Randomized comparative study of omeprazole and famotidine in reflux esophagitis

BACKGROUND: Although proton pump inhibitors (PPI) and H2-receptor antagonists (H2-RA) are routinely used in the treatment of reflux esophagitis (RE), no consensus has been reached yet as to whether the first-choice drug should be PPI or H2-RA. In this study, the effects of omeprazole (OMP) and famotidine (FAM) on RE have been examined in a randomized comparative study. METHODS: Protocols of OMP 20 mg once daily or FAM 20 mg twice daily for 8 weeks were allocated to 56 cases with RE at random, using an envelope randomization method. Their efficacy in achieving healing was examined endoscopically and a relief from subjective symptoms was compared. RESULTS: Patient's background such as sex, age, recurrence, hiatal hernia, smoking and drinking habits, and complications, and the severity of esophagitis at the time of enrolment were not significantly different between the two groups. Healing in the OMP group and the FAM group was observed in 72 and 32% (P = 0.025) of patients at week 4 and 95 and 53% (P = 0.003) of patients at week 8, respectively. Subjective symptoms were relieved more frequently in the OMP group (at week 2, 67% compared with 29%, P = 0.005; at week 4, 95% compared with 55%, P = 0.009), but this superiority was not significant at week 8 (94% compared with 65%, P = 0.085). No serious adverse events occurred. CONCLUSIONS: Omeprazole provided quicker healing and a greater relief from subjective symptoms than did FAM in the treatment of RE, and was considered more suitable as a first-choice drug.     

Reflection in the arterial system and the risk of coronary heart disease

BACKGROUND: Although it was reported that the augmentation index and inflection time are closely related to reflection in the arterial system and large artery function, it is not known whether these indices of the ascending aortic pressure waveform increase the risk of coronary heart disease (CHD). The purpose of this study was to evaluate whether the aortic reflection of the ascending aortic pressure waveform is related to an increased risk of CHD. METHODS: We enrolled 190 men and women who had chest pain, normal contractions, no local asynergy, and no history of myocardial infarction. We measured the ascending aortic pressure using a fluid-filled system. The inflection time was defined as the time interval from initiation of a systolic pressure waveform to the inflection point. We investigated the association between the inflection time and augmentation index of the ascending aorta and the risk of CHD. RESULTS: Both the inflection time and augmentation index were associated with an increased risk of CHD. The crude prevalence rates of CHD were 66.0% for the shortest quartile and 10.6% for the longest quartile of the inflection time, and 17.0% for the lowest quartile and 40.4% for the highest quartile of the augmentation index. The multiple-adjusted odds ratio of CHD was 30.8 (95% confidence interval [CI] 7.43-128.05) for the shortest quartile of the inflection time compared with the longest quartile and was 3.82 (95% CI 1.26-11.59) for the highest quartile of the augmentation index compared with the lowest quartile. CONCLUSIONS: The augmentation index and inflection time were associated with an increased risk of CHD.     

Uptake of lamivudine by rat renal brush border membrane vesicles

Uptake of lamivudine, a nucleoside analogue antiviral agent, by brush border membrane vesicles (BBMV) prepared from rat renal cortex was investigated. Initial uptake of lamivudine by BBMV was stimulated in the presence of an outward pH gradient. Determination of the kinetic parameters of the initial uptake yielded apparent Km and Vmax values of 2.28 mm and 1.56 nmol (mg protein)(-1) (20 s)(-1), respectively. The pH-driven uptake of lamivudine was inhibited by organic cations such as trimethoprim and cimetidine. The inhibitory effect of trimethoprim on lamivudine uptake was competitive, with an apparent Ki of 27.6 microM. The uptake of lamivudine was also inhibited by nitrobenzylthioinosine, a representative inhibitor of nucleoside transport, and by other nucleoside analogues, such as azidothymidine and dideoxycytidine, that are excreted by renal tubular secretion. These findings suggest that efflux of lamivudine at the brush border membrane of renal tubular epithelium is mediated by an H+/lamivudine antiport system, which may correspond to the H+/organic cation antiport system, and that this system is also involved in the renal secretion of other nucleoside analogues.     

Conformation of ligands bound to the muscarinic acetylcholine receptor

Many biogenic amines evoke a variety of physiological responses by acting on G protein-coupled receptors. We have determined the conformation of two acetylcholine analogs, (S)-methacholine and (2S,4R,5S)-muscarine, bound to the M(2) muscarinic acetylcholine receptor (M(2) mAChR) by NMR spectroscopy. The analysis of the transferred nuclear Overhauser effect indicated that the receptor selectively recognized the conformers of (S)-methacholine and (2S,4R,5S)-muscarine with the gauche O-C2-C1-N dihedral angle at +60 degrees. This is distinct from the predominant conformations of these ligands in solution with O-C2-C1-N dihedral angle (+80 to approximately 85 degrees ) in the absence of the M(2) mAChR, as assessed by analyses of the coupling constants and nuclear Overhauser effect spectroscopy. We have also built a molecular model of the M(2) mAChR-(S)-methacholine complex, based on the X-ray crystallographic structure of rhodopsin. This model indicated that the conformation with the gauche O-C2-C1-N dihedral angle at +55.5 degrees, which is similar to the one determined by NMR measurement, is energetically favored in the binding of (S)-methacholine to the receptor. We suggest that this conformation represents the binding of the agonist to the M(2) mAChR in the absence of G protein.     

Leukotriene C4 synthase gene A(-444)C polymorphism and clinical response to a CYS-LT(1) antagonist,pranlukast, in Japanese patients with moderate asthma

CysLT(1) antagonists are effective for a subset of patients with asthma; however, there has been no good way to predict a given patient's response. We examined the interaction between the clinical response to a cysLT(1) antagonist, pranlukast, and DNA sequence variant A(-444)C in leukotriene C(4) synthase (LTC(4) S) gene in Japanese patients with moderate asthma. The frequency of LTC(4) S C(-444) allele was 21.6% in the Japanese general population (n = 171) and 19.4% in the asthmatic subjects ( n= 349). A 4-week prospective, open trial of pranlukast (225 mg twice daily) was performed in 50 patients with moderate asthma who had been well controlled with inhaled corticosteroid (beclomethasone 400-800 microg/day or fluticasone 200-400 microg/day). The C(-444) allele carriers (n = 16) responded better to pranlukast compared to the A(-444) allele homozygotes ( n= 31) [14.3 5.3% vs. 3.1 2.4% improvement of forced expiratory volume in one second (FEV(1) ), 0.01], while LTC(4) S genotype-stratified response to inhaled beta-agonist salbutamol (200 microg) was not observed (17.5 2.1% vs. 18.7 2.2% improvement of FEV(1) ). Univariate analysis demonstrated that the better response to pranlukast (more than 10% improvement of FEV(1) ) was correlated with LTC(4) S genotype (P < 0.01) and pretreatment airway reversibility to salbutamol (P < 0.01), but not with sex, age, atopic status, urinary leukotriene E(4) excretion rate, or daily dose of inhaled corticosteroid. Furthermore, multivariate regression analysis suggested that LTC(4) S genotype and the bronchodilatory effect of salbutamol were independent variables to predict the clinical response to pranlukast (P < 0.05). We conclude that LTC(4) S genotype is predictive of the clinical response to a cysLT(1) antagonist, pranlukast, in Japanese patients with moderate asthma.     

Modulation by nicotine of the ionic currents in guinea pig ventricular cardiomyocytes. Relatively higher sensitivity to IKr and IKl

The effects of nicotine on the ionic currents in guinea pig cardiomyocytes were investigated using a whole-cell voltage-clamp technique. Nicotine (30 microM to 1 mM) inhibited the ionic currents in a concentration-dependent manner. Nicotine at 30 microM did not affect the Ca2+ current (ICa), but at 300 microM inhibited ICa at 10 mV by 29.3 +/- 2.4% (n = 6, P < .01) and at 1 mM almost blocked the ICa (by approximately 90%, n = 5, P < .001). After 5- to 10-min washout, these responses had 50-70% recovery. The fast time constant (tau f) of the inactivation phase for ICa at 10 mV was not affected, but the slow one (tau s) increased from 35.7 +/- 2.8 to 39.5 +/- 2.4 ms (n = 7) at 300 microM nicotine. Nicotine at 100 microM also inhibited the delayed rectifier K+ current (IK) at 60 mV by 42.7 +/- 3.0% (n = 7, P < .01), and at 30 microM inhibited the inwardly rectifying K+ current (IKl) at -110 mV by 43.0 +/- 2.5% (n = 7, P < .01). The responses to nicotine were not significantly modified by atropine, hexamethonium, and nicotine receptor antagonists (d-tubocurarine and benzoquinonium). The IK is composed of two components for rapidly and slowly activated currents (IKr and IKs). Nicotine markedly decreased the tail current of IKr, but had less or no effect on that of IKs. However, the activation and inactivation kinetics (d infinity and f infinity) for ICa and its activation kinetics (P infinity) for IKr and IKs were not modified. These results suggest that nicotine inhibits the ionic currents with relatively higher sensitivity to IKl and IKr, resulting in modulation of the cardiac functions.     

Immunohistochemical expression of inducible nitric oxide synthase (iNOS) in human brain tumors: relationships of iNOS to superoxide dismutase (SOD) proteins (SOD1 and SOD2), Ki-67 antigen (MIB-1) and p53 protein

In this study, inducible nitric oxide synthase (iNOS) expression in a series of 158 human primary brain tumors was analyzed. To gain some insight into the biological significance of iNOS expression in tumor cells, comparative immunohistochemical analyses were employed to characterize the expression of iNOS, superoxide dismutase (SOD) proteins (SOD1 and SOD2), Ki-67 antigen (MIB-1) and p53 protein in these cells. Sixteen (39.0%) of the 41 glioblastoma multiforme (GBM) specimens showed iNOS immunoreactivity. Positive immunoreactions with iNOS were also detected in 2/8 anaplastic astrocytomas, 1/17 astrocytomas, 1/14 medulloblastomas and 1/11 primitive neuroectodermal tumors, but no positive reactions were observed in oligodendrogliomas (0/11), ependymomas (0/5), schwannomas (0/21), meningiomas (0/23) or pituitary adenomas (0/7). The MIB-1 labeling index of GBMs that expressed iNOS was significantly higher than that of GBMs that did not (0.025< P <0.05, Wilcoxon rank-sum test). Unlike iNOS-negative tumors, all iNOS-positive tumors coexpressed SOD1 or SOD2. In particular, there was a significant correlation between iNOS induction and SOD1 expression (P =1.65x10(-10), Fisher's exact test) in GBM specimens. There was no significant relationship between iNOS and p53 protein in any type of primary brain tumor (P >0.05, Fisher's exact test). No significant immunohistochemical reactions with iNOS, MIB-1 or p53 protein were observed in normal brain tissue sections. We conclude that primary brain tumors express iNOS, and that iNOS expression in brain tumor cells may depend, in part, on cellular proliferation potential. Based on the fact that SOD1 scavenges oxidative-stress species originating from large amounts of nitric oxide (NO) produced by iNOS, iNOS-expressing brain tumor cells may protect themselves against NO cytotoxicity by overinducing SOD1.     

Platelet-sparing effect of paclitaxel in heavily pretreated ovarian cancer patients

 Carboplatin has proven to be effective in the treatment of patients with recurrent ovarian cancer who have responded to platinum-based first-line chemotherapy. However, thrombocytopenia is a problem in heavily pretreated patients. Paclitaxel has a so-called platelet-sparing effect, but until now it was unknown whether this effect could be obtained in heavily pretreated patients. We treated four patients with recurrent epithelial ovarian cancers who had previously undergone heavy chemotherapy. Because these patients had responded to platinum-based first-line therapy, single carboplatin administration was employed. Although satisfactory tumor marker responses were obtained, thrombocytopenia occurred. When paclitaxel was administered before the carboplatin infusion in the subsequent treatments, the thrombocytopenia became milder. It was concluded that a platelet-sparing effect was also observed in patients who had undergone heavy prior chemotherapy. Received: January 9, 2002 / Accepted: March 29, 2002 Correspondence to:H. Ishikawa     

Association between aldehyde dehydrogenase gene polymorphisms and the phenomenon of field cancerization in patients with head and neck cancer

Patients with squamous-cell carcinoma in the head and neck (HNSCC) often develop second primary esophageal squamous-cell carcinomas (ESCC). In addition, widespread epithelial oncogenic alterations are also frequently observed in the esophagus and can be made visible as multiple Lugol-voiding lesions (multiple LVL) by Lugol chromoendoscopy. Multiple occurrences of neoplastic change in the upper aerodigestive tract have been explained by the concept of 'field cancerization', usually associated with repeated exposure to carcinogens such as alcohol and cigarette smoke. However, the etiology of second ESCC in HNSCC patients remains unclear and acetaldehyde, the first metabolite of ethanol, has been implicated as the ultimate carcinogen in alcohol-related carcinogenesis. We first investigated the relation between second ESCC and multiple LVL in 78 HNSCC patients. Multiple LVL and second ESCC were observed in 29 (37%) and 21 (27%) patients, respectively. All of the second ESCC were accompanied by multiple LVL. This may indicate that episodes of multiple LVL are precursors for second ESCC. We then examined the association of multiple LVL with the patients' characteristics, including genetic polymorphisms of the alcohol metabolizing enzymes, alcohol dehydrogenase type 3 (ADH3) and aldehyde dehydrogenase type 2 (ALDH2). We also investigated acetaldehyde concentrations in the breath of 52 of the 78 patients. All the patients with multiple LVL were both drinkers and smokers. Multivariable logistic analysis showed that the inactive ALDH2 allele (ALDH2-2) was the strongest contributing factor for the development of multiple LVL (odds ratio 17.6; 95% confidence intervals 4.7-65.3). After alcohol ingestion, acetaldehyde in the breath was elevated to a significantly higher level in all patients with the ALDH2-2 allele than in those without it. The high levels of breath acetaldehyde were significantly modified by the slow-metabolizing ADH3-2 allele. These results reveal strong evidence for a gene-environmental interaction between the ALDH2-2 allele and alcohol consumption, for the risk of developing multiple LVL, resulting in the development of second ESCC in patients with HNSCC. Ultimately, increased local acetaldehyde exposure thus appears to be a critical determinant of the phenomenon of 'field cancerization'.     

Decreased expression of hippocampal cholinergic neurostimulating peptide precursor protein mRNA in the hippocampus in Alzheimer disease

Hippocampal cholinergic neurostimulating peptide (HCNP) is involved in the phenotype development of the septo-hippocampal system. HCNP precursor protein (HCNP-pp) is known to interact with other molecules including phosphatidylethanolamine and Raf-1 kinase, and is also known as phosphatidylethanolamine-binding protein and raf kinase-inhibitory protein. To assess whether HCNP-pp is involved in the pathogenesis of Alzheimer disease (AD), the expression levels of its mRNA in the hippocampus of autopsy brains from patients with dementia (including AD and ischemic vascular dementia) were compared with those of non-demented control subjects. The in situ hybridization analysis revealed that the expression of HCNP-pp mRNA in patients with clinically late-onset AD was decreased in the hippocampal CA1 field, but not in the CA3 field or the dentate gyrus. The early-onset AD patients showed a wide range of expression levels in the hippocampal sub-regions. Northern blot analysis of HCNP-pp mRNA in brain tissue supported these observations. Since HCNP is known to stimulate the enzymatic activity of choline acetyltransferase in neurons, its low expression in the CAI field of AD patients may explain the downregulation of cholinergic neurons seen in these patients and may thus contribute to the pathogenic processes underlying AD.