AD-1590, a potent antagonist of lipopolysaccharide-induced fever in rabbits

The antipyretic activity of AD-1590 (2-[8-methyl-10,11-oxodibenz[b,f]oxepin-2-yl]propionic acid), a non-steroidal anti-inflammatory drug with a novel chemical structure, was investigated in rabbits with lipopolysaccharide (LPS)-induced fever and monkeys with leucocytic pyrogen-induced fever. AD-1590 produced a dose-related inhibition of the LPS-fever at oral doses of 0·1 mg kg⁻¹ or more (ED50 = 0·089 mg kg⁻¹). Its potency was 10–12, 20–35, 100–170, 400–540, >1500 and >2000 times that of ketoprofen, diclofenac sodium, indomethacin, ibuprofen, mefenamic acid and aspirin, respectively. The fever caused by leucocytic pyrogen was significantly inhibited by intravenous administration of 0·1–0·2 mg kg⁻¹ of AD-1590. AD-1590 (10 mg kg⁻¹ oral or i.v.) did not affect body temperature in afebrile rabbits or monkeys. These results suggest that AD-1590 shows a potent antipyretic activity in the rabbit and monkey and is a potent antagonist of LPS-fever.     

Metabolism of a new positive inotropic agent, 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)- quinolinone (OPC-8212) in the rat, mouse, dog, monkey and human

1. After OPC-8212 was orally given to rats, mice, dogs, monkeys and humans, its metabolites were identified by n.m.r. and mass spectrometry, and their concentrations in the plasma, urine and faeces of these species were measured by high-performance liquid chromatography (h.p.l.c.). 2. Hydrolysis of the amide group, oxidation and cleavage of the piperazine ring, O-demethylation of the methoxy group, and conjugation were proposed as metabolic pathways of OPC-8212. 3. In rats, mice and monkeys given OPC-8212 orally, metabolites M-1 to M-6 were detected in the plasma, urine and faeces, while M-1, -4, -5 and M-6 were detected in dogs, and M-1, M-3, M-4, M-5 and M-6 were detected in humans. 4. Conjugates of metabolites M-6 and M-7, with glucuronic acid and sulphuric acid, were observed in the urine of rats and humans.     

A case of periodic ataxia]

We report a sporadic case of periodic ataxia characterized by recurrent attacks of vertigo and ataxia. A 62-year-old male was known to have nystagmus at the age of 18. He has had recurrent episodes of vertigo and ataxia since the age of 48. During an attack remarkable downbeat nystagmus, limb ataxia predominant in the lower extremities and ataxic gait were present. MRI demonstrated an atrophy of the anterosuperior region of the cerebellar vermis. Vertical nystagmus, dysesthesia of gloves and stocking type and deep sensory disorder persisted during interictal intervals. There is no finding which supports this case to be vascular disorder, congenital anomaly, tumor, infection or demyelinating disease. We thought this case to be periodic ataxia and to belong to vestibulocerebellar ataxia reported by Farmer and his colleagues.     

Behavioral changes after focal cerebral ischemia by left middle cerebral artery occlusion in rats

Behavioral changes after occlusion of the left middle cerebral artery (MCA) in rats were investigated for 16 weeks. Impairment of motor coordination and incidence of neurological deficits including hemiplegia and abnormal posture were present for the first 2 and 4 weeks after MCA occlusion, respectively. Learning behavior in one-trial passive avoidance task was disturbed for the entire 16-week period when rats were trained at days 3 after MCA occlusion. Reacquisition was also impaired when rats were retrained on 8 weeks after MCA occlusion. Except for synchronized EEG at days 2 after MCA occlusion, significant changes in spontaneous movement and EEG were not observed in the MCA-occluded group. These results suggest that this rat model of MCA-occlusion is useful for quantitatively measuring functional changes in chronic phase of focal cerebral ischemia.     

Vocal cord abductor paralysis (VCAP) in Parkinson''s disease: difference from VCAP in multiple system atrophy

Vocal cord abductor paralysis (VCAP) is rare in Parkinson's disease (PD), while it is frequent in multiple system atrophy (MSA). Although VCAP is a life-threatening complication it has not yet been clarified whether there is any difference in the mechanism of VCAP between PD and MSA. Examining 3 autopsy-proven PD patients who developed severe VCAP requiring tracheostomy, we found the following differences in the mechanism of VCAP between MSA and PD: (1) clinical and laryngofiberscopic examination showed that VCAP in PD was not exacerbated during sleep, unlike in MSA; (2) On histological examination of the intrinsic laryngeal muscles, the posterior cricoarytenoid muscle demonstrated no abnormalities in PD, while the muscle showed characteristic neurogenic atrophy in MSA. There seemed to be two types of VCAP, namely the nonparalytic type observed in PD, and the paralytic type observed in MSA. Severe dysphagia requiring tube-feeding was common among PD patients who presented with VCAP. Although the relationship between VCAP and dysphagia is unknown, one should be aware of the possibility of fatal VCAP in PD patients with severe dysphagia.     

Thyroid involvement by malignant histiocytosis of Langerhans' cell type

Involvement of the thyroid gland by Langerhans' cell histiocytosis is quite rare. We describe the case of a 58-year-old man referred for treatment of a progressively enlarging goitre. The trachea was severely stenotic and adjacent structures such as the left carotid vein and the thyroid cartilage were also involved. Central diabetes insipidus and severe combined immunodeficiency were associated. Although fine needle aspiration biopsy of the thyroid was initially interpreted as papillary carcinoma, anaplastic thyroid cancer was suspected. Treatment with prednisolone, doxorubicin and irradiation controlled the tracheal compression. A diagnosis of thyroid Langerhans' cell histiocytosis was finally made on the basis of the presence of Birbeck granules and CD1a and CD4 antigen in the thyroid tumour cells. Furthermore, positive staining for CD68 and lysozyme suggested that the tumour cells may have had the character of phagocytic cells in addition to their dendritic cell nature. This is the first case of thyroid involvement by malignant histicytosis of Langerhans' cell type with unusual phagocytic markers.