Studies on prodrugs. 10. Possible mechanism of N-dealkylation of N-masked norfloxacins having several active methylene groups

As a prodrug approach to norfloxacin (NFLX, 2), we have prepared several N-masked NFLXs (1a-f) and studied the cleavage mechanism of the C-N bond of N-masked NFLXs utilizing the following experiments: (1) the oxidation of N-masked NFLXs (1a-f) with m-chloroperbenzoic acid (MCPBA) and their subsequent cleavage to 2 in chloroform at room temperature or at 50 degrees C; (2) the liberation of NFLX from N-masked NFLXs after oral administration in mice. It was found that the chemical oxidative dealkylation of N-masked NFLXs proceeded when anion-stabilizing groups (e.g., CN, COR, COOR) are present on the alpha carbon of the nitrogen atom. In in vivo experiments, N-masked NFLXs having acidic hydrogens on the alpha carbon to the nitrogen atom also liberated NFLX (2) after oral administration.     

Neither adrenergic nor cholinergic antagonists in the central nervous system affect 2-deoxy-d-glucose(2-DG)-induced hyperglycemia

To investigate whether the brain adrenergic and cholinergic neurotransmitter systems are involved in the regulation of 2-deoxy-d-glucose (2-DG)-induced hyperglycemia, we studied the effects of adrenergic and cholinergic antagonists on 2-DG-induced secretion of epinephrine and glucagon, and hyperglycemia, in anesthetized fed rats. When 2-DG (10 mg/10 μl) was injected into the third cerebral ventricle, hepatic venous plasma glucose, glucagon, and epinephrine concentrations were significantly increased. Co-administration of phentolamine, propranolol, atropine and hexamethonium (1 × 10⁻⁷ mol) with 2-DG did not modify the hyperglycemia responses normally observed after the administration of 2-DG alone. From this evidence we concluded that neither brain adrenoceptive nor cholinoceptive neurons are involved in the regulation of 2-DG-induced hyperglycemia.     

Clinical study of rhG-CSF (KRN8601) in patients with myelodysplastic syndrome]

A clinical study of rhG-CSF (KRN8601) in patients with myelodysplastic syndrome (MDS) was performed to investigate the hematopoietic effects and the increase of neutrophils. The rhG-CSF was administered daily by intravenous infusion over 30 min. to 21 patients with MDS (PARA = 11, RAEB = 4, RAEB in T = 6). The dose was escalated stepwise from 50 to 400 microgram/m2 every week. Within one week to 26 days after commencement of rhG-CSF administration, the increases of absolute neutrophil counts in peripheral blood were observed in all patients. Treatment with rhG-CSF enhanced normal marrow myeloid cell differentiation and maturation in 3 of 9 PARA patients and in 3 of 4 RAEB patients. None of patients changed to acute leukemia attributable to rhG-CSF, but one of RAEB patient and two of RAEB in T patients progressed to leukemic phase in 21 days or two months after treatment. Minor side effects or abnormal laboratory findings were observed in 3 patients (14.3%). These results suggested that treatment with rhG-CSF was well tolerated and effective for improving the neutropenia between 50 to 400 micrograms/m2 in patients with MDS.     

Anti-cytoplasmic autoantibodies reactive with epithelial cells of the salivary gland in sera from patients with Sjögren's syndrome: their disease- and organ-specificities

To test whether the autoantibodies reactive with epithelial cells of the salivary gland in sera from Sjögren's syndrome (SS) patients are specific for the organ and the disease, tissue reactivities of serum IgG obtained from the patients with SS and oral lichen planus (OLP), another immune-mediated oral mucosal disease, were examined by immunohistochemistry and Western blotting. IgG purified from the sera of SS patients specifically localized not only on the nuclei but also on the cytoplasm of the salivary gland epithelial cells. On the other hand, no convincing staining of the epithelial cells was observed when IgG purified from the sera of OLP patients or those from healthy controls were used for immunohistochemistry. No cytoplasmic staining was observed when sections of kidneys and pancreas were stained with SS patients'IgG. In Western blotting performed by using lysates of a submandibular gland as antigens, all the IgG prepared from the SS patients reacted prominently with several protein bands, including those specific for the disease and the organ. These results suggest that production of autoantibodies reacting with the cytoplasm of salivary gland epithelial cells is a characteristic of SS, and may play a role in the pathogenesis of the sialadenitis.     

Increased MR signal intensity secondary to chronic cervical cord compression

Summary Magnetic resonance images of 128 patients with compressive lesions of the cervical spinal canal were reviewed to determine whether a high signal intensity lesion within the spinal cord was present on T2 and proton density weighted spin echo images. Such high signal intensity was observed in 24 cases or 18.8%. The incidence was higher in herniated disk (32.4%), atlanto-axial dislocation (28.6%), and ossification of the posterior longitudinal ligament (22.7%), whereas the abnormality was found sporadically in cervical spondylosis and vertebral body tumors. The high intensity lesion on T2 weighted images was generally observed in patients with constriction or narrowing of the spinal cord. The lesion was not demonstrated on T1 weighted spin echo images. Spinal cord constriction or localized narrowing seemed to be the most important portant predisposing factor in producing such a high signal intensity. The pathophysiologic basis of such an abnormality was presumed to be myelomalacia or cord gliosis secondary to a long-standing compressive effect of the spinal cord.     

Nodule‐aggregating lesion of the ileum: Report of a case and a review of the literature

We describe here a rare case of nodule‐aggregating lesion of the terminal ileum detected by colonoscopy. An 82‐year‐old Japanese woman was admitted to our hospital with diarrhea. Colonoscopy revealed a flat elevated tumor with conglomerated nodular surface involving the entire circumference of the terminal ileum, suggesting a nodule‐aggregating lesion. Magnifying the colonoscopic view showed the branch‐like or gyrus‐like pits. On biopsy, the tumor was diagnosed as a tubulovillous adenoma. Retrograde ileogram using a colonoscope revealed an elevated tumor with nodular irregularity, measuring 5 cm in length. Ileocecal resection was performed. Macroscopically, the tumor in the terminal ileum, 8 cm distant from the ileocecal valve, showed a nodule‐aggregating lesion, measuring 44 × 60 × 6 mm in size. Histologically, the tumor showed a focal carcinoma in tubulovillous adenoma. To our knowledge, this is the fifth case of early cancer of the ileum in Japan, and the first case of nodule‐aggregating lesion of the ileum detected by colonoscopy in the world.     

The mechanism of ergonovine-induced airway smooth muscle contraction

There have been three articles in the clinical literature of ergonovine maleate-induced bronchospasm. The effect of the alkaloid on isolated canine tracheal smooth muscle was analyzed to investigate the mechanism of ergonovine-induced airway smooth muscle contraction. Both ergonovine and 5-hydroxytryptamine (5HT, serotonin) contracted the smooth muscle preparations with EC50s of 1.35 X 10(-8) mol/L and 5.06 X 10(-7) mol/L, respectively. The maximal contractile response observed with ergonovine was approximately 30% less than that observed with 5HT. Methysergide competitively blocked both ergonovine and 5HT responses with similar calculated pKB values (8.33 against ergonovine and 8.46 against 5HT) and also similar pA2 values determined by Schild plots (8.50 and 8.45, respectively). The relative affinity and efficacy of ergonovine versus 5HT were determined by use of a concentration of the irreversible antagonist, phenoxybenzamine, which partially blocked receptor sites. The calculated affinity of ergonovine was about 16 times higher than that of 5HT. The relative efficacy at EC100 for ergonovine was 0.2, but at EC10 it was 41.9 (5HT efficacy = 1). Ergonovine 10(-9) or 10(-8) mol/L shifted the 5HT dose-response curve to the right without reducing the maximal response, but the shift was nonparallel. Blockade of muscarinic (atropine), alpha 1-adrenergic (prazosin), beta-adrenergic (propranolol), H1 (pyrilamine), or H2 (cimetidine) receptors did not alter ergonovine-induced contraction. These data indicate that ergonovine directly contracts canine tracheal smooth muscle as a result of its combination with 5HT receptors. This effect may result in precipitation of an asthmatic attack in susceptible individuals.