Effects of edaravone on experimental brain injury in view of free radical reaction.

The purpose of this study is to clarify the influence of a novel free radical scavenger edaravone on experimental brain injury. Male Wistar rats were anesthetized with 1-2% halothane. Brain injury was produced using a controlled cortical impact injury device. Experimental rats were divided into 2 groups. In the edaravone group, edaravone (3 mg/kg) was twice administered intravenously for 30 minutes. In the saline group, saline solution was administered in the same way. This administration of edaravone or saline solution made it possible to evaluate the relative effects of edaravone by assessment of free radical reaction and water content. As a result, the level of oxygen free radicals at 50 minutes after brain injury was significantly lower in the edaravone group than in the saline group. The water content in the injured brain at 180 minutes was significantly lower in the edaravone group than in the saline group. Therefore, we propose that edaravone may be effective for treatment in head injury.

Risk factors and predictors of coronary arterial lesions in Japanese hypertensive patients.

The morbidity rate of coronary artery disease has recently increased in Japan. This is attributable to changes from traditional to more westernized lifestyles. In this study, we therefore examined the risk factors and predictors of coronary arterial lesions in Japanese patients with essential hypertension. Coronary angiography was performed in 109 consecutive essential hypertension patients (57 men and 52 women; 66 +/- 8.0 years of age) with either angina pectoris or atypical chest pain, who were chosen from 485 consecutive hypertensive patients in a hypertension clinic in Sendai, Japan. Coronary arterial stenosis of greater than 50% was defined as significant and used as a dependent variable for the multiple regression analysis. Risk factors were defined as factors confirmed to have a causal relationship with coronary arterial lesions, whereas arteriosclerotic complications and hypertensive target organ damage were defined as predictors. Multiple logistic regression analysis was performed using these parameters as independent variables. Of 109 patients, 25 had a coronary arterial stenosis greater than 50%. A smoking habit (odds ratio (OR): 4.48; 95% confidence interval (CI): 1.13-17.82; p<0.05), hypercholesterolemia (OR: 5.34; 95% CI: 1.52-18.73; p<0.05), and 24-h diastolic blood pressure (OR: 2.33; 95% CI: 1.06-5.16; p<0.05) were significant risk factors, whereas carotid intima-media thickness (OR: 5.85; 95% CI: 1.48-23.2; p<0.05) was a significant predictor of coronary arterial lesion. When two of the major risk factors (a smoking habit, hypercholesterolemia, or impaired glucose tolerance including diabetes mellitus) were clustered in addition to the hypertension, the risk of coronary arterial lesions increased by 6.7 to 10.1 times. These findings indicate that the major risk factors established in Caucasians, i.e., a smoking habit, hypercholesterolemia and blood pressure level, are also risk factors for coronary arterial lesions in Japanese with essential hypertension. The presence of two or more risk factors increases the risk of coronary arterial lesions synergistically in the presence of hypertension.

Survey of antibiotic resistance in Pseudomonas aeruginosa by The Tokyo Johoku Association of Pseudomonas Studies.

Pseudomonas aeruginosa resistance (minimum inhibitory concentration [MIC], > or =16 microg/ml defined as resistant) to meropenem, imipenem, panipenem, piperacillin, ceftazidime, cefozopran, cefoperazone, sulbactam/cefoperazone, amikacin, and tobramycin, as well as cross-resistance profiles, were investigated in P. aeruginosa strains isolated at eight hospitals in the Johoku area, Tokyo, during November 1998. Overall, 8.3% of isolates were imipenem-resistant and 4.6% were ceftazidime-resistant. However, the incidence of antibiotic-resistant P. aeruginosa was distinctly different at each hospital. P. aeruginosa resistance to imipenem ranged from (MIC) 1 to 64 microg/ml (MIC90 32 microg/ml), and its resistance to ceftazidime ranged from 2 to more than 128 microg/ml (MIC90, 64 microg/ml). Meropenem (MIC range, < or =0.25 to 16 microg/ml) was more active than panipenem (MIC range, 2 to 64 microg/ml). Cefozopran was more active than piperacillin, cefoperazone, or sulbactam/cefoperazone, but many strains were resistant to cefoperazone (17/57). Our analysis found cross-resistance to many beta-lactams, but the degree of cross-resistance was very variable.

Recurrent craniopharyngioma with nasopharyngeal extension.

We report the case of a 10-year-old boy having a recurrent craniopharyngioma with nasopharyngeal extension during a course of growth hormone therapy, in whom the nasopharyngeal craniopharyngioma was totally resected despite its extensive growth by using a transbasal approach. There has been no evidence of recurrence during 6 years of follow-up. A literature review was made with respect to nasopharyngeal extension of craniopharyngiomas, and the efficacy of the transbasal approach for those tumors is discussed.

Effect of HSR-903, a new fluoroquinolone, on the concentration of theophylline in serum.

The effect of HSR-903, a new fluoroquinolone, on the concentration of theophylline in serum in healthy male volunteers was investigated. The concentration of theophylline in serum and the urinary excretion rates of theophylline on day 5 of concomitant dosing with HSR-903 tended to increase compared to those on day 4, when theophylline was given alone; however, the urinary excretion rates of 1-methyluric acid and 3-methylxanthine on day 5 of concomitant dosing with HSR-903 tended to decrease in comparison to those on day 4, when theophylline was given alone.

[A trial case of coronary bypass surgery under heart beat in a patient with severe functional disorders of kidney].

Coronary artery bypass grafting (CABG) was performed under heart beat without conducting extracorporeal circulation in a patient with severe functional disorders of kidney, and satisfactory results were attained. The patient was a 71-year-old male with past history of severe functional disorders of kidney and cerebral infarction. He had triple-vessel disease. First, CABG was performed for the primary branches under heart beat without adopting extra-corporeal circulation, then later, percutaneous transluminal coronary angioplasty (PTCA) was performed for the residual lesions, which lead to complete revascularization without causing aggravation of cerebral infarction or functional disorders of kidney or subjective symptoms such as chest pain. CABG conducted under heart beat is less aggressive not only to myocardium but to other important organs, and is thought to be effective for patients who have severe concurrent diseases to which extracorporeal circulation is likely to entail risks. Furthermore, concurrent therapy with PTCA is thought to expand the scope of application of CABG under heart beat including the cases of multiple-vessel diseases.

[A case of sellar T cell type malignant lymphoma].

A case of primary T cell type malignant lymphoma of the sellar region was reported. This 53-year-old male was admitted to our neurosurgical service because of slowly progressive occipitalgia and diplopia over the previous 5 months. On admission neurological examination revealed a slight limitation of the lateral movement of the left eye. Endocrinological examination showed no abnormalities. Despite a mild neurological deficit, a CT scan revealed an extensive bony destruction around the sellar region including the dorsum sellae, the bilateral petrous apices, and the upper two thirds of the clivus. Magnetic resonance imaging (MRI) disclosed that the tumor was slightly hypointense on T1-weighted image, isointense on T2-weighted image, and faintly and homogeneously enhanced after administration of Gd-DTPA. Since the tumor was enhanced faintly on MRI, it was diagnosed as an invasive pituitary adenoma, but it was thought that chordoma and germinoma should be considered. The patient underwent a transsphenoidal surgery. A firm, grayish and avascular tumor was partially removed. The histopathological examination using monoclonal surface marker of the specimen revealed the tumor was stained with UCHL-1 and CD3 antibodies directed against T cells, and diagnosed as T cell type malignant lymphoma of the sellar region (diffuse, large cell type; LSG). Postoperatively he received radiation therapy. His symptoms much improved and no regrowth of the residual tumor has been found in follow-up studies to the present. Primary malignant lymphomas very rarely occur in the skull base. As far as we are aware, this is the only second case of primary T-cell lymphoma in the sellar region reported so far in the medical literature. Although preoperative diagnosis is extremely difficult because of a paucity of data, malignant lymphomas should be kept in mind in the differential diagnosis of sellar tumors, especially if neuroimaging studies show an extensive bony destruction in the skull base.

En bloc mastoidectomy to avoid postoperative retroauricular deformity in the transpetrosal approach.

The authors describe a surgical technique to avoid postoperative retroauricular deformity following the transpetrosal approach. After removing a one-piece temporal and suboccipital bone flap, the mastoid process is cut obliquely by using a sagittal saw towards an imaginary line drawn from the point on the petrous ridge just lateral to the arcuate eminence to the burr hole opened medial to the occipital groove. This technique allows en bloc removal of the mastoid process without resulting bone defects. Three patients who were treated with this technique and followed up for more than 1 year showed good cosmetic results with no complications including cerebrospinal fluid leakage. We believe this en bloc mastoidectomy offers a definite advantage in regard to avoid postoperative retroauricular deformity.

Interaction of citrus juices with pranidipine, a new 1,4-dihydropyridine calcium antagonist, in healthy subjects.

OBJECTIVES: The study was conducted to investigate whether oral co-administration with citrus juices significantly affects the pharmacokinetics and/or pharmacodynamics of pranidipine, a new 1,4-dihydropyridine calcium antagonist, in healthy male subjects. Grapefruit juice and orange juice, which were both commercially available, were used in this study. METHODS: Sixteen healthy male Japanese subjects participated in this study and were divided into two groups for grapefruit juice and orange juice treatment. The study followed an open-labelled crossover design, comparing the effects of a single oral dose of 2 mg pranidipine taken together with 250 ml citrus juice or 250 ml water. Serum pharmacokinetics of pranidipine, adverse reactions, blood pressure, heart rate, 12-lead ECG, haematology, clinical chemistry and urinalysis were measured throughout the study. RESULTS: For grapefruit juice, mean Cmax and AUC0-24 h were significantly higher than those of water (P=0.0003 and 0.0005, respectively, ANOVA) with the ratios of log transformed values being 1.50 and 1.74, respectively. There were no differences in tmax and t1/2 between the juice and water treatments. A significant increase in heart rate (P=0.0240, ANOVA with repeated measurements) was observed in the juice treatment whereas there were no significant differences in systolic and diastolic blood pressure between the two treatments. For orange juice, a small decrease in mean Cmax was observed compared with water (P=0.0218, ANOVA) with the ratio being 0.86, but there was no significant difference in AUC0-24h between the two treatments. No marked differences were observed in tmax and t1/2. Oral pranidipine administration with orange juice did not affect heart rate, systolic and diastolic blood pressures or other parameters for safety evaluation. CONCLUSIONS: Oral co-administration with grapefruit juice and pranidipine was associated with increased bioavailability and changed the pharmacodynamics of pranidipine, particularly with regard to heart rate. Orange juice intake with pranidipine did not markedly affect the pharmacokinetics and no clinically significant changes were observed in the pharmacodynamics and safety evaluation.

Functional roles of phenylalanine(7) of thymic humoral factor-gamma 2 in the impaired blastogenic response of uremic T-lymphocytes.

The peptide analogs of thymic humoral factor-gamma 2 (THF-gamma 2) in which phenylalanine residue at the 7th position are replaced by phenylglycine (Phg), homophenylalanine (Hph), and 1-naphthylalanine (1-Nal) were synthesized by a solid-phase method and the immunological significance of the aromatic amino acid of this position was comparatively investigated. The in vitro restoring effect of the synthetic peptides on the impaired phytohemagglutinin (PHA) response of T-lymphocytes from uremic patients was tested. The observed activities of these peptides were in order (1-Nal7) thymic humoral factor [THF]-gamma 2 > 4-Fluoro (Phe7) THF-gamma 2 > THF-gamma 2. However, the other two analogs, [Phg7] THF-gamma 2 and [Hph7] THF-gamma 2, had no restoring effect even at a higher concentration.

Comparison of the effects of acarbose and voglibose in healthy subjects.

Acarbose and voglibose are alpha-glucosidase inhibitors. Although the pharmacologic effects and incidence of abdominal adverse events associated with the two drugs have been reported to differ, no study has directly compared acarbose and voglibose. To compare the pharmacologic effects and gastrointestinal adverse events associated with the two drugs, a randomized, placebo-controlled, double-masked, fivefold crossover study was performed in 20 healthy male subjects. To assess the pharmacologic effects, plasma immunoreactive insulin (IRI), plasma glucose, and 24-hour urinary connecting-peptide immunoreactivity (CPR) excretion were measured. Although the postprandial increase in plasma glucose level was reduced significantly with both acarbose and voglibose, the rate of reduction was small. The maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) of plasma IRI after meals decreased significantly with all treatments except voglibose 0.3 mg compared with placebo. Overall, the Cmax and AUC of plasma IRI decreased more when subjects received acarbose than voglibose. Urinary CPR excretion decreased by 30.6% and 41.7%, respectively, in subjects who received acarbose 50 mg or 100 mg compared with the previous day when no drug was given, whereas the urinary CPR excretion did not decrease significantly with voglibose. There was no significant difference in the frequency of gastrointestinal adverse events between groups, including the placebo group. One-day administration of acarbose and voglibose at currently recommended clinical doses demonstrated that acarbose was more effective in sparing endogenous insulin secretion than was voglibose.

[A chronic encapsulated expanding hematoma with cyst formation caused by rupture of arteriovenous malformation: a case report].

A 57-year-old male was admitted to our hospital complaining of a headache with disturbance of consciousness on November 7, 1994. CT scans revealed an intracerebral hematoma of 25ml in volume in the left frontal lobe with adjacent spotty calcification. An arteriovenous malformation (AVM) with a nidus of 2.0 x 2.0cm in size was found to be the cause of the hematoma by cerebral angiography. Since the patient complained of mild right hemiparesis 10 days after the onset, CT scans were taken and a slightly enlarged hematoma with capsule formation was observed. On the 31st day after the onset, the hematoma had liquefied and the surrounding capsule was clearly visible on CT. Since the patient's only symptom was a slight headache, and he displayed no other serious conditions, a palliative operation was planned. The AVM was removed and the capsule was resected 41 days after the onset. The capsule or cyst wall of the liquefied hematoma was composed of three layers: a granulation layer with a neovascular system on the inside, a collagenous layer in the middle, and a reactive brain tissue layer on the outside. The structure of the capsule was the same as the structure of the cyst wall in chronic hematomas that have been reported as cystic AVM or encapsulated expanding hematoma in the literature. We would therefore like to propose that chronic encapsulated expanding hematomas form with time due to intermittent bleeding or exudation form the neovascular system of a cyst wall.

Differential stereoselective pharmacokinetics of pantoprazole, a proton pump inhibitor in extensive and poor metabolizers of pantoprazole--a preliminary study.

Pantoprazole (PAN) is a proton pump inhibitor that is administered as a racemic mixture. The pharmacokinetics of PAN enantiomers were investigated in extensive metabolizers (EMs) and apparent poor metabolizers (PMs) of PAN who received a single, 40, 60, or 80 mg oral dose of racemic PAN as enteric-coated formulation. In the EMs, the serum concentrations of (-)-PAN were slightly higher than those of (+)-PAN at each dose level. The (+)/(-) ratios for the area under the concentration-time curve (AUC) and the half-life were 0.58-0.89 and 0.62-0.88, respectively. In the PMs, the serum concentrations and both enantiomers were much higher than those in the EMs at each dose level and significant differences in pharmacokinetics of (+)- and (-)-PAN were observed. The half-lives for (+)-PAN were 2.67-3.77 times longer than those for (-)-PAN. The AUCs for (+)-PAN were 2.65-3.45 times greater than those for (-)-PAN. Therefore, the metabolism of (+)-PAN is impaired to a greater extent than (-)-PAN in the PMs, which resulted in the stereoselective disposition of PAN in the PMs. It has been suggested that the EMs and the PMs of PAN could be differentiated by determining the (+)/(-) enantiomer ratio in serum at one time point, possibly 2-6 h after oral dosing, because the (+)/(-) enantiomer ratios in the PMs were opposite those in the EM subjects.

Functional roles of Phe of deacetyl-thymosin beta4 in the impaired blastogenic response of uraemic T-lymphocytes.

Phe(12) of deacetyl-thymosin beta(4) is one of the structural essentials for restorative effect on the impaired blastogenic response of uraemic T-lymphocytes. In order to evaluate the functional roles of this phenyl group in the restorative effect on impaired T-lymphocytes, two analogues, [1- Nal(12)]deacetyl-thymosin beta(4) and [Cha(12)]deacetyl4 thymosin beta(4), were synthesized by a solid-phase method and evaluated for restorative effect on the impaired blastogenic response of uraemic T-lymphocytes. The results indicated that [1-Nal(12)]deacetyl-thymosin beta(4) which had a bulky naphthyl ring showed a stronger restorative effect than that of deacetyl-thymosin beta(4), but it was slightly weaker than that of [Phe(4F)(12)]deacetyl-thymosin beta(4). However, [Cha(12)]deacetyl-thymosin beta(4) showed no restorative effect on the impaired blastogenic response of uraemic T-lymphocytes.

Pharmacokinetics and tolerance of pantoprazole, a proton pump inhibitor after single and multiple oral doses in healthy Japanese volunteers.

The pharmacokinetics and tolerance of pantoprazole were investigated after single (20, 40, 80, and 120 mg) and multiple (80 mg once a day for 7 days) oral administration as enteric-coated tablet formulation to healthy male Japanese volunteers. Pantoprazole was well tolerated with no serious adverse events at all doses. Pantoprazole was rapidly absorbed in the fasted state. The mean maximum concentration in serum (Cmax) ranged from 1.77-9.25 micrograms/ml for the 20-120 mg dose and the mean time to reach Cmax (tmax) ranged from 1.92-2.42 h. The half-life (t1/2) ranged from 0.74-1.16 h. A good linear correlation was found between the administered doses (20-120 mg) and the resulting area under the concentration-time curve (AUC) and Cmax with the correlation coefficients of 0.9088 and 0.9263, respectively. Within 24 h, pantoprazole was excreted into urine as the unchanged drug to a negligible extent. In the multiple dose study, 2 apparent poor metabolizers (PMs) of pantoprazole were observed. The means of Cmax, AUC and t1/2 for these 2 PMs were 1.6, 6.7, and 6.8 times higher than those of the extensive metabolizers (EMs). The pharmacokinetic parameters such as Cmax, AUC, and t1/2 after the 7th oral dose were not significantly different from those after the 1st dose both in the PMs and the EMs, which indicated that there was virtually no drug accumulation.

[Outcome of long-term nasal intermittent positive pressure ventilation in 41 patients with hypercapnic respiratory failure].

Nasal intermittent positive pressure ventilation (NIPPV) is widely used in domiciliary treatment of chronic ventilatory disorders. The outcomes of long-term NIPPV were analyzed in 41 patients with hypercapnic respiratory failure due to pulmonary tuberculosis sequelae (PTS; n = 17), neuromuscular disease (NMD; n = 8), kyphoscoliosis (KS; n = 7), chronic obstructive pulmonary disease (COPD; n = 6), and miscellaneous diseases (n = 3). Twenty-seven patients with chronic conditions but without acute exacerbations began receiving NIPPV, and fourteen patients began receiving NIPPV after an acute exacerbation. Outcome measures included the probability of continuing NIPPV, survival after starting NIPPV, survival after starting home oxygen therapy (HOT), arterial blood gases, nocturnal oxygen saturation, pulmonary function, and the number of hospital days. Two patients with PTS died, 7 and 40 months after starting NIPPV. Two patients (one with PTS and one with COPD) switched from NIPPV to intermittent positive pressure ventilation via a tracheostomy. The condition of one patient with NMD improved and NIPPV was discontinued. The three-year and five-year probabilities of continuing NIPPV in all patients were 82%, and 71%, respectively. The survival rates three and five years after starting NIPPV were 97% and 85%, respectively. The survival rates one to nine years, and ten to eleven years after starting HOT were 98% and 65%, respectively. The arterial PO2 and PCO2, nocturnal oxygen saturation, vital capacity, and forced expiratory volume, in one second all improved after NIPPV was begun. NIPPV also reduced the number of hospital days, particularly in patients with KS. In conclusion, the long-term outcome of NIPPV in patients with hypercapnic respiratory failure is encouraging.

A surgical technique to avoid postoperative enophthalmos in the cranioorbital approach. Technical note.

The authors describe a surgical technique to avoid postoperative enophthalmos when using the cranioorbital approach. To perform osteotomies with a less demanding technique, two separate bone flaps were created: 1) a free frontotemporal bone flap and 2) en bloc removal of the superior and lateral orbital rims: Because the latter bone flap includes both the orbital roof and the posterolateral wall of the orbit with the greater wing of the sphenoid bone, unnecessary bone defects in the lateral orbital wall are avoided. The technique has been performed in seven patients treated for medially located skull base neoplasms or complex anterior circulation aneurysms without postoperative enophthalmos or other cosmetic problems. The authors believe this cranioorbital approach, with its simpler, less invasive surgical technique, offers a definite advantage by avoiding postoperative enophthalmos.

Syntheses and immunological effects of thymic humoral factor-gamma 2 and its Phe7-substituted analogues.

Thymic humoral factor-gamma 2 and five analogues modified at position 7 with various phenylalanine derivatives were synthesized by a solid-phase method. The synthetic peptides were tested for their effects on the impaired blastogenic response of phytohemagglutinin-stimulated T lymphocytes of uremic patients with infectious diseases. The synthetic thymic humoral factor-gamma 2 enhanced the blastogenic response of T lymphocytes in the blood of the 2 patients tested. Of the synthetic peptides, [Phe(4F)7]thymic humoral factor-gamma 2 exhibited the most potent effect.

Contralateral transcondylar approach for aneurysms of the posterior inferior cerebellar artery-vertebral artery complex.

We report a patient with an aneurysm of the left vertebral artery (VA)-posterior inferior cerebellar artery (PICA) complex that was treated successfully via a contralateral transcondylar approach. The aneurysm was small, pointed laterally to the right, and was located across the midline just above the level of the foramen magnum. This unusual location required special consideration during diagnostic evaluation and surgical planning. To simulate the operative view, the patient's head was turned 45 degrees. This extreme oblique view offered useful information with respect to the choice of side from which the surgical approach should be made. Removal of the posteromedial part of the occipital condyle allowed us to clip the aneurysmal neck without difficulty although the surgical approach was made on the side contralateral to the parent artery. We conclude that the contralateral approach for VA-PICA aneurysms should be considered when aneurysms cross the midline, and that extradural removal of the basal bony structures, including the occipital condyle, can provide a wide wirking space without excessive retraction on the brain stem.

Indoxyl-beta-D-glucuronide and 3-indoxyl sulfate in plasma of hemodialysis patients.

The content of indoxyl-beta-D-glucuronide, which has been found in patients' plasma as a new indicator of renal failure, logarithmically correlated with that of 3-indoxyl sulfate (indican) in the plasma of hemodialysis patients, showing another weak correlation with beta(2)-microglobulin content. The content ratio of indoxyl-beta-D-glucuronide to 3-indoxyl sulfate (IG/IS) gradually increased depending on the duration of hemodialysis treatment. Indoxyl-beta-D-glucuronide could be easily dialyzed in the hemodialysis treatment, in contrast to hardly dialyzable 3-indoxyl sulfate which bound to plasma proteins. Therefore, glucuronide conjugation in indole excretion is favorable for hemodialysis patients in that it eliminates indoxyl compounds in blood by hemodialysis.