCT04254913 (PEG tube administration), www. CLINICALTRIALS: gov.

[Malignant Lymphoma of the Brain, and Dementia].

A differential diagnosis of acute and subacute progressive dementias includes malignant lymphoma of the brain. We reviewed primary central nervous system lymphoma (PCNSL), intravascular lymphomatosis (IVL), lymphomatosis cerebri, and the relapse and invasion of systemic lymphomas. PCNSL is confined to the central nervous system; the infiltration and compression by the lymphoma result in adverse neurological symptoms. IVL is a rare form of malignant lymphoma that is characterized by the proliferation of primarily B-cell type lymphoma cells within the blood vessels of various organs. This causes ischemia and results in the associated neurological symptoms. Medical history and neuroimaging studies provide crucial informations to distinguish the lymphomas from other diseases that cause dementia, such an Alzheimer's disease. MRI imaging of the brain using contrast agent, and the biopsy of diseased tissues are essential for the diagnosis of the lymphomas. A histopathological examination is the most effective way to diagnose malignant lymphomas of the brain. Presently, the treatment of choice for PCNSL is the intravenous administration of high dose methotrexate with and without radiation therapy. Futhermore, Rituximab-containing chemotherapy has proved to greatly improve the prognosis of IVL. A better outcome can be achieved with the earlier diagnosis and treatment of the malignant lymphoma of the brain.

α-Hydroxy and α-Oxo Selenoamides: Synthesis via Nucleophilic Selenocarbamoylation of Carbonyl Compounds and Characterization.

Carbonyl compounds were added to selenocarbamoyllithiums to generate α-hydroxy and α-oxo selenoamides. Their conformations were determined by X-ray analyses. These compounds adopted conformations that were almost identical to those of ordinary amides. Unlike the consistency of the chemical shifts of the C═Se groups of the selenoamides in (13)C NMR spectra and the (1)J coupling constants of the C═Se groups, the substituents far from the selenium atom influenced the chemical shifts in (77)Se NMR.

Airspace enlargement with fibrosis shows characteristic histology and immunohistology different from usual interstitial pneumonia, nonspecific interstitial pneumonia and centrilobular emphysema.

The histologic characteristics of air space enlargement with fibrosis (AEF) are compared with usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP) and centrilobular emphysema (CLE) to determine similarities and differences. Lung specimens from 39 patients were studied; 9 with AEF, 13 with UIP and 5 with CLE identified in lobectomy specimens for cancer and 12 NSIP cases identified on surgical lung biopsies. We determined the characteristics of cystic structures (i.e. abnormal airspace), degree of inflammation and severity of pneumocyte injury semi-quantitatively. In AEF, the wall thickness of the cystic lesions (0.8 mm) was thinner than in UIP (2.1 mm) and thicker than in CLE (0.07 mm). The degree of inflammation and granulation tissue were milder in AEF than in UIP and NSIP and CLE showed milder inflammatory cells than AEF. As for pneumocyte injury, AEF had fewer erosions (0.1/case) and fewer ubiquitin-positive pneumocytes than UIP (4.8 cells/slide) and NSIP (9.8 cells/slide). Our data suggested that the histological characteristics of AEF differed significantly from UIP, NSIP and CLE.

Relationship between slowing of the EEG and cognitive impairment in Parkinson disease.

A previous study using the quantitative EEG technique confirmed that diffuse slowing of the EEG is present in Parkinson disease. The present study was the first to assess the relationship between cognitive impairment and quantitative EEG in Parkinson disease. A total of 100 patients with Parkinson disease with a mean Hoehn-Yahr stage of 2.68 were serially enrolled. Cognitive impairment was assessed using the Mini-Mental State Examination. Lack of ischemic lesions was confirmed in all the patients by MRI. Absolute power values were measured for four frequency bands from δ to ß. The electrodes were divided among six locations as follows: frontal pole and frontal, central, parietal, temporal, and occipital locations. Spectral ratio was calculated as the sum of power values for the α- and ß-waves divided by the sum of values for slow waves. The relationship between Mini-Mental State Examination score and spectral ratio was assessed by the Jonckheere-Terpstra trend test. At all electrode locations, spectral ratio significantly decreased with a decline in Mini-Mental State Examination score (frontal pole, P = 0.017; frontal, P = 0.028; central, P = 0.019; parietal, P = 0.004; temporal, P = 0.002; occipital, P = 0.006). The rate of patients with Parkinson disease with slowing of the EEG was more frequent with serious cognitive impairment.

[Neurological disturbances caused by intravascular lymphomatosis].

Intravascular malignant lymphomatosis (IML) is a relatively rare type of malignant lymphoma that is mostly caused by B-cell type neoplastic lymphocytes and rarely by T-cell and NL-cell type cells. B-cell type IML is currently considered to consist of 2 types: a conventional European type and an Asian variant that was originally reported from Japan. In IML, the tumor cells primarily grow within the blood vessel lumina but may cause minimal extravascular infiltration around the involved vessels in some patients. IML usually affects elderly patients and is characterized by B symptoms, general fatigue, disorders of various organs, and elevated serum lactate dehydrogenase (LDH) and soluble interleukin-2 receptor (sIL-2R) levels. Common symptoms include skin eruptions, neurological abnormalities, and gastrointestinal abnormalities. The skin changes and neurological symptoms are more frequent in the conventional type of IML but are not rare in the Asian variant. Neurological manifestations are primarily caused by varying degrees of ischemia due to intravascular tumor cells. These symptoms are usually subacute in onset and have a progressive course: They include, in the order of frequency, 1) multiple cerebral infarcts, 2) disorders of lumbosacral cord and its nerve roots accompanied by paraparesis, 3) subacute encephalopathy, and 4) mononeuropathy and multiple mononeuropathy that include cranial nerves. The most important diagnostic finding in IML is the histological demonstration of tumor cells within small vessel lumina. Although the antemortem diagnosis of IML has been difficult, the results of recent studies involving random skin biopsy are promising for such a diagnosis. Since the recent addition of rituximab to CHOP therapy has proven to markedly improve the prognosis of IML. We should therefore try to avoid overlooking this treatable disease.

Ubiquitin-positive pneumocytes and inclusion bodies are present in secondary organizing pneumonia.

OBJECTIVE: We previously reported that various types of interstitial pneumonia (IP) patterns contain intracytoplasmic eosinophilic inclusions or Mallory bodies (inclusions) that are ubiquitin positive (Ub+). In the present study, we examined tissues with the organizing pneumonia pattern (OP) to determine if they contain inclusions and Ub+ pneumocytes using lobectomized specimens. METHODS: Tissues from 34 patients with secondary OP, which appeared in 33 carcinomas and 1 pulmonary abscess, were histologically evaluated for the type of intraluminal granulation tissue and the presence of erosions and inclusions. Granulation tissues were classified into polypoid, mural and occluded subtypes according to Basset's criteria and scored. RESULTS: Inclusions were noted in 5.9% of the secondary OP cases with light microscope. Ub+ pneumocytes were detected after immunostaining and all inclusions were Ub+. Ub+ pneumocytes (inclusions) were noted in 14.7% of the secondary OP cases. OP contained pneumocyte erosions and inflammatory cell infiltration without a significant difference in the Ub+ and Ub- subgroups. Although there was no significant difference in the polypoid type of granulation tissue between the Ub+ and Ub- negative (Ub-) subgroups, the Ub+ subgroup had significant increases (p<0.05) in the mural-occluded type of granulation tissue (Ub+: 1.76±0.64, n=5 vs. Ub-: 0.72±0.87, n=29) as compared to the Ub- subgroup. CONCLUSION: Some patients with secondary OP had Ub+ inclusions as pneumocyte injury.

The haplotype of the CACNA1B gene associated with cerebral infarction in a Japanese population.

Cerebral infarction (CI) is thought to be a multifactorial disease that is affected by several environmental factors and genetic variants. N-type voltage-gated calcium channels (VGCCs), which are expressed primarily in the neurons, have various roles in neuronal functions and are especially involved with neurotransmitter release at the sympathetic nerve terminals. We considered the α1B subunit of the N-type voltage-gated calcium channel (CACNA1B) to be representative of the general characteristics of this channel type. The aim of the present study was to assess the association of the human CACNA1B gene with the occurrence of CI via a haplotype-based case-control study that used single nucleotide polymorphisms (SNPs) from the Japanese population. A total of 165 CI patients and 314 controls were enrolled in the case-controlled studies that examined three SNPs of the human CACNA1B gene (rs7042521, rs11137351, rs10780199). There were significant differences between the CI and control groups for the overall distribution of the genotypes and the presence of the recessive rs10780199. Multiple logistic regression analyses revealed that even after adjusting for confounding factors (odds ratio: 1.716), the frequencies of the A/G and G/G genotypes of rs10780199 in the CI group were significantly higher than those observed in the control group (p = 0.021). Furthermore, the C-C-G and G-G-G haplotypes of rs7042521-rs11137351-rs10780199 were significantly more frequent in the CI group than in the control group (p = 0.024 and p < 0.000). In conclusion, significant differences were noted between the CI and control patients for the specific SNPs and haplotypes in the CACNA1B gene. The results indicate that these polymorphisms and haplotypes might be genetic markers for CI.

Dural arteriovenous fistula on the convexity presenting with pure acute subdural hematoma.

Non-traumatic dural arteriovenous fistula/malformation (dural AVF/AVM) presenting with pure subdural hematoma (SDH) is relatively rare. We report on a male patient who showed pure acute SDH and was diagnosed as having dural AVF on the convexity near the superior sagittal sinus (SSS), based on angiographic findings. A 27-year-old man was admitted to our hospital due to headache with acute onset. The patient did not have a history of head trauma or injury. Head CT showed an abnormal high-density area on the surface of the cerebral hemisphere on the left side, indicating acute SDH. Angiography during the arterial phase demonstrated that an abnormal artery originating from the left occipital artery was connected with a dural vein and a diploic vein on the convexity near the SSS. We concluded that a dural AVF existed at this area, and that the dural AVF had caused the acute SDH. Dural AVF/AVM which causes non-traumatic SDH is usually accompanied by intracerebral hemorrhage (ICH) and/or subarachnoid hemorrhage (SAH). In contrast, non-traumatic dural AVF/AVM presenting with pure SDH is rare, and our patient represents such a rare case. We should consider dural AVF/AVM and perform angiography if necessary when we encounter a patient showing non-traumatic SDH without ICH and/or SAH.

Atrophy of the parahippocampal gyrus and regional cerebral blood flow in the limbic system in chronic alcoholic patients.

This study investigated regional cerebral flood flow (CBF) in chronic alcoholic patients, focusing primarily on the limbic system, including the hippocampus and the callosomarginal region, because of their susceptibility to damage in such patients. The degree of hippocampal atrophy in such patients was also examined. Regional CBF and the degree of parahippocampal gyrus atrophy were studied in 22 chronic alcoholic male patients with no neurological or psychological symptom (mean age, 59.3+/-4.1 years). Their findings were compared with those of 22 age-matched, male, normal controls (mean age, 59.7+/-3.9 years). Single-photon emission computed tomography was performed using the (99m)Tc-ethylcysteinate dimer ( (99m)Tc-ECD) Patlak Plot method, and the three-dimensional stereotaxic region of interest (ROI) template (3DSRT) and the fine stereotaxic ROI template (fine SRT) developed by Takeuchi et al were used to evaluate regional CBF, focusing primarily on the limbic system. These methods make it possible to precisely and objectively measure the details of regional CBF. The voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) was used to determine the degree of parahippocampal gyrus atrophy in chronic alcoholic patients. VSRAD is a method developed by Hirata et al for evaluating the degree of atrophy of the parahippocampal gyrus. The results were analyzed using Z scores (>2 indicating significant atrophy). Blood flows in the callosomarginal region, pericallosal region, thalamus, hippocampus, parahippocampal gyrus, amygdaloid body, anterior cingulate gyrus, and middle cingulate gyrus were lower in the chronic alcoholic group than in the control group. Parahippocampal gyrus atrophy was not observed in the control group (average Z score, 0.62+/-0.29). In contrast, an atrophic tendency was observed in the chronic alcoholic group (average Z score, 1.88+/-0.44). Clinically intact, chronic alcoholic patients with no neurological or psychological symptom had decreased CBF in the limbic system and a tendency to parahippocampal gyrus atrophy.

Effect of motor imagery and voluntary muscle contraction on the F wave.

We tested the validity of instructing patients to minimally contract the muscle to facilitate F-wave recording in clinical practice. In 12 healthy subjects, F waves were recorded from the first dorsal interosseous muscle at rest, during motor imagery, and at up to 30% of the maximal voluntary contraction (MVC). F-wave persistence increased significantly from 32.5 +/- 11.9% (mean +/- SD) at rest to 58.3 +/- 15.2% during motor imagery and 90.0 +/- 8.7% during 3% MVC. It then remained the same during stepwise changes to and from 30% MVC before decreasing significantly from 80.8 +/- 18.5% during 3% MVC to 48.7 +/- 23.8% during motor imagery and 27.0 +/- 16.0% at rest. The trial average of F-wave amplitude showed a similar pattern of facilitation. Motor imagery enhances F-wave persistence and amplitude, which further increase with a slight muscle contraction and show no additional change with a stronger effort.

Clinical study of the responsible lesion for dysarthria in the cerebellum.

There have been few reports describing the lesion for cerebellar dysarthria. We compared MRI findings of 4 reported patients (including our previously reported patient) to that of our patient who showed ataxic speech and ataxic gait. The lesions of 4 patients involved lobulus quadrangularis and lobulus simplex, and the lesion of the present patient involved lobulus semilunaris superior and lobulus simplex. Since lobulus simplex and lobulus quadrangularis were involved in many patients, we speculated that the cerebellar dysarthria of the present patient was due to the damage of these areas in the upper cerebellum.

Quantitative EEG analysis of executive dysfunction in Parkinson disease.

Quantitative EEG evaluation in Parkinson disease (PD) reveals diffuse slowing. This is the first quantitative EEG evaluation of the differences between PD with and without executive dysfunction (ExD). The subjects were 32 PD patients without remarkable dementia. The lack of ischemic lesions was confirmed by magnetic resonance imaging. ExD was defined as <70 points on the age-controlled standardized score of the Behavioral Assessment of the Dysexecutive Syndrome. Absolute power was measured for four frequency bands from delta to beta. Electrodes were placed at frontal pole, frontal, central, parietal, occipital, and temporal locations. Spectral ratio was calculated as the sum of power values for alpha and beta waves divided by the sum of values for the slow waves. In multiple logistic regression analysis of each electrode location, the dependent variable was ExD or not, and the independent variables were spectral ratio, age, and Unified Parkinson Disease Rating Scale. The only significant predictor of ExD was spectral ratio at the frontal pole (P = 0.031) and frontal (P = 0.048) locations. PD with ExD exhibited an increase in slow wave activity and a decrease in alpha and fast wave activities in these locations. These findings indicated that the ExD in PD was caused by frontal dysfunction.

Current perception threshold in subacute myelo-optico-neuropathy.

We report the first current perception threshold (CPT) examination of sensory disturbance in subacute myelo-optico-neuropathy (SMON). SMON patients experience serious neurological symptoms, including dysesthesia, sensory loss, motor weakness, and visual impairment. During CPT examination, 5 Hz, 250 Hz, and 2,000 Hz stimulations were used to stimulate C fibers, A-delta fibers, and A-beta fibers, respectively. Ten SMON patients (mean age, 73.8 +/- 8.4 years) and ten age-matched controls (72.3 +/- 6.3 years) were studied using CPT measured at the index finger and near the external malleolus. The CPTs to 250 Hz and 2,000 Hz stimulations near the external malleolus were significantly higher and the CPT to 5 Hz stimulation was significantly lower in the SMON group than in the control group. Although peripheral nerve impairment is mild in SMON, pathological examination shows a decrease of large fibers. This is thought to increase the CPTs to 250 Hz and 2,000 Hz stimulations. The center of the gate control of pain exists in the posterior horn receiving information from the dorsal root ganglion. The dorsal root ganglion at the lumber cord is strongly impaired in SMON; therefore, the gate control may not work effectively, and decreases CPT to 5 Hz stimulation.

Pathological study of pseudohypertrophy of the inferior olivary nucleus.

There have been only a few reports about the immunohistochemical study of pseudohypertrophy of the inferior olivary nucleus (PH-IO). We therefore performed the detailed immunohistochemical study of 10 PH-IOs in 8 patients to clarify the mechanism of neuronal degeneration and its related phenomenon of PH-IO. We used various antibodies to alphaB-crystallin (alphaBC), synaptophysin (SYP), microtubule-associated protein 2 (MAP2), Lys-Asp-Glu-Leu (KDEL) receptors, heat shock protein (HSP) 27 as well as SMI-31. We found alphaBC-positive neurons on the ipsilateral side of 10 PH-IOs. SMI-31-positive neurons were also observed in 6 PH-IOs. Confocal laser microscopy showed co-localization of alphaBC and SMI-31 in some neurons. However, there were no HSP27-positive neurons or astrocytes in any of the 10 PH-IOs. MAP2 immunostaining showed MAP2-positive hypertrophic thick neurites around hypertrophic neurons on the ipsilateral side of 7 PH-IOs and demonstrated "glomeruloid structures" in 3 PH-IOs. In addition, fine granular SYP-immunoreactivity was decreased in the neuropils on the ipsilateral side of all 10 PH-IOs. SYP-immunoreactive dots were scattered in the neuropils and on the neuronal cell bodies on the side of 7 PH-IOs, and the aggregation of SYP-immunoreactive dots scattered in the neuropils was shown in 3 PH-IOs. Double-immunostainings using anti-MAP2 and anti-SYP antibodies demonstrated frequent SYP-immunoreactive dots along the MAP2-positive hypertrophic thick neurites and their cell bodies. Periphery-stained KDEL-positive neurons were also found on the side of 7 PH-IOs. We showed that the change of the distribution of presynaptic terminals correlated well to the hypertrophic thick neurites in PH-IO. Our immuohistochemical stainings demonstrated various changes which occurred to the neurons in PH-IO, and their neurites and presynaptic terminals. We considered that alphaBC was expressed in the neurons in PH-IO, induced by cellular stress. Such a detailed immunohistochemical investigation has not been reported previously.

Phase II study of ifosfamide, carboplatin, and etoposide in patients with a first recurrence of glioblastoma multiforme.

OBJECT: The prognosis of recurrent glioblastoma multiforme (GBM) remains unsatisfactory. The authors conducted a Phase II study of ifosfamide, carboplatin, and etoposide (ICE) for a first recurrence of GBM to determine whether it prolonged a patient's good-quality life. METHODS: This trial was an open-label, single-center Phase II study. Forty-two patients with a first GBM relapse after surgery followed by standard radiotherapy (60 Gy) and first-line temozolomide- or nimustine-based chemotherapy were eligible to participate. The primary end point was progression-free survival at 6 months after the ICE treatment (PFS-6), and secondary end points were response rate, toxicity, and overall survival. Chemotherapy consisted of ifosfamide (1000 mg/m(2) on Days 1, 2, and 3), carboplatin (110 mg/m(2) on Day 1), etoposide (100 mg/m(2) on Days 1, 2, and 3), every 6 weeks. RESULTS: Progression-free survival at 6 months after ICE treatment was 35% (95% CI 22-50%). The median duration of PFS was 17 weeks (95% CI 10-24 weeks). The response rate was 25% (95% CI 9-34%). Adverse events were generally mild and consisted mainly of alopecia. CONCLUSIONS: This regimen was well tolerated and has some activity and could be one of the options for patients with recurrent GBM.

The relationship between slowing EEGs and the progression of Parkinson's disease.

The previous association study confirmed that diffuse slowing of EEGs was present in Parkinson's disease (PD), demonstrated with the use of the quantitative EEG technique. This study was the first to assess the relationship between progression of PD and quantitative EEG. A total of 106 patients with PD with a mean Hoehn-Yahr stage of 2.73 were serially enrolled. Lack of ischemic lesions was confirmed in all patients by magnetic resonance imaging. Absolute power values were measured for four frequency bands from delta to beta. The electrodes were divided among six locations: frontal pole, frontal, central, parietal, temporal, and occipital locations. Spectral ratio was calculated as the sum of power values for the alpha and beta waves divided by the sum values for the slow waves. The relationship between the progression of PD and spectral ratio was assessed by the Jonckheere-Terpstra trend test. At all electrode locations, spectral ratio significantly decreased with progression of Hoehn-Yahr stage (frontal pole, P = 0.007; frontal, P = 0.005; central, P = 0.031; parietal, P = 0.017; temporal, P = 0.005; occipital, P = 0.010). This shows that the slowing of EEGs became more obvious with PD progression.

Ubiquitin-positive foam cells are identified in the aortic and mitral valves with atherosclerotic involvement.

AIM: Our aim was to determine the roles of the ubiquitin (Ub)-proteasome system (UPS) in valvular diseases by immunohistochemically identifying Ub-positive cells in aortic and mitral valves and determining if Ub+cells were associated with the severity of valvular diseases. METHODS: We evaluated surgically removed aortic and mitral valves from 60 patients (mean age, 64.5 years) for thickening, fibrosis, foam cell infiltration, thrombus, and atheromatous plaques by using grading scores. U+cells were detected immunohistochemically. RESULTS: We found Ub+cells in 16 (26.7%) of the 60 patients. Eleven (28.2%) of the 39 aortic valves and 5 (23.8%) of the 21 mitral valves were Ub-positive. Ub was found with granular depositions in the cytoplasm of monocyte-derived foam cells that were CD68+. The aortic valvular thickness of the Ub+group was significantly greater than that of the Ub- group (3.9+/-1.6mm vs. 3.2+/-1.6mm, p<0.05). Foam cells and fibrosis were greater in the Ub+group (p<0.05), and calcifications were prominent in aortic valves. There was no difference in the number of apoptotic cells in Ub+ and Ub- groups. Ub+cells were present in the affected valves and ubiquitinated proteins were accumulated in macrophage-derived foam cells. CONCLUSIONS: Ub+ foam cells are present in valves that are vulnerable to valvular disease, and UPS may contribute to the development of atherosclerosis through the inflammatory process.