Anti-inflammatory and analgesic effects of a novel pyrazole derivative, FR140423.

The pharmacological profile of a novel and newly discovered non-steroidal anti-inflammatory and analgesic compound, 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl]pyraz ole (FR140423), was investigated. In recombinant human cyclooxygenase enzyme assays, the inhibition of prostaglandin E2 formation by FR140423 was 150 times more selective for cyclooxygenase-2 than cyclooxygenase-1. Oral administration of FR140423 dose dependently reduced carrageenin-induced paw edema and adjuvant arthritis. These effects were two- to three-fold more potent than those of indomethacin. Unlike indomethacin, FR140423 did not induce mucosal lesions in the stomach. FR140423 showed dose-dependent anti-hyperalgesic effects in the yeast-induced hyperalgesic model. This effect was five-fold more potent than that of indomethacin. Furthermore, FR140423 increased the pain threshold in non-inflamed paws and, unlike indomethacin, it produced an analgesic effect in the tail-flick test. These analgesic effects were blocked by the mu-opioid antagonist naloxone. These results suggest that FR140423, a selective cyclooxygenase-2 inhibitor, is a potent non-steroidal anti-inflammatory drug (NSAID) without gastrointestinal side effects and is a unique compound having morphine-like analgesic effects.

Purification and characterization of a glucuronyltransferase involved in the biosynthesis of the HNK-1 epitope on glycoproteins from rat brain.

The glucuronyltransferase involved in the biosynthesis of the HNK-1 epitope on glycoproteins was purified to an apparent homogeneity from the Nonidet P-40 extract of 2-week postnatal rat forebrain by sequential chromatographies on CM-Sepharose CL-6B, UDP-GlcA-Sepharose 4B, asialo-orosomucoid-Sepharose 4B, Matrex gel Blue A, Mono Q, HiTrap chelating, and HiTrap heparin columns. The purified enzyme migrated as a 45-kDa protein upon SDS-polyacrylamide gel electrophoresis under reducing conditions, but eluted as a 90-kDa protein upon Superose gel filtration in the presence of Nonidet P-40, suggesting that the enzyme forms homodimers under non-denatured conditions. The enzyme transferred glucuronic acid to various glycoprotein acceptors bearing terminal N-acetyllactosamine structure such as asialo-orosomucoid, asialo-fetuin, and asialo-neural cell adhesion molecule, whereas little activity was detected to paragloboside, a precursor glycolipid of the HNK-1 epitope on glycolipids. These results suggested that the enzyme is specifically associated with the biosynthesis of the HNK-1 epitope on glycoproteins. Sphingomyelin was specifically required for expression of the enzyme activity. Stearoyl-sphingomyelin (18:0) was the most effective, followed by palmitoyl-sphingomyelin (16:0) and lignoceroyl-sphingomyelin (24:0). Interestingly, activity was demonstrated only for sphingomyelin with a saturated fatty acid, i.e. not for that with an unsaturated fatty acid, regardless of the length of the acyl group.

Thoracic flexion myelopathy. Case report.

A case of thoracic flexion myelopathy is reported in a 36-year-old man. The patient had a history of gradually progressing transverse thoracic myelopathy. Conventional myelography in the neutral position failed to reveal cord compression; however, a severe block of the dye column was evident on studies in the flexed position. Excellent recovery from this condition was obtained with posterolateral fusion of the thoracic spine in the neutral position.

[A case of dural sarcoidosis].

A 26 year-old man, who was treated for meningitis in our hospital previously, was rehospitalized 1 year later because he developed disturbance of consciousness, gait disturbance and urinary incontinence. Blood examination revealed accelerated ESR, elevated GPT, slight elevation of serum Ca, strong positive CRP, and a decrease in PHA and Con A. ACE was within normal range and tuberculin reaction was negative. Lumbar puncture revealed that the initial pressure was 310 mmH2O, cells were 152/3, and protein was 343 mg/dl. Bilateral hilar lymphadenopathy was absent in chest X ray film. Head CT revealed enlarged lateral ventricles and irregularly enhancing nodular lesions in the anterior half of the falx cerebri, and abnormally strong enhancement of the choroid plexus. Ventriculoperitoneal shunt was performed. As a diagnosis was difficult to obtain from the clinical data, biopsy of the nodular lesions was performed. The histopathologic diagnosis was sarcoidosis. Steroid hormone was administered thereafter, and the nodular lesions of the falx disappeared in the follow-up. In the literature, only 8 cases of sarcoidosis of the dura mater have been reported. Since intracranial sarcoidosis is a part of systemic sarcoidosis, its diagnosis is not difficult in most cases. However, in cases difficult to diagnose as in our case, biopsy may be necessary. When nodular lesion occurs in the dura mater, sarcoidosis must be included as a possibility in the differential diagnosis in addition to the usual meningioma, lymphoma, and metastatic brain tumor.

[Left ventricular wall motion mimicking stunned myocardium in hypertrophic obstructive cardiomyopathy with normal coronary arteries: a case report].

A 63-year-old woman was admitted to the coronary care unit of Hyogo College of Medicine because of cardiogenic shock. She previously had been hospitalized in the Gynecology Department for the treatment of recurrent uterine cancer. She had poor appetite due to chemotherapy which was given for 10 days prior to her admission. On admission, echocardiography and cardiac catheterization revealed hypertrophic obstructive cardiomyopathy and extensive left ventricular wall motion abnormalities. Coronary arteriography showed no coronary artery disease. Left ventriculography as well as echocardiography performed on the 21st post-admission day revealed that the wall motion abnormalities had completely resolved and the systolic anterior motion of the mitral valve (SAM) was no longer evident. The systolic pressure at the apex of the left ventricle was 200 mmHg on admission. The increased ventricular pressure and the simultaneous resolution of the wall motion abnormality and SAM suggest that marked obstruction of the left ventricular outflow tract is more likely to be involved in transient ventricular wall motion abnormality rather than acute myocardial ischemia. The mechanism of the SAM in the present case seemed to be related to a Venturi effect which was augmented by the decreased preload due to hypovolemia. In addition, papillary muscle contraction seemed to pull the mitral valve toward the interventricular septum during systole.

[Intracerebral granuloma with serum anti-human ascaris antibody: case report].

A 1.5-year-old girl with a convulsion attack due to intracerebral granuloma in the right frontal lobe is reported. Her serum was positive with anti-human ascaris antibody, although no ova of the parasites were detected in the feces. She had grown up intimately with several cats in the home. These findings suggested that the granuloma was due to larva migrans of toxocara, which cross-reacts immunologically with human ascaris. Histological examination of the granuloma revealed no eosinophilic infiltration. No systemic reactions such as eosinophilia and hepatomegaly were found except for elevation of protein in cerebrospinal fluid. These were similar to those of ocular type of toxocara larva migrans.

[Combination of radiation and PVB chemotherapy for intracranial malignant germ cell tumor].

Intracranial malignant germ cell tumors such as embryonal carcinoma, endodermal sinus tumor, and choriocarcinoma are neoplasms of poor prognosis in the pediatric age group. Recently evidences of effectiveness of combination chemotherapy using cisplatin, vinblastine, and bleomycin (PVB therapy) have been reported. The authors experienced two cases with these tumors treated with radiation therapy and PVB therapy. PVB therapy was performed along with irradiation in hoping the effect of radiation sensitizer of cisplatin. Both patients showed no signs of tumor recurrence and no re-elevation of tumor makers even in the cerebrospinal fluid after more than ten months from the onset. Cisplatin has radiation sensitizing effect besides antitumor activity, but its permeability through the blood-CSF barrier is very poor. Also true is that germ cell tumors often disseminate in the cerebrospinal fluid. From these points, combination of irradiation and chemotherapy using cisplatin seems reasonable, though the superiority of this radiochemotherapy to simple PVB therapy can not be concluded from the present experience. Side effects of this combination therapy were the same as PVB therapy alone and tolerable.

[Case of calcified prolactinoma combined with Rathke's cleft cysts].

A case of chromophobe adenoma with capsular calcification combined with Rathke's cleft cysts is presented. A 28-year-old woman presented with a seven-year history of amenorrhea. Several months before admission to our department of neurosurgery on November 6, 1982, she developed galactorrhea and difficulty in reading because of visual failure. Neurological examination on admission revealed bitemporal hemianopsia, visual disturbance, left optic atrophy. Plain skull films and CT scan showed suprasellar capsular calcification. The patients hormonal status was assessed pre- and postoperatively. The basal serum prolactin (PRL) level was elevated at 790ng/ml, but other hormone basal plasma levels were within normal limits despite decrease in FSH, LH, The LH, FSH and PRL demonstrated a blunted response to LH-RH (100 micrograms). Both TSH and PRL demonstrated a blunted response to TRH (500 micrograms). The GH showed no response to insulin tolerance test (0.1 U/kg). On November 24, right frontal craniotomy was performed. A grayish bulging mass was noted surrounded by a calcified layer(2-3 mm) in the suprasellar region. When incised this calcified hard layer, showed multi-small cysts with yellow fluid. Under the cyst layer, there was a soft mass which was curetted easily. Histologically, under the ossified layer, there were multi-small cysts, lined by a single layer of ciliated columnar epithelium. The central soft mass was regarded as a chromophobe adenoma with no calcified body. Following partial removal of the tumor, there was prompt improvement in clinical signs and plasma PRL level.(ABSTRACT TRUNCATED AT 250 WORDS)

[Etiology of water and electrolyte metabolism imbalance following the rupture of cerebral aneurysms--with special reference to preoperative condition].

One hundred fourteen patients with ruptured cerebral aneurysms were reviewed in regard to the incidence and etiological factors of preoperative disturbances of water and electrolyte metabolism. Patients with inadequate salt intake, evidence of renal disease, cardiac failure or excessive diuretic therapy were excluded. Twenty-five (21.9%) patients developed water and electrolyte disturbances. Hyponatremia (less than 130 mEq/l) occurred in 18 (15.8%) of 114 patients. The majority of those patients with hyponatremia showed laboratory findings and/or clinical features suggesting the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). The mean interval between the last subarachnoid hemorrhage (SAH) and the development of hyponatremia was 13.5 days (range 6 to 26 days). No patients developed hypernatremia (more than 155 mEq/l). Preoperative diabetes insipidus (DI) occurred in 7 (6.1%) of 114 patients. The mean interval between the last SAH and the onset of DI was 26.5 days (range 15 to 35 days). When compared with the onset of hyponatremia following SAH, the development of DI was significantly delayed. The present study showed that the following five types of patients significantly related to the development of preoperative water and electrolyte disturbances after SAH due to cerebral aneurysms. The patients with ruptured aneurysms of anterior communicating, anterior cerebral artery or internal carotid artery. The patients in grade III, IV according to Hunt & Hess. The patients with high density in the basal subarachnoid space on the CT scan. The patients with a small hematoma in the region of the basal frontal interhemispheric fissure in cases with aneurysms of the anterior communicating or anterior cerebral artery.(ABSTRACT TRUNCATED AT 250 WORDS)

[Diabetes insipidus following the rupture of cerebral aneurysms--with special reference to preoperative cases].

The authors reported 4 cases with preoperative diabetes insipidus (DI) following the rupture of cerebral aneurysms. In addition, the incidence of preoperative DI and the mechanisms as the cause of DI in cases with the ruptured cerebral aneurysms were also discussed. In the 114 cases underwent clipping of the ruptured cerebral aneurysms more than 14 days after the bleed, only 4 cases (3.5%) developed DI preoperatively. The time period between last subarachnoid hemorrhage and the onset of DI ranged from 23 to 35 days. This delayed onset of DI after subarachnoid hemorrhage was different from previous reports. A few of mechanisms had been suggested through which DI could be brought about in cases with cerebral aneurysm. That is; direct compression to the hypothalamo-hypophysial system by a giant aneurysm. compression and destruction of the hypothalamus by a hematoma or hemorrhage, ischemic changes in the hypothalamo-hypophysial system caused by vasospasm. In the present 4 cases, no had giant aneurysms. Although CT scan revealed subarachnoid clot in all cases, it did not show apparent hypothalamic lesion except case 1 who had small hematoma in the region of the basal frontal interhemispheric fissure. Symptomatic vasospasm was recognized in 3 cases. However, one of them had mild vasospasm restricting in M1 portion and case 3 was free of any vasospasm. Furthermore, the time period from the identification of vasospasm until the onset of DI ranged from 2 to 3 weeks. These results suggest that another mechanism in addition to a hemorrhage, hematoma and/or vasospasm may exist.(ABSTRACT TRUNCATED AT 250 WORDS)

[Albumin therapy for patients with increased intracranial pressure: oncotic therapy].

Albumin plays an important role in maintaining an adequate plasma colloid osmotic pressure (COP). On the basis of the Starling's law, we postulated that elevation of plasma COP produced by infusion of serum albumin would result in the withdrawal of cerebral interstitial fluid. To test the hypothesis that an oncotic gradient would produce cerebral dehydration and result in reduction of intracranial pressure (ICP), we infused intravenously 25% solution of salt-poor human serum albumin, 2g/kg over 60 minutes for 10 patients with increased ICP. In these 10 patients, the degree of brain edema was not severe but mild to moderate by judging from CT scan findings. In addition to ICP, various parameters such as mean arterial blood pressure (MABP), central venous pressure (CVP), pulse rate, PaCO2 and urine volume were measured before, during and after albumin infusion. Hematological studies including COP, total protein, albumin-globulin ratio, protein fractions, hematocrit (Ht), blood urea nitrogen (BUN), creatinine and electrolytes were also performed before, during and after administration of albumin. The raised ICP (27.4 +/- S.E. 1.6 mmHg) decreased significantly down to 19.1 (+/- 1.9) mmHg and remained stable for at least 240 minutes without any changes of MABP, pulse rate and PaCO2. CVP elevated significantly and remained at higher levels in comparison with control despite increase of urine output after administration of albumin. This results suggested that an adequate circulatory volume was maintained. A significant increase of total protein, serum albumin concentrations and albumin-globulin ratio was noted.(ABSTRACT TRUNCATED AT 250 WORDS)

[Cerebral vasospasm following subarachnoid hemorrhage in arteriovenous malformation].

Cerebral vasospasm after SAH from AVMs is rare. Only few reports have been made. Vasospasm was confirmed in 4 out of 13 patients with SAH from AVMs at the Sagamihara National Hospital in the past 5 years. The incidence of vasospasm following rupture of AVM is higher than those in previous reports ranging between 8 and 12 percent. This high incidence (31%) might be attributable to the timing from the last SAH attack until angiography. The existence of massive subarachnoid blood clots around the arteries of the circle of Willis is the most important factor causing vasospasm after SAH from AVMs.