Cardiovascular Effects of Azelnidipine in Comparison with Those of Amlodipine Assessed in the Halothane‐Anaesthetized Dog

Abstract: Azelnidipine is a new dihydropyridine Ca²⁺ channel blocker with long plasma half‐life. To understand the in vivo cardiovascular profile of azelnidipine, it was assessed in the halothane‐anaesthetized, closed‐chest canine model and compared with the effect of amlodipine. We administered azelnidipine in doses of 10, 20 and 70 μg/kg, i.v. or amlodipine in doses of 30, 70 and 200 μg/kg, i.v. cumulatively to the animals. The hypotensive effects of azelnidipine and amlodipine were slow in onset and long‐lasted, while their extents of dose‐related hypotensive effects were similar. Azelnidipine hardly affected the heart rate or plasma noradrenaline concentration at any doses, whereas the high dose of amlodipine increased these parameters. Azelnidipine as well as amlodipine tended to increase the ventricular contraction, which did not achieve statistical significance. During autonomic receptor blockade with atropine and propranolol, neither drug affected the heart rate, ventricular contraction or plasma noradrenaline concentration, although a more significant hypotensive action was observed. These results indicate that azelnidipine and amlodipine do not directly affect cardiac function. Amlodipine may induce sinus tachycardia via reflex‐mediated increase in sympathetic tone. Such lack of reflex tachycardia with azelnidipine will provide potential therapeutic strategy for treatment of patients with cardiovascular diseases, being more beneficial than amlodipine.     

A New Experimental Model for Drug Studies: Effects of Phenobarbital and Phenytoin on Photosensitivity in the Lateral Geniculate-Kindled Cat

Photosensitivity was acquired as a result of kindling in the lateral geniculate body (GL), and the GL-kindled cat pretreated with DL-allylglycine showed a stable level of photosensitivity. To test the usefulness as a model for the evaluation of anticonvulsant drugs, the effects of phenobarbital (PB) and phenytoin (PHT) on photosensitivity were studied in the GL-kindled cat under DL-allylglycine. PB (5 and 10 mg/kg intravenously, i.v.) completely suppressed photically induced seizures in most subjects at plasma concentrations of 7-16 micrograms/ml, and this anticonvulsant action persisted for at least 4 h after the injection. PHT (15 mg/kg, i.v.) at plasma concentrations of 9-15 micrograms/ml produced toxic signs, e.g., pupil dilatation, hypersalivation, and tachypnea. At this dose, PHT was inactive against photically induced myoclonus but prevented the elicitation of a generalized tonic-clonic convulsion. From these results showing that the effects of anticonvulsant drugs on photically induced seizures can be assessed in relation to plasma concentration and acute neurologic toxicity, we suggest that the GL-kindled cat is a potentially useful animal model of epilepsy for testing the efficacy of anticonvulsant drugs.     

Dynamic MR cholangiography after fatty meal loading: cystic contractility and dynamic evaluation of biliary stasis.

PURPOSE: Dynamic MR cholangiography was conducted on patients with cholelithiasis or choledocholithiasis who had consumed a fatty test meal (Molyork) and the cystic contractility and dynamics of biliary stasis was evaluated. SUBJECTS AND METHOD: The subjects were 25 with intracystic cholelithiasis, 10 with choledocholithiasis and 10 normal controls. For an imaging sequence, the rapid acquisition with relaxation enhancement (RARE) method was employed and imaging was conducted for 40 min (every 30 s following Molyork administration) without breath-holding. The gallbladder contraction ratio was computed and the contractile ratio for the common bile duct was calculated. To determine the bile flow to the duodenum, the high-intensity signal, indicating the flow from the lower common bile duct, and perfusion of the duodenum were observed in dynamic mode on the monitor with the naked eye and interpreted as positive bile flow. The frequency of this flow was visually monitored. RESULTS: The gallbladder contractile ratio was significantly reduced in patients with cholelithiasis or choledocholithiasis compared with the controls. In a comparison with the normal controls, no sequential changes were noted in the mean contractile ratio of the common bile duct of the patients with cholelithiasis or choledocholithiasis. The mean frequency of bile flow observed for each 40 min period was 13+/-2.4, 6+/-2.2, and 4+/-1.3 times for the controls, those with intracystic cholelithiasis, and those with choledocholithiasis, respectively. Compared with the controls, the latter two patient groups showed evident reductions in the frequency of bile flow to the duodenum (p<0.001). CONCLUSION: Dynamic MRC combined with Molyork loading makes it possible to compute cystic contractile ratios and perform a dynamic examination of bile flow under non-invasive, near-physiological conditions.     

Dietary catechol causes increased oxidative DNA damage in the livers of mice treated with acetaminophen

We have shown that direct reaction of catechol with nitric oxide (NO) results in generation of reactive oxygen and nitrogen species (RNS) through semiquinone radical formation, leading to oxidative DNA damage in rat forestomach. In the present study, we investigated whether dietary catechol systemically exerts the same effects under NO-rich circumstances, when given before and during induction of inflammatory lesions. Male ICR mice were treated with or without 0.8% catechol in the diet for 2 weeks followed by acetaminophen (APAP) administration at a dose of 300 mg/kg by single i.p. injection. Along with several indicators of APAP-induced hepatitis, 8-hydroxydeoxyguanosine (8-OHdG) levels and immunohistochemistry for 3-nitrotyrosine (NO₂Tyr) in the livers were examined at 1.5, 4 and 24 h after APAP injection. 8-OHdG was significantly increased at 24 h in the co-treatment group, but not with either catechol or APAP alone. Elevation of serum ALT and AST activities, decrease of reduced glutathione levels and histopathological liver changes were observed to the same extents in both APAP-treated groups. In view of the finding of positive hepatocytes for NO₂Tyr prior to generation of 8-OHdG, the process of oxidative DNA damage might involve RNS formation. Precise quantitative analysis of NO₂Tyr by means of liquid chromatography with tandem mass spectrometry (LC-MS/MS) in an additional study with the same experimental protocol confirmed increase of RNS due to the reaction of catechol with NO produced after APAP-induced hepatitis. The overall data imply that antioxidants with a catechol structure can cause oxidative DNA damage under inflammatory conditions.     

EFFICACY OF AZATHIOPRINE IN MILD OR MODERATE RELAPSE IN CROHN'S DISEASE: CLINICAL AND ENDOSCOPIC EVALUATION

Aim: The present study was aimed at evaluating the efficacy of azathioprine (AZA) in patients with active and relapsing Crohn's disease (CD) and the usefulness of endoscopy in this evaluation. Methods: The 53 patients with active CD treated with AZA at our hospital were subjected to the following retrospective analysis: (i) evaluation of the clinical efficacy of AZA through comparison of the Crohn's disease activity index (CDAI); (ii) analysis of the relationship of the clinical efficacy to the difference in the mean corpuscular volume (MCV); (iii) evaluation of mucosal healing through analysis of the scores of the endoscopic findings in 16 patients; and (iv) analysis of the relapse rate. Results: (i) Among the 53 patients, treatment was rated as having induced complete remission in 22.6%, as being effective in 41.5%, and as being ineffective in 13.3% of patients. The treatment was discontinued in 22.6% of patients. (ii) The post‐treatment MCV was significantly increased after treatment. (iii) When the ulcer score estimated after treatment was compared with that before the start of treatment, a significant improvement of the score was noted. (iv) When the non‐relapse rate after AZA therapy was calculated in the 41 patients followed up for 12 months, it was 84.8%. Conclusion: AZA was shown to cause endoscopic mucosal healing as well as clinical efficacy. In the present study, it was inferred that the efficacy of AZA therapy in CD patients is manifested clinically first and that mucosal healing is an effect that occurs later.     

The secretion of amelogenins is associated with the induction of enamel and dentinoid in an ameloblastic fibro-odontoma

Ameloblastic fibro-odontoma is the unique entity of epithelial-ectomesenchymal odontogenic tumors, which is characterized by enamel formation in addition to dentine. We examined immunohistochemically a case of this tumor in which enamel having prism structures was developed in the absence of odontoblast differentiation but was in contact with mesenchymal matrices. Histological examination showed diverse morphological features of epithelial tumor cells, e.g., cuboidal cells comprising tooth bud-like projections, ameloblast- and stellate reticulum-like cells, and residual cells in forms of extended cords or islands of odontogenic epithelium. Immunostaining with anti-amelogenin sera proved that the intracellular production of amelogenins was initiated at the tooth bud-like stage. The secreted amelogenins were detected almost exclusively in the induced enamel and dentinoid areas, as well as in the core region of cementicle-like spheres deposited in the encapsulating stroma. The results obtained indicate that the odontogenic tumor epithelia and its products, i.e., amelogenins, participate in multifaceted aspects of dental hard tissue formation that takes place during oncogenesis.     

Efficacy of dynamic MRI with superparamagnetic iron oxide (SH U 555 A): vascularity evaluation in hepatocellular carcinoma.

PURPOSE: A study was conducted to determine the possibility of evaluating the blood flow in cases of hypervascular hepatocellular carcinoma (HCC) by employing dynamic MRI with superparamagnetic iron oxide (SH U 555 A), which can be rapidly injected via an intravenous route. METHODS: Six patients with hypervascular HCC (23 nodules) served as the subjects. Dynamic MRI includes images obtained at precontrast and at 10 (perfusion phase), 60, 120, 180, 240, 300 and 600 s after the start of injection of SH U 555 A. CT hepatic arteriography (CTHA) and CT during arterial portography (CTAP) were used as the standards of reference, and these were performed in all patients three days after dynamic MRI. The signal changes were evaluated at each phase, especially at the perfusion phase from the viewpoints of a lesion-to-liver contrast-to-noise ratio (CNR) and visual examination. RESULTS: A total of 23 hypervascular HCC were detected on CTHA and CTAP. Of the 23 lesions, 17 were detected on SH U 555 A enhanced MRI. Incorrect timing during acquisition of the perfusion phase was considered in two cases with three lesions. Of 14 lesions, excluding two cases with incorrect timing, a reduction in the transient signal in the lesions at the perfusion phase was visually recognized in 10 lesions (71%). Significant differences were seen in tumor size between visible and non-visible tumors involving transient signal reduction (p< 0.05). CNR gradually increased after rapidly decreasing in the perfusion phase. CONCLUSION: SH U 555 A enhanced MRI is valuable in limited cases. Evaluation of tumor blood flow employing dynamic MRI with SH U 555 A is affected by tumor size and requires optimal timing of the perfusion phase.     

OBLIQUE‐VIEWING ENDOSCOPE FACILITATES ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY AND ASSOCIATED PROCEDURES IN POST‐BILLROTH II GASTRECTOMY PATIENTS

Background: Endoscopic retrograde cholangiopancreatography (ERCP) and associated procedures have been reported to be difficult to perform in patients with Billroth II gastrectomy. We evaluated the feasibility of using an oblique‐viewing endoscope equipped with a cannula deflector for these procedures in such patients. Patients and Methods: Twenty‐four patients with Billroth II gastrectomy were enrolled in the present study and underwent ERCP, endoscopic sphincterotomy, endoscopic nasobiliary drainage, expandable metal stent placement or tube stent placement. All procedures were performed with an oblique‐viewing endoscope equipped with a cannula deflector. Results: In all patients, afferent loops were entered. Reaching the papilla of Vater was achieved in 22 (91.7%) patients, in whom all planned procedures were accomplished. One patient experienced acute pancreatitis, hemorrhage from the papilla of Vater after sphincterotomy, and intestinal perforation. Conclusions: We believe an oblique‐viewing endoscope equipped with a cannula deflector to be useful in performing ERCP and associated procedures in many patients with Billroth II gastrectomy. However, one should be aware of major complications, such as perforation, that may occur.     

Ileal J-pouch perforation at the blind end: Report of a case

A 34-year-old woman presented with severe abdominal pain 8 years after undergoing ileal J-pouch anal anastomosis for ulcerative colitis (UC). Computed tomography (CT) showed free air and ascites in the abdomen, so she underwent laparotomy. A perforation was found at the ileal J-pouch blind end, which was remarkably enlarged. When we resected the blind end surgically, we observed a 3-mm perforation and some small ulcers. About 2 months after this operation, the patient complained of abdominal pain and an increased frequency of bowel movements. Based on our endoscopic observation of multiple ulcers, we diagnosed pouchitis. We report this case to show that the combination of an enlarged J-pouch blind end and pouchitis can result in perforation. To prevent such complications, we recommend avoiding the formation of a blind end during construction of a J-pouch.     

Lifestyle risk factors for intrahepatic stone: Findings from a case–control study in an endemic area, Taiwan

Background and Aim:  To examine associations between lifestyle risk factors and intrahepatic stone (IHS), we conducted a case–control study in Taiwan, which has the highest incidence of IHS in the world.
Methods:  Study subjects were 151 patients newly diagnosed with IHS at Chang Gung Memorial Hospital between January 1999 and December 2001. Two control subjects per case were selected randomly from patients who underwent minor surgery at the same hospital and from family members or neighbors of the hospital staff. Controls were matched to each case by age and gender. Information on lifestyle factors was collected using a self-administered questionnaire. Strength of associations was assessed using odds ratios derived from conditional logistic models.
Results:  Female patients were significantly shorter than female controls. Compared to subjects with two or fewer children, odds ratios for those with six or more children were 20.4 in men (95% confidence interval, 1.89–221) and 2.82 (0.97–8.22) in women. Increasing level of education lowered the risk of intrahepatic stone (trend P  = 0.004 for men and < 0.0001 for women). Women who had consumed ground-surface water for a long period had a somewhat increased risk (trend P  = 0.05).
Conclusion:  Lower socioeconomic status and poor hygiene may be involved in the development of intrahepatic stones.