Efficacy of adding sodium alginate to omeprazole in patients with nonerosive reflux disease: a randomized clinical trial.

Nonerosive reflux disease (NERD) is the most common form of gastroesophageal reflux disease. Patients with NERD have a lower response rate to proton pump inhibitors (PPIs) than patients with erosive esophagitis when gauged from relief of heartburn. Sodium alginate decreases the acidity of refluxate and protects the esophageal mucosa. However, whether the addition of sodium alginate to PPI therapy can improve NERD symptoms remains unknown. Accordingly, the aim of this study was to evaluate the efficacy of adding sodium alginate to basal PPI therapy for NERD. Patients who had experienced heartburn on at least 2 days per week during the 1-month period before entering the study and had no endoscopic mucosal breaks (grade M or N according to Hoshihara's modification of the Los Angeles classification) were randomized to one of two treatments for 4 weeks: omeprazole (20 mg once daily) plus sodium alginate (30 mL four times a day) (group A) or omeprazole (20 mg once daily) alone (group B). Eighty-seven patients were enrolled, and 76 patients were randomly assigned to group A (n = 36) or group B (n = 40). Complete resolution of heartburn for at least 7 consecutive days by the end of treatment was significantly more common in group A (56.7%) than in group B (25.7%). One patient from group A had mild drug-related diarrhea that was not clinically serious. In conclusion, omeprazole combined with sodium alginate was better than omeprazole alone in Japanese patients with NERD.

Improvement of left ventricular function after changing the pacing site in a child with isolated congenital complete atrioventricular block and dilated cardiomyopathy.

We report a case of isolated congenital complete atrioventricular block with left ventricular dysfunction after pacemaker implantation that improved after the pacing site was changed. During the neonatal period, a pacemaker wire was implanted on the right ventricular epicardium and pacing was initiated. Decreased ejection fraction and a perfusion defect around the septum on myocardial scintigraphy were observed during follow-up. Induced left bundle branch block was thought to be causing interventricular asynchrony, and the pacing site was change to the left ventricular epicardium. Ejection fraction improved and the perfusion defect resolved. Lead relocation may be useful for left ventricular dysfunction that develops during right ventricular pacing.

Restrictive ventilatory impairment and arterial oxygenation characterize rest and exercise ventilation in patients after fontan operation.

The objective of this study was evaluate the relationships between abnormal pulmonary circulation, lung function, and respiratory response during exercise in Fontan patients. Pulmonary function and cardiopulmonary exercise tests were performed in 101 Fontan patients and 122 controls. A small vital capacity (VC) with a high residual volume-to-total lung capacity ratio and a slight but significant low arterial saturation with hypocapnia were observed in Fontan patients. The number of surgical procedures determined VC. Total cavopulmonary connection, fenestration, higher pulmonary arterial wedge pressure, and smaller VC were independent determinants of low arterial saturation, which was the only determinant of hypocapnia. Arterial saturation decreased during exercise and resting arterial saturation correlated with that at peak exercise. Improvement in dead space ventilation was less in Fontan patients and was independently determined by resting arterial saturation. A steeper minute ventilation-carbon dioxide production slope was determined by resting arterial saturation, arterial carbon dioxide tension, and peak oxygen uptake. In Fontan patients, in addition to dead space ventilation, surgery-related reduced VC, the type of repair, and high pulmonary arterial wedge pressure cause arterial desaturation with subsequent hypocapnia, resulting in accelerated inefficient ventilation at rest and during exercise.

Orally active cephalosporins. Part 3: synthesis, structure-activity relationships and oral absorption of novel C-3 heteroarylmethylthio cephalosporins.

A series of 7beta-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(heteroarytmethylthio)cephalosporins was designed, synthesized and evaluated for antibacterial activity and oral absorption in rats. Antibacterial activity was markedly influenced by the structure of the heteroaromatic ring moiety. Oral absorption was influenced by the heteroaromatic ring moiety as well as by the arrangement of heteroatoms. Among these compounds, FK041 (2o), having a 4-pyrazolylmethylthio moiety, showed potent antibacterial activity against both gram-positive and gram-negative bacteria including Haemophilus influenzae. Further, it showed higher oral absorption than CFDN.

Studies on anti-Helicobacter pylori agents. Part 2: new cephem derivatives.

The synthesis and optimization of the anti-Helicobacter pylori activity of a novel series of cephem derivatives are described. Introduction of thio-heterocyclic groups containing N- and S-atoms to the 3-position and phenyl or thienyl acetamido groups to the 7-position of the cephem nucleus dramatically improved the activity. From this series of derivatives, compound 13i was found to have extremely potent in vitro anti-H. pylori activity, superior therapeutic efficacy compared to AMPC and CAM, no cross-resistance between CAM or MNZ and low potential for causing diarrhea due to instability to beta-lactamase.

Anti-Helicobacter pylori agents. 4. 2-(Substituted guanidino)-4-phenylthiazoles and some structurally rigid derivatives.

In order to find a new class of anti-Helicobacter pylori (H. pylori) agents, a series of 4-[(3-acetamido)phenyl]-2-(substituted guanidino)thiazoles and some structurally rigid analoges were synthesized and evaluated for antimicrobial activity against H. pylori. Among the compounds obtained, high anti-H. pyrori activities were observed in benzyl derivative 34 (MIC = 0.025 microg/mL) and phenethyl derivatives 35 and 36 (MIC = 0.037 microg/mL and 0.017 microg/mL). Though alkyl derivatives generally showed lower activity, the 2-methoxyethyl derivative 28 preserved significant activity (MIC = 0.32 microg/mL) and also exhibited more potent gastric antisecretory activity than ranitidine. Structural restriction by bridging between the thiazole and the phenyl rings with an alkyl chain did not improve the activity in this series.

[A case of Down syndrome with moyamoya syndrome presenting extensive multiple cerebral infarction during measles infection].

We report a case of a 2-year-old boy with Down syndrome complicated by Moyamoya syndrome who developed extensive multiple cerebral infarction after status epilepticus on the third day of a measles infection. MR angiography revealed the occlusion of the terminal portion of the bilateral internal carotid artery and the basilar artery. Fever, dehydration, activation of coagulation associated with the infection, relatively decreased cerebral blood flow during status epilepticus, and central nervous invasion of the measles virus may have played a role in the development of the infarction. Moyamoya like cerebrovascular lesions occur more often and is more aggressive in children with Down syndrome than in the general pediatric population, and their clinical presentation is always the infarction type. In patients with Down syndrome complicated by Moyamoya syndrome, an early diagnosis and prevention of infarction are important.

In vitro activities of a new lipopeptide antifungal agent, FK463, against a variety of clinically important fungi.

The in vitro antifungal activity and spectrum of FK463 were compared with those of amphotericin B, fluconazole, and itraconazole by using a broth microdilution method specified by National Committee for Clinical Laboratory Standards document M27-A (National Committee for Clinical Laboratory Standards, Wayne, Pa., 1997). FK463 exhibited broad-spectrum activity against clinically important pathogens including Candida species (MIC range, <==0.0039 to 2 microg/ml) and Aspergillus species (MIC range, <==0.0039 to 0.0313 microg/ml), and its MICs for such fungi were lower than those of the other antifungal agents tested. FK463 was also potently active against azole-resistant Candida albicans as well as azole-susceptible strains, and there was no cross-resistance with azoles. FK463 showed fungicidal activity against C. albicans, i.e., a 99% reduction in viability after a 24-h exposure at concentrations above 0.0156 microg/ml. The minimum fungicidal concentration (MFC) assays indicated that FK463 was fungicidal against most isolates of Candida species. In contrast, the MFCs of FK463 for A. fumigatus isolates were much higher than the MICs, indicating that its action is fungistatic against this species. FK463 had no activity against Cryptococcus neoformans, Trichosporon species, or Fusarium solani. Neither the test medium (kind and pH) nor the inoculum size greatly affected the MICs of FK463, while the addition of 4% human serum albumin increased the MICs for Candida species and A. fumigatus more than 32 times. Results from preclinical in vitro evaluations performed thus far indicate that FK463 should be a potent parenteral antifungal agent.

Synthesis and anti-Helicobacter pylori activity of FR182024, a new cephem derivative.

The synthesis and anti-Helicobacter pylori activity of a novel cephem derivative FR182024 (1) are described. FR182024 having a (5-methyl-1,3,4-thiadiazol-2-yl)-thio moiety at the 3-position and a phenylacetamido at the 7-position was found to have extremely potent in vitro anti-H.pylori activity, superior therapeutic efficacy to AMPC and CAM, and low potential for causing diarrhea.

In vitro antibacterial activity of FK041, a new orally active cephalosporin.

The in vitro activity of FK041, a new orally active cephem antibiotic, against a wide variety of clinical isolates of bacteria was investigated and compared with those of cefdinir (CFDN) and cefditoren (CDTR). FK041 exhibited broad spectrum activity against reference strains of Gram-positive and Gram-negative aerobes and anaerobes. FK041 was active against clinical isolates of Gram-positive organisms except Enterococcus faecalis with MIC90s less than 1.56 microg/ml. FK041 was more active than CFDN and CDTR against Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus agalactiae and was comparable to CFDN and CDTR against Streptococcus pyogenes and Streptococcus pneumoniae. FK041 had no activity against methicillin-resistant staphylococci, like CFDN and CDTR. FK041 showed moderate activity against penicillin-resistant S. pneumoniae with an MIC range of 0.05 approximately 3.13 microg/ml, and was superior to CFDN but inferior to CDTR. Against clinical isolates of many Gram-negative organisms such as Neisseria gonorrhoeae, Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis, FK041 had good activity comparable or superior to those of CFDN and CDTR. However, it was inferior to CDTR in activity against Moraxella catarrhalis, Haemophilus influenzae, Morganella morganii, and Serratia marcescens, and was inactive against Pseudomonas aeruginosa. With FK041 a small difference between MIC and MBC against S. aureus, E. coli, K. pneumoniae, and H. influenzae was found, indicating that its action is bactericidal against these species. FK041 was stable to group 2beta-lactamase hydrolysis but was unstable to group 1beta-lactamase hydrolysis. The stability of FK041 to these enzymes was similar to those of CFDN and CDTR. FK041 showed high affinity for the main penicillin-binding proteins (PBPs) of S. aureus (PBP 3, 2, and 1) and E. coli (PBP 3, 4, lbs, 2, and 1a).

FR145715, a novel histamine H2 receptor antagonist, with specific anti-Helicobacter pylori activities.

The pharmacological profile of N-[3-[2-[N'-(2-methoxyethyl)guanidino]thiazol-4yl]benzyl-ace tamide (FR145715), a novel histamine H2 receptor antagonist, was examined in both in vitro and in vivo models using experimental animals in comparison with ranitidine. In isolated guinea-pig atria, FR145715 antagonized the effect of histamine on heart rate with approximately three times more potent activity than ranitidine. In in vivo experiments, intraduodenal FR145715 dose-dependently inhibited spontaneous gastric acid secretion in rats (Shay's rats), with a ED50 value of 18.4 mg/kg, which was comparable to that of ranitidine (30.5 mg/kg). FR145715 also inhibited histamine-stimulated acid secretion in stomach-perfused anaesthetized rats (Schild's rats), when given intravenously and intraduodenally with ED50 values of 0.59 and 2.72 mg/kg, respectively. Ranitidine displayed more potent activity having respective ED50 values of 0.10 and 0.17 mg/kg. In Heidenhain pouch dogs, intravenous and oral FR145715 dose-dependently inhibited gastrin-stimulated acid secretion with respective ED50 values of 0.12 and 0.32 mg/kg, which were similar to those of ranitidine (0.09 and 0.33 mg/kg). In gastric ulcer models, FR145715 dose-dependently inhibited water immersion restraint stress- and acidified aspirin-induced gastric lesions with ED50 values of 3.2 and 15.1 mg/kg (p.o.), respectively. The comparative compound, ranitidine, also showed beneficial effects on stress-induced gastric ulcers with an ED50 value of 1.5 mg/kg (p.o.). However, it failed to inhibit acidified aspirin-induced gastric ulcers. FR145715 inhibited HCl-induced gastric lesions in rats, while pre-treatment with indomethacin abolished its beneficial effects, suggesting that FR145715 has a so-called cytoprotective effect which is dependent on endogenous prostaglandin production. In addition to its atypical profile as a histamine H2 receptor antagonist, FR145715 exhibited strong anti-microbial activities against strains of Helicobacter pylori (H. pylori) with a mean minimal inhibitory concentration value of 0.32 microg/ml. Moreover, FR145715 showed no anti-microbial effects on 25 other bacteria examined. In addition, in vivo experiments using gnotobiotic piglets infected with H. pylori, FR145715 (16 mg/kg, t.i.d.) completely eliminated the organism with reduced intensity of inflammation, when treated orally for 10 days. These data demonstrate that FR145715 is a novel histamine H2 receptor antagonist having potent and selective anti-H. pylori activities as well as cytoprotective properties. The present data suggest that FR145715 might be useful for the patients suffering from ulcer relapse, since the drug might be able to eradicate H. pylori in the stomach, which is considered a key factor to cause ulcer recurrence in humans.

Anti-Helicobacter pylori agents. 3. 2-[(Arylalkyl)guanidino]-4-furylthiazoles.

A series of 2-[(arylalkyl)guanidino]-4-[(5-acetamidomethyl)furan-2-yl]thiazole s and some 4-acetamidomethyl positional isomers were synthesized and evaluated for antimicrobial activity against Helicobacter pylori. Among the compounds that had potent antimicrobial activity (MIC < 0. 1 microgram/mL), compounds 31 and 36 additionally possessed H2 antagonist and gastric antisecretory activities. Though compound 51, an analogue incorporating a methyl group onto the furan nucleus of 36, and compound 54, a positional isomer of 51, also showed potent anti-H. pylori activity, the H2 antagonism profile was eliminated from these compounds. Thus, two types of potent anti-H. pylori agents could be derived from the same scaffold.

Studies on anti-Helicobacter pylori agents. Part 1: Benzyloxyisoquinoline derivatives.

The synthesis and optimization of the anti-Helicobacter pylori activity of a novel series of benzyloxyisoquinoline derivatives that was discovered by a random screening process, are described. In the in vitro assay, compound 10c containing a 3-acetamido-2,6-dichlorobenzyl substituent was found to have extremely potent activity against H. pylori and no activity against other common bacteria. The anti-H. pylori activity of 10c was superior to that of amoxicillin (AMPC) (1) and clarithromycin (CAM) (2). However, 10c did not show in vivo efficacy in a mouse infection model; a feature attributed to the lack of strong bactericidal activity at short contact times.

Inhibitors of acyl-CoA:cholesterol O-acyltransferase. 3. Discovery of a novel series of N-alkyl-N-[(fluorophenoxy)benzyl]-N'-arylureas with weak toxicological effects on adrenal glands.

A series of N-alkyl-N-[(fluorophenoxy)benzyl]-N'-arylureas were prepared and evaluated for their ability to inhibit intestinal acyl-CoA:cholesterol O-acyltransferase and to inhibit accumulation of cholesteryl esters in macrophages in vitro. In vivo hypocholesterolemic activity was assessed in cholesterol-fed rats by oral administration as a dietary admixture and/or by gavage in a PEG400 vehicle. Modification of the alkyl substituent on the N'-aryl moiety and on the urea nitrogen significantly influenced macrophage assay in vitro. Toxicological study revealed a distinct relationship between macrophage assay and the toxicity observed in adrenal glands of rabbits treated with representatives of this series of compounds. Investigations utilizing the macrophage assay as an indicator for adrenal toxicity led to the identification of compounds 1g (FR190809) and 1k (FR186485, or FR195249 as its hydrochloride salt) as potent, nonadrenotoxic, orally efficacious ACAT inhibitors irrespective of the administration method.

Difference of (Ca2+)i movements in platelets stimulated by thrombin and TRAP: the involvement of alpha(IIb)beta3-mediated TXA2 synthesis.

This study investigated the difference of [Ca2+]i movement in platelets in response to thrombin and TRAP. The involvement of alpha(IIb)beta3 in this signaling was also studied. Stimulation of platelets with thrombin at 0.03 U/ml caused platelet aggregation and a two-peak increase in [Ca2+]i. The second peak of [Ca2+]i, but not the first peak was abolished by the inhibition of platelet aggregation with alpha(IIb)beta3 antagonists or by scavenging endogenous ADP with apyrase. A cyclooxygenase inhibitor, aspirin, and a TXA2 receptor antagonist, BM 13505, also abolished the second peak of [Ca2+]i but not the first peak, although these regents did not inhibit aggregation. Under the same assay conditions, measurement of TXB2 demonstrated that alpha(IIb)beta3 antagonists and aspirin almost completely inhibited the production of TXB2. In contrast to thrombin-stimulation, TRAP caused only a single peak of [Ca2+]i even in the presence of platelet aggregation, and a high level of [Ca2+]i increase was needed for the induction of platelet aggregation. The inhibition of aggregation with alpha(IIb)beta3 antagonists had no effect on [Ca2+]i change and TXB2 production induced by TRAP. Inhibition studies using anti-GPIb antibodies suggested that GPIb may be involved in the thrombin response, but not in the TRAP. Our findings suggest that low dose thrombin causes a different [Ca2+]i response and TXA2 producing signal from TRAP. Endogenous ADP release and fibrinogen binding to alpha(IIb)beta3 are responsible for the synthesis of TXA2 which results in the induction of the second peak of [Ca2+]i in low thrombin- but not TRAP-stimulated platelets.

Inhibitors of acyl-CoA:cholesterol O-acyltransferase. 2. Identification and structure-activity relationships of a novel series of N-alkyl-N-(heteroaryl-substituted benzyl)-N'-arylureas.

A series of N-alkyl-N-(heteroaryl-substituted benzyl)-N'-arylurea and related derivatives represented by 2 and 3 have been prepared and evaluated for their ability to inhibit acyl-CoA:cholesterol O-acyltransferase in vitro and to lower plasma cholesterol levels in cholesterol-fed rats in vivo. Among these novel compounds, the type 3 series was superior. A pyrazol-3-yl group on the N-benzyl group of this trisubstituted urea (i.e. 3, Ar1 = pyrazol-3-yl) was identified as a heteroaromatic ring providing a good profile of biological activity. As a result of optimization of the combination with the N-alkyl group (R) and N-aryl group (Ar3), compound 3aq (FR186054) was identified as a new, orally efficacious ACAT inhibitor, which exhibited potent in vitro ACAT inhibitory activity (rabbit intestinal microsomes IC50 = 99 nM) and excellent hypocholesterolemic effects in cholesterol-fed rats, irrespective of administration mode (ED50 = 0.046 mg/kg dosed via the diet, ED50 = 0. 44 mg/kg administered by gavage in PEG400 vehicle). Moreover, a toxicological study revealed compound 3aq to be nontoxic to the adrenal glands of dogs when tested at a single dose of 10 mg/kg po.

Comparison of the antithrombotic effects of FK633, GPIIb/IIIa antagonist, and aspirin in a guinea pig thrombosis model.

Antiplatelet and antithrombotic effects of FK633 (a GPIIb/IIIa antagonist) and aspirin were compared. FK633 at 0.32 mg/kg i.v. or aspirin at 10 mg/ kg i.v. inhibited ex vivo collagen-induced aggregation by >50% for 1 hour in guinea pigs. However, aspirin was very weak in inhibiting ADP-induced aggregation. In vivo antithrombotic effects of FK633 and aspirin were compared using a FeCl3-induced carotid artery thrombosis model in guinea pigs. Pretreatment with 0.32 mg/kg i.v. of FK633 significantly prevented occlusive thrombus formation, but aspirin at 10 mg/kg i.v. did not. In thrombolysis experiments, adjunctive use of FK633 (0.32 mg/kg i.v.) with rt-PA (0.3 mg/kg bolus+1.0 mg/kg/hr) achieved reperfusion in five of five animals without reocclusion. Aspirin (10O mg/kg i.v.) with rt-PA also achieved reperfusion in three of five animals with high incidence of reocclusion. These results suggest that FK633 may be a more effective antithrombotic agent than aspirin due to its agonist-independent antiplatelet effects.