Synthesis and glycogen phosphorylase inhibitor activity of functionalized 1,4-benzodioxanes.

A series of novel 1,4-benzodioxanes 11a-e and rac-12a-d carrying thiazolidine-2,4-dione moiety was synthesized and their glycogen phosphorylase inhibitor activity was also evaluated.

Peroxynitrite decreases arrhythmias induced by ischaemia reperfusion in anaesthetized dogs, without involving mitochondrial KATP channels.

BACKGROUND AND PURPOSE: Exogenous peroxynitrite from nanomolar to micromolar concentrations exerts cardioprotection. Here, we have assessed its effects on ischaemia- and reperfusion-induced ventricular arrhythmias in vivo and a possible role for mitochondrial K(ATP) channels in these effects, using the channel inhibitor 5-hydroxydecanoate (5-HD). EXPERIMENTAL APPROACH: Chloralose-urethane-anaesthetized dogs were treated twice for 5 min with peroxynitrite (100 nM, by intracoronary infusions) in both the absence and presence of 5-HD (150 microg kg(-1) min(-1)), and then subjected to 25 min occlusion of the left anterior descending coronary artery. The severity of ischaemia and of arrhythmias, as well as the levels of nitrotyrosine were assessed and compared with a group of control dogs, subjected only to a 25 min occlusion and reperfusion insult. KEY RESULTS: Compared with controls, infusion of peroxynitrite markedly suppressed the number of ventricular premature beats (388+/-88 vs 133+/-44), the incidence of ventricular fibrillation both during occlusion (50% vs 10%) and reperfusion (100% vs 44%), and increased survival (0% vs 50%; all P<0.05). The severity of ischaemia (epicardial ST-segment changes, inhomogeneity of electrical activation) during occlusion and nitrotyrosine levels on reperfusion were significantly less in the peroxynitrite-treated dogs than in the controls. 5-HD did not modify the cardioprotective effects of peroxynitrite. CONCLUSION AND IMPLICATIONS: Exogenous peroxynitrite provided antiarrhythmic protection in vivo, which might have been on account of a reduction in endogenous peroxynitrite formation. This protection seemed not to be mediated through mitoK(ATP) channels.

Chiroptical properties of 2,3-dihydrobenzo[b]furan and chromane chromophores in naturally occurring O-heterocycles.

The correlation between the helicity (absolute conformation) of the O-heterocyclic ring of chiral 2,3-dihydrobenzo[b]furan (1) and chromane (2) derivatives and their (1)L(b) band CD was investigated. The same helicity rule was found for both unsubstituted chromophores: P/M helicity of the heterocyclic ring leads to a negative/positive CD within the (1)L(b) band. While the substitution of the fused benzene ring by achiral substituents does not change this helicity rule for the chromane chromophore, it leads to its inversion for the 2,3-dihydrobenzo[b]furan chromophores. On the basis of these observations, the published absolute configurations of natural flavonol and pterocarpan derivatives were confirmed and the configurational assignments of several natural neolignans revised.

Simple synthesis of benzofuranoid neolignans from Myristica fragrans.

The total synthesis of four neolignans-fragnasols A (1), B (2), and C (3) and dehydrodiisoeugenol (4)-starting from the readily available phenol derivative isoeugenol (5) was accomplished. The key step of the synthesis of these natural products is a novel type of dimerization of 5 into 4 with iodobenzene diacetate.

Octreotide in the prevention of pancreatic injury associated with endoscopic cholangiopancreatography.

BACKGROUND: Data on whether long-acting somatostatin analogue octreotide causes or prevents pancreatic injury following endoscopic retrograde cholangiopancreatography (ERCP) are controversial. AIM: This multicentre, prospective trial studied the effect of octreotide on pancreatic injury in a large unselected group of patients after ERCP and endoscopic sphincterotomy. METHODS: The study was carried out in a prospective random manner on 2102 patients in 11 endoscopic centres. Patients in the study received 0.1 mg octreotide acetate and those in the control group received isotonic sodium chloride, subcutaneously before and 45 min after ERCP. Pancreatic injury was assessed by clinical symptoms such as pain, fever and abdominal tenderness. Serum amylase and blood sugar were determined prior to, and 6 and 24 h after the endoscopic procedure. RESULTS: Data from 599 patients in the study group and 600 in the control group were included in the final evaluation. When all the patients were considered, octreotide did not induce pancreatic injury as assessed by clinical symptoms, and diminished the increase of serum amylase levels following ERCP. However, when subgroups of patients were studied, the frequency of increased amylase levels decreased significantly in patients with chronic obstructive pancreatitis and in patients who underwent endoscopic sphincterotomy (P < 0.01). The peak serum glucose level was higher in the treated group when compared to the controls. CONCLUSION: The prophylactic use of long-acting somatostatin does not alter the frequency of post-ERCP pancreatic injury, but it may diminish the rate of increased serum amylase levels in patients with chronic obstructive pancreatitis and also in those with an endoscopic sphincterotomy.

A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-associated Ulcer Treatment (ASTRONAUT) Study Group.

BACKGROUND: Suppressing acid secretion is thought o reduce the risk of ulcers associated with regular use of nonsteroidal antiinflammatory drugs (NSAIDs), but the best means of accomplishing this is uncertain. METHODS: We studied 541 patients who required continuous treatment with NSAIDs and who had ulcers or more than 10 erosions in either the stomach or duodenum. Patients were randomly assigned to double-blind treatment with omeprazole, 20 mg or 40 mg orally per day, or ranitidine, 150 mg orally twice a day, for four or eight weeks, depending on when treatment was successful (defined as the resolution of ulcer and the presence of fewer than five erosions in the stomach, and fewer than five erosions in the duodenum, and not more than mild dyspepsia). We randomly assigned 432 patients in whom treatment was successful to maintenance treatment with either 20 mg of omeprazole per day or 150 mg of ranitidine twice a day for six months. RESULTS: At eight weeks, treatment was successful in 80 percent (140 of 174) of the patients in the group given 20 mg of omeprazole per day, 79 percent (148 of 187) of those given 40 mg of omeprazole per day, and 63 percent (110 of 174) of those given ranitidine (P<0.001 for the comparison with 20 mg of omeprazole and P=0.001 for the comparison with 40 mg of omeprazole). The rates of healing of all types of lesions were higher with omeprazole than with ranitidine. During maintenance therapy, the estimated proportion of patients in remission at the end of six months was 72 percent in the omeprazole group and 59 percent in the ranitidine group. The rates of adverse events were similar between groups during both phases. Both medications were well tolerated. CONCLUSIONS: In patients with regular use of NSAIDs, omeprazole healed and prevented ulcers more effectively than did ranitidine.

Ebrotidine versus ranitidine in the healing and prevention of relapse of duodenal ulcer. A multicentre, double-blind, parallel, randomized, controlled study.

Two hundred and fifty patients were included in a double-blind, parallel, randomized, controlled clinical trial. Duodenal ulcer treatment lasted up to 8 weeks. Forty-nine patients were followed up for prevention of ulcer relapse for up to one year. All patients received either ranitidine (300 mg/day in the healing phase and 150 mg/day in the follow-up phase) or ebrotidine (N-[(E)-[[2-[[[2-[(diaminomethylene)amino]-4 -thiazolyl]methyl]thio]ethyl]amino]methylene]-4-bromo-benzenesulfonamide , CAS 100981-43-9, FI-3542) (400 mg/day in both phases) as a single dose at bedtime. Both groups were matched in all demographic parameters, except for a significantly higher percentage of smokers in the ranitidine group. The percentage of total healing was almost the same with both products. Healing occurred in a higher percentage with ebrotidine at weeks 4 (75% versus 66.7%) and 6 (87% versus 79.7%). A higher effect of ebrotidine on the incidence of duodenitis was identified during the whole study, but only reached statistical significance at week 6. The relapse rate during the follow-up phase showed no differences between the two study treatments, relapse percentage figures being 25% for ebrotidine and 24% for ranitidine. There were no differences in the number of unscheduled visits between the two groups, although 57% of patients in the ranitidine group had to make a second follow-up visit, as compared with 33% in the ebrotidine group. Both drugs caused hardly any side effects, affecting only one patient from each group: one patient with ebrotidine suffered from diarrhoea and one patient with ranitidine developed a skin rash on the limbs. Administration of ebrotidine in a single dose (400 mg/d) was at least as effective and safe as ranitidine both for healing and relapse prevention in patients with duodenal ulcer.

[Complex screening of family members at risk for familial adenomatous polyposis]. / Familiáris adenomatosus polyposisos családok praesymptomás diagnosztikán alapuló komplex gondozása.

151 members of 10 affected families with FAP have been registered at the authors' regional polyposis registry, among them 51 FAP patients were verified histologically. The disorder is autosomal dominant thus the chance for the inheritance of the mutated allele is fifty percent in the offspring of an affected patient. Because of the high risk the registration and regular control of family members is recommended. They can be divided into high risk and low risk group based on presymptomatic tests. The examination of retina pigmentepithel was the only possibility for presymptomatic diagnosis earlier. After localization and identification of APC gene responsible for the disease molecular genetic methods have been introduced for presymptomatic diagnosis. The authors performed presymptomatic tests based on ophthalmologic and molecular genetic methods among family members at risk. Ophthalmologic examination was done in 53 while molecular genetic investigation in 54 cases. All the results of endoscopic, ophthalmological and molecular genetic examinations were available in 35 persons, among them 19 FAP have been found. Ophthalmological examination were informative in 33 out 35 cases (unequivocal positive or negative) while results of molecular genetic methods and sigmoidoscopy were correlated in every case. Authors stress the significance of complex screening of affected families with FAP in the prevention of colorectal cancer and extracolonic malignant processes.

[Evaluation of the effectiveness of pantoprazole and ranitidine in the treatment of duodenal ulcer. Result of an international multicenter study]. / A pantoprazol és a ranitidin hatékonyságának vizsgálata nyombélfekély kezelésére. Nemzetközi multicentrikus vizsgálat eredménye.

A double-blind, randomized, multicenter, multicountry study (Poland, Chech Republic, Hungary) was carried out in 1995 on patients (n = 326) with endoscopically confirmed duodenal ulcer treated with ranitidine vs. pantoprazole. In Hungary-in 4 gastroenterology centers-123 patients have been involved (age 18-75 years). The treatment schedule has been 300 mgs of ranitidine or 40 mgs of pantoprazole q. d. for 2 or if necessary for 4 weeks. In the Hungarian study 60 DU patients were treated with pantoprazole vs. 63 ones with ranitidine. Having finished the two-week schedule the healing rates of duodenal ulcer were as follows: pantoprazole 71%/72% (Hungary/International) vs ranitidine 57%/51%, (p < 0.001). After 4 weeks the corresponding values showed the following: pantoprazole 98%/94% vs. ranitidine 88%/86%, respectively, (p < 0.005). Both drugs have shown to be effective and safe to cure duodenal ulcer however in our study pantoprazole was significantly more efficacious and provided quicker healing than ranitidine.

[Octreotide in the prevention of hyperamylasemia following ERCP (a controlled multicenter study)]. / Octreotid az endoszkópos retrográd cholangiopancreatographiát követó hyperamylasaemia prevenciójában (Multicentrikus kontrollált tanulmány).

UNLABELLED: The aim of the multicentric trial was to study the effect of octreotide (Sandostatin) on the rise of pancreatic amylase in the serum after ERCP based on a large number of patients. The study was carried out in a prospective random manner in 2102 patients in 11 endoscopic centers. Patients in the treated group received 0.1 mg octreotide acetate, and those of the nontreated (control) group received isotonic sodium-chloride subcutaneously before the ERCP and 45 minutes after. Serum amylase and blood sugar were checked before the endoscopic procedure, 6 and 24 hours later. Out of the total number of patients involved, data of 1199 patients (599 in the treated group, and 600 in the control group) were evaluated. Octreotide diminished the percentual increase of serum amylase levels following ERCP. However, the frequency of hyperamylasaemia was decreased only after in patients with chronic obstructive pancreatitis or in such patients after endoscopic sphincterotomy. The peak serum level of blood sugar was higher in the treated group compared to the controls. There was no difference in the clinical symptoms following ERCP between the two groups. CONCLUSION: the prophylactic use of long-acting somatostatin may diminish the frequency of hyperamylasemia after ERCP in patients with chronic obstructive pancreatitis or in those patients who subsequently underwent EST.

Efficacy of nizatidine, clarithromycin and bismuth subcitrate therapy for Helicobacter pylori eradication in duodenal ulcer patients--a preliminary report.

The triple combination of nizatidine, clarithromycin, and bismuth subcitrate resulted in an ulcer healing rate of 98% and an H. pylori eradication rate of 90%. Corresponding 'intention-to-treat' figures were 92% and 84%, respectively. These results suggest that further studies, shorter in duration, using lower dosages, and possibly testing other combinations with a double-blind methodology, are required.

[Endoscopic management of benign strictures of the common bile duct]. / A ductus hepaticus communis benignus szükületeinek endoscopos kezelése.

UNLABELLED: 3 females with benign hepatic duct strictures were treated endoscopically. The treatment consisted of placement of one or two endoprostheses in all cases and endoscopic balloon dilatation in two cases. The stent was removed from the first patient--who had hepatic duct stones as well--after a 15 months stenting period and mechanical lithotripsy and balloon dilatation were performed with good results. The second and third patient-after stent insertion--was operated with suspicion of malignancy. Tumor was not proved. In the second patient the endoscopically placed stent was changed by a large diameter teflon stent surgically. The third patient's stents were left in place. These stents were removed after 3 months and balloon dilatation was performed. Patients' jaundice subsided and cholangitis improved following the stent insertion. COMPLICATIONS: Stent occlusion developed and common bile duct stones occurred once. There was not observed any other complication. Benign hepatic duct strictures can be treated by combination of prolonged endoscopic biliary stenting and balloon dilatation successfully.

[Palliative endoscopic treatment of proximal malignant biliary stenosis]. / Májkapui malignus epeúti stenosisok endoscopos palliatív kezelése.

24 patients (median age 71.5 years) with inoperable proximal malignant biliary obstruction were treated by insertion of endoscopic endoprostheses from January 1991 to August 1994. 10 patients had gallbladder cancer, 6 cancer of body or tail of pancreas, 5 cholangiocarcinoma and 3 other metastatic malignancy, respectively. 13 patients had type I, 10 had type II and 1 had type III proximal biliary stenosis (Bismuth classification). Stent occlusion or dislocation required a secondary stent insertion in 9 patients. In all cases there was adequate biliary drainage after stent insertion. Complications were: early cholangitis developed in 2 patients, late cholangitis in 5, stent dislocation in 3. One patient underwent an operation because of necrotising cholecystitis and subhepatic abscess. There was no bleeding, retroperitoneal perforation or pancreatitis. 18 patients died (median survival time 28 weeks) and 6 have been alive at the time of review for 15 weeks in average. Endoscopic stent insertion can be applied effectively also in the palliative treatment of proximal malignant biliary obstruction.

Patterns of cigarette sales and lung cancer mortality in some central and eastern European countries, 1960-1989.

BACKGROUND: Remarkable increases in lung cancer risk recently have been observed in the Central and Eastern European (CEE) area. This study examines the patterns of lung cancer mortality rates and cigarette sales in 1960-1989 in seven CEE countries with a total population of 97.5 million and 43,000 deaths from lung cancer in the last year under study. METHODS: Trends in cigarette sales and mortality rates from lung cancer in seven CEE countries were compared for the years 1960-1989. RESULTS: Among males, recent lung cancer death rates were the highest in Europe, and trends by country largely reflected the varied prevalence and duration of smoking in previous decades. For females, lung cancer mortality rates were much lower, although there were exponential rate increases. In the more recent birth cohorts, there were some declines in mortality rates among males, but not among females. CONCLUSIONS: The rising cigarette consumption through the 1960s, 1970s, and, in some countries, the 1980s is accompanied in most of the countries by rising lung cancer mortality rates for young adults. This increasing cigarette consumption will determine future trends in lung cancer, which will increase well beyond the turn of the century and will continue longer for females than for males. This outlook underlines the urgent need for comprehensive lung cancer prevention with the concerted control of smoking as a priority. The role of cofactors and their interaction with smoking deserve further exploration.

[One year results after extracorporeal shock wave lithotripsy of gallbladder stones]. / Extracorporalis lökéshullám-kezelés egy éves eredményei epehólyag-kövességben.

512 patients with gallbladder stones (393 females, mean age 52.7 years; 119 males, mean age 46.9 years) were treated by extracorporeal shock wave lithotripsy with an electrohydraulic Dornier MPL 9000 lithotripter. The Munich criteria were used for patients selection. Midazolam (15 mg im) and piritramid (mean 7.5 mg iv) were administered as analgetics. Stone fragmentation was achieved after an average of 1.92 treatment sessions. In 12 cases (2.3%) there was no fragmentation. Ursodeoxycholic acid (10 mg/kg/day) was administered as adjuvant litholytic therapy until 3 months after total fragment clearance. During a period of a year the patients returned for follow-up investigations in decreasing number. The total fragment clearance rate was 43.3%, for the I. group (single stone of 5 to 20 mm) was 58%, for the II. group (single stone of 21 to 30 mm) was 28.6%, for the III. group (2 or 3 stones of 30 mm maximum diameter) was 21.4%. In 12 cases (1.2%) vasovagal reactions, in 31 cases (3.1%) atrial and ventricular extrasystoles, in 27 cases (2.7%) transient gross hematuria were observed. During a period of a year 18 cholecystitis (3.5%), 8 pancreatitis (1.56%) and 5 obstructive jaundice (0.97%) developed. 28 cholecystectomies (5.4%), 1 necrectomy because of necrotic pancreatitis (0.19%) and 5 endoscopic sphincterotomies (0.97%) were required.

[Thr role pf extracorporeal shock wave therapy in the removal of common bile duct stones]. / Az extracorporalis lökéshullám-kezelés szerepe nagyméretü choledochus kövek eltávolításában.

Extracorporeal shock wave lithotripsy was performed on 4 high risk patients with large common bile duct stones by a Dornier MPL 9000 lithotripter and X-ray positioning. Every patient was treated twice using 2000 shock wave discharges and 21 kV average generator voltage in a single session. Average treatment time was 51 minutes. Desintegration of 3 patients stone was successful and fragments were removed by Dormia basket extraction and by biliary lavage. One out of the four patients stone failed to be desintegrated this patient underwent an operation. Apart from mild fleabite-like petechiae and some atrial and ventricular extrasystoles no other side effects were observed.

Teratogenicity and transplacental pharmacokinetics of 13-cis-retinoic acid in rabbits.

No embryotoxic or teratogenic effects, considered to be treatment related, were observed in rabbits after daily oral doses of 3 mg/kg of 13-cis-retinoic acid (13-cis-RA) from Day 8 to Day 11 of gestation. In contrast, treatment with 15 mg/kg/day significantly increased the rate of fetal resorptions (22%) and 13 out of 68 surviving fetuses (16%) were malformed. Pharmacokinetic studies with both dosing regimens of 13-cis-RA in pregnant rabbits showed that on Day 11 of gestation, high concentrations of parent compound, 13-cis-RA, and its major metabolite, 13-cis-4-oxoRA, existed in maternal plasma. Much lower concentrations were found for all-trans-4-oxoRA and all-trans-RA. The area under the concentration-time curve (AUC) of all-trans-RA following the 15 mg/kg/day dosing regimen of 13-cis-RA was only 1.2% that of parent compound 13-cis-RA. At this dose, embryo levels of 13-cis-RA, 13-cis-4-oxoRA, and all-trans-4-oxoRA were 2.5-, 4.7-, and 3.6-fold higher by AUC comparison (24-hr period of Day 11) compared with the dose of 3 mg/kg. However, embryo levels of all-trans-RA were virtually identical at both doses and were, in fact, somewhat lower than endogenous concentrations measured in untreated rabbit embryos. In contrast to mice, where isomerization from 13-cis- to all-trans-RA was suggested to be crucial for the teratogenic action of 13-cis-RA, we found that the teratogenic action of 13-cis-RA (15 mg/kg/day) in rabbits is characterized by increased whole embryo concentrations of 13-cis-RA, 13-cis-4-oxoRA, and all-trans-4-oxoRA, but not of all-trans-RA.

[Surgical treatment of gallbladder diseases in patients over 70 years of age]. / A 70 éven felüliek epebetegségének sebészeti kezelése.

The authors give a retrospective analysis of the results of 162 biliary operations performed in a five-year period on patients over 70 years of age. The mortality rate of 87 elective operations was 3.45%, of 75 acute operations 6.17%. During the same period 321 ERCPs and 120 ESTs were carried out in patients over 70, out of whom 2 were operated on and lost (mortality: 1.67%) because of bleeding after EST. The total mortality rate was 7.41% (n = 12). The circumstances of negative and positive choledochotomies were analysed together with the relationship between the operating time and the course of the disease. Out of the negative choledochotomised patients (n = 10) 3, out of the positive ones (n = 40) 5 patients died. For each patient over 70, to shorten the operative time and to prevent perioperative complications, the authors recommend the consideration of ERCP prior to biliary operation, and in certain cases, instead of elective biliary surgery, for bile duct stone, EST and stone extraction is advisable, leaving the calculous gallbladder "in situ". Further investigations are necessary, in the authors opinion, to decide whether prior to emergency operation on patients over 70 urgent ERCP and, when bile duct stone is diagnosed, EST with stone extraction is justified, too.

Effect of exogenous pyruvate on acrylamide neuropathy in rats.

The protective effect of exogenous sodium pyruvate on the distal-proximal progression of experimental acrylamide neuropathy in rats was examined. Incorporation of 2% (w/w) sodium pyruvate powder in the diet of rats receiving subcutaneous injections of an aqueous solution of acrylamide (35 mg/kg/day, 5 days/week) retarded the onset and development of functional, morphological, and biochemical measures of acrylamide neuropathy. Pyruvate supplementation did not alter hexobarbital sleep time or zoxazolamine paralysis time, two in vivo measures of microsomal mixed-function oxidase activity, and the disposition of radioactivity in plasma or sciatic nerve following subcutaneous injection of [14C]acrylamide. Although acrylamide can interfere with energy metabolism at a variety of sites where pyruvate can rescue neurons (axons), the data of this study are consistent with our earlier hypothesis that acrylamide neuropathy may be associated with a glycolytic deficit. The exact site of pyruvate protection is unknown. Exogenous pyruvate is perhaps utilized by axons to circumvent toxin-induced glycolytic inhibition and provide chemical energy for fast axonal transport.