Stereoselectivity of a potent calcium antagonist, 1-benzyl-3-pyrrolidinyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

Four enantiomers (3a-d) of the title compound, YM-09730 (3), were synthesized by the reaction of (-)- or (+)-5-(methoxycarbonyl)-2, 6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (1a or 1b) with (S)- or (R)-1-benzyl-3-pyrrolidinol (2a or 2b). [3H]Nitrendipine binding affinity and coronary vasodilating activity of these compounds were evaluated. The absolute configuration of the most potent enantiomer (3a) with the longest duration was unequivocally determined to be (S)-1,4-dihydropyridine-C4 and (S)-pyrrolidine-C3 (S,S) by X-ray crystallographic study on 3a X HBr as well as 3a X HCl. The configuration of 1a corresponds to R, and the other enantiomers of 3 were respectively determined by chemical correlation. The potency order of the four enantiomers was (S,S)-3a greater than (S,R)-3b greater than (R,R)-3d greater than (R,S)-3c. Latent chiral characters of nifedipine derivatives with the identical ester groups were assigned by comparison of their puckering modes of 1,4-dihydropyridine (DHP) rings with those found in 3a X HCl or 3a X HBr. On the basis of the assignment, it has been revealed that the (S)-DHP nifedipine derivatives possess the synperiplanar carbonyl group at C5. The conformational restriction may be a factor causing stereoselectivity of antagonism.     

Case of severe ulcerative colitis successfully treated with intravenous cyclosporine without high dose corticosteroid]

A 44-year-old women developed marked myopathy one year earlier, when she was treated with intravenous prednisolone for acute severe exacerbation of ulcerative colitis. When she was admitted to our hospital for another severe exacerbation, intravenous cyclosporine A was administered as monotherapy because she could not tolerate corticosteroid. The treatment was successful and she obtained complete remission. Cyclosporine A monotherapy is considered to be a valuable alternative to proctocolectomy for severe ulcerative colitis patients who cannot tolerate corticosteroid.     

Preparation of two-drug composite microparticles to improve the dissolution of insoluble drug in water for use with a 4-fluid nozzle spray drier.

In this study, we used a novel 4-fluid nozzle spray drier to prepare composite microparticles of a water-insoluble drug, flurbiprofen (FP), and a water-soluble drug, sodium salicylate (SS), for the purpose of improving the water solubility of FP. An ethanol solution of FP and an aqueous SS solution were simultaneously introduced through different liquid passages in the 4-fluid nozzle spray drier and then spray-dried. Quantitative elemental analysis suggested that the FP/SS ratio in each composite microparticle was nearly the same as the formulation ratio. We also found that SS and FP exist in a low crystallinity state in the composite particles. Release of FP from dissolved composite microparticles was markedly improved because of an increase in the effective surface area following rapid dissolution of SS. This study shows that it is possible to prepare FP-SS composite microparticles using a 4-fluid nozzle spray drier in single process and that this can improve the ability of FP to dissolve in water.     

Long-term results and its managements after coronary bypass surgery

Between 1970 and 1985, 221 patients with coronary artery occlusive disease underwent aorto-coronary bypass (A-C bypass) and other procedures. Among these patients, 187 had A-C bypass alone and A-C bypass in addition to correction of valvular lesions or arterialization of the coronary vein, myocardial puncture by laser. The remaining 34 had surgical corrections for myocardial infarction and its complications. Subjects were 100 patients who underwent A-C bypass alone over 6 months ago and whose follow-up study could be performed in 93 survival cases [corrected]. Subsequently, 94% of the patients have met the criteria for grade I of NYHA functional capacity and have returned to normal work at a mean of 4 years and 2 months after surgery. Improved left ventricular function has been maintained postoperatively in the patients with complete revascularization. Improved operative technique, in addition to intraoperative balloon angioplasty and onlay patch grafting, have increased the patency rate (78% in 1 mm, 94% in 2 mm of coronary diameter) of the grafts with postoperative anticoagulant therapy. On the basis of our long-term observations, coronary bypass surgery, particularly in complete revascularization, provides for significant improvement in both the quality and life expectancy of patients with severe coronary heart disease. Treadmill exercise test and magnetic resonance image (MRI) were useful, non-invasive and acceptable examinations in long-term follow up.     

Clinical study on norfloxacin in children

Norfloxacin (NFLX, AM-715), a new synthetic antibacterial agent, was administered to 18 child patients with infectious diseases. The patients included 5 boys and 13 girls from 3 to 14 years of ages. They were given orally dosage ranging 5.2-17.9 mg/kg/day for 4 to 14 days. Clinical efficacies were excellent in 1 case, good in 16 cases, unknown in 1 case, hence the total efficacy rate was determined to be 100%. There were no cases which showed side effects of the drug and no abnormal laboratory test values were observed during the treatment.     

The role of hemoglobin in arterial narrowing after subarachnoid hemorrhage

A porcine model for subarachnoid hemorrhage has been developed to allow the selective application of blood and its components to cerebral arteries. Whole blood was centrifuged to produce two fractions consisting of washed erythrocytes (red blood cells, RBC's) and white blood cells (WBC) plus platelet-rich plasma (PRP); the RBC fraction was subsequently separated into hemoglobin (Hb)-containing cytosol and erythrocyte membranes. Each fraction was selectively applied to the middle cerebral artery (MCA) of pigs for 10 days; after which, vessels were perfusion-fixed and examined by light and transmission electron microscopy and immunohistochemical studies. By morphometric analysis, a marked reduction in the MCA lumen cross-sectional area was observed after selective application of RBC's or Hb/cytosol but not of WBC/PRP or erythrocyte membranes. In both RBC- and Hb/cytosol-treated vessels, luminal narrowing was associated with a differential increase in vessel wall thickness of the ventral (subarachnoid) compared to the dorsal (brain) aspect of the artery, but no significant change in cross-sectional area of the vessel wall. After 10 days of exposure to RBC's or Hb/cytosol, there was a spectrum of ultrastructural changes in the vessel wall comparable to those seen after periadventitial application of whole blood. Selective application of commercially available Hb to MCA produced similar structural and morphometric changes. The degree of luminal narrowing after exposure to whole blood or RBC's was proportional to the volume of the erythrocyte mass adjacent to the vessel at sacrifice. These data suggest that arterial narrowing after SAH is mediated by mechanisms related to prolonged exposure of the vessel wall to hemoglobin or its catabolites from lysing subarachnoid erythrocytes.     

Mu rhythm: clinical assessment of the atypical type]

Of 5,218 patients who received EEG examination at our laboratory during a 9-month period in 1989, 241 showed the 7-13 Hz arch-shaped activity originating from over the Rolandic area known as mu rhythm. These subjects were divided into two groups as follows: Group 1, 171 subjects showing typical mu rhythm, i.e., recorded during wakefulness and not affected by visual stimulation but blocked voluntary movements or tactile stimuli; and, Group 2, 70 subjects showing atypical mu rhythm, i.e., accentuated or activated by drowsiness, photic stimuli, or hyperventilation. No difference between the two groups was found with regard to frequency, amplitude or origin of the mu rhythm. Age distribution for Group 1 showed a peak between the ages of 6 and 15 (67.5%), while that for Group 2 peaked between the ages of 11 and 15 (35.7%) considering high incidence in older age range. There was no significant difference between the two groups in regard to gender. Although both groups showed a high incidence of epilepsy, Group 2 showed higher incidence of intractable epilepsy (p less than 0.05), as well as of severe intracranial trauma and of organic brain disease. On EEG recorded among epileptic patients, paroxysmal discharge was more frequent in Group 2 (p less than 0.01), although no other difference between the two groups was observed. Atypical mu rhythm may indicate more severe epilepsy, and careful observation of patients with atypical mu rhythm is recommended.     

Frontal spindle activity that appears in conjunction with nontraumatic diffuse encephalopathy.

This peculiar 11-14 Hz spindle activity appears predominantly in the frontal area, and was observed in eight patients with impaired consciousness caused by nontraumatic diffuse encephalopathy. Characteristic of this frontal spindle activity is its transience and accordance with changes in the arousal level of the patient. When the degree of impaired consciousness in the patient was minimal and clinically not very apparent, this spindle activity appeared during light drowsiness. In lethargic patients, it was observed when the patient's level of consciousness rose (e.g. immediately after opening and closing the eyes). These frontal spindles disappeared at the onset of Stage 2 sleep, when normal physiologic spindle waves that are dominant in the vertex area appeared. A paroxysmal discharge was sometimes recorded in association with the frontal spindle activity and it disappeared at about the same time as these spindles. The prognosis was satisfactory for all patients in whom frontal spindle activity was observed; its correlation to spindle coma is also studied.