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PubMed2002

Anti-Helicobacter pylori flavonoids from licorice extract.

Licorice is the most used crude drug in Kampo medicines (traditional Chinese medicines modified in Japan). The extract of the medicinal plant is also used as the basis of anti-ulcer medicines for treatment of peptic ulcer. Among the chemical constituents of the plant, glabridin and glabrene (components of Glycyrrhiza glabra), licochalcone A (G. inflata), licoricidin and licoisoflavone B (G. uralensis) exhibited inhibitory activity against the growth of Helicobacter pylori in vitro. These flavonoids also showed anti-H. pylori activity against a clarithromycin (CLAR) and amoxicillin (AMOX)-resistant strain. We also investigated the methanol extract of G. uralensis. From the extract, three new isoflavonoids (3-arylcoumarin, pterocarpan, and isoflavan) with a pyran ring, gancaonols A[bond]C, were isolated together with 15 known flavonoids. Among these compounds, vestitol, licoricone, 1-methoxyphaseollidin and gancaonol C exhibited anti-H. pylori activity against the CLAR and AMOX-resistant strain as well as four CLAR (AMOX)-sensitive strains. Glycyrin, formononetin, isolicoflavonol, glyasperin D, 6,8-diprenylorobol, gancaonin I, dihydrolicoisoflavone A, and gancaonol B possessed weaker anti-H. pylori activity. These compounds may be useful chemopreventive agents for peptic ulcer or gastric cancer in H. pylori-infected individuals.

Anti-Bacterial Agents↗
PubMed2004

[A study of standardization to the rapid detection of Mycobacterium tuberculosis based on phage amplified biologically assay].

OBJECTIVE: To evaluate the phage amplified biologically (PhaB) assay in the rapid detection of Mycobacteria tuberculosis in samples. METHODS: The conditions of the PhaB assay, including various infection times prior to addition of virucide and the effect of the inactivation agents which could inactive the extracellular phages, were investigated and compared. The sensitivity, specificity and accuracy of PhaB assay were tested when it was used in rapid detection of Mycobacterium tuberculosis. Some agents of the method, including Mycobacteriophage, virucide and help cells (Mycobacterium smegmatis) were investigated at different times when they were preserved at 4 degrees C. RESULTS: (1) The optimal infection time prior to addition of virucide was between 3 and 4 hours. Four percent FAS (ferrous ammonium sulphate) could inactive 1 x 10(9) PFU (plaque-forming unit) in five minutes. (2) The samples were positive when 80 - 200 CFU of Mycobacterium tuberculosis were present. However, the positive rate of non-Tuberculosis Mycobateria (NTM) was varied. All bacteria lived in the respiratory tract were negative. (3) The important agents used in this test showed optical effect when they were preserved at 4 degrees C. CONCLUSIONS: The method based on mycobacteriophage-amplified biologically assay could rapidly detect Mycobacterium tuberculosis, and it was effective, accurate, and simple to perform. It was appropriate for using in developing countries, compared with a variety of molecular techniques.

Antitubercular Agents↗
PubMed2005

Urgent clinical challenges in children with ischemic stroke: analysis of 1065 patients from the 1-800-NOCLOTS pediatric stroke telephone consultation service.

BACKGROUND AND PURPOSE: Clinical trials are lacking in pediatric stroke. As a result, physicians caring for children with stroke face significant challenges. The patient characteristics and specific nature of clinical challenges facing practicing clinicians can inform the design of and priorities for developing relevant clinical trials. METHODS: Physicians consulted the 1-800-NOCLOTS toll-free pediatric stroke telephone consultation service on children (birth to 18 years) with ischemic stroke. Pediatric neurologist or hematologists provided telephone consultation and documented caller and patient characteristics, antithrombotic treatments and callers' questions for entry into a computerized database. Children referred from January 1, 1995 to January 1, 2004, comprised the study cohort. RESULTS: Stroke consults were completed on 1065 children located predominantly in the United States (76%). Children had arterial ischemic stroke (AIS; 679; 64%) or cerebral sinovenous thrombosis (CSVT; 386; 36%) and were 54% male and 16% neonates. Risk factors and antithrombotic agents (none, aspirin, warfarin, and heparins) differed by stroke type. In 60% of patients, callers had not initiated antithrombotic therapy. Callers' questions for both stroke types usually concerned treatment selection (83%), but for AIS, questions more frequently (P<0.0001) concerned the selection and interpretation of etiological investigations. CONCLUSIONS: Research is urgently needed in pediatric stroke to provide direction for management in "real-life" settings. Research efforts should address the unique challenges within different stroke types and include observational studies addressing investigation of the child with AIS. For AIS and CSVT, randomized controlled trials investigating the efficacy of antithrombotic treatment are urgently needed.

Adolescent↗
PubMed1998

Evolution of linguistic diversity in a simple communication system.

This article reports on the current state of our efforts to shed light on the origin and evolution of linguistic diversity using synthetic modeling and artificial life techniques. We construct a simple abstract model of a communication system that has been designed with regard to referential signaling in nonhuman animals. We analyze the evolutionary dynamics of vocabulary sharing based on these experiments. The results show that mutation rates, population size, and resource restrictions define the classes of vocabulary sharing. We also see a dynamic equilibrium, where two states, a state with one dominant shared word and a state with several dominant shared words, take turns appearing. We incorporate the idea of the abstract model into a more concrete situation and present an agent-based model to verify the results of the abstract model and to examine the possibility of using linguistic diversity in the field of distributed AI and robotics. It has been shown that the evolution of linguistic diversity in vocabulary sharing will support cooperative behavior in a population of agents.

Animal Communication↗
PubMed2002

Myocardial and microcirculatory kinetics of BR14, a novel third-generation intravenous ultrasound contrast agent.

OBJECTIVES: This study sought to investigate the myocardial and microvascular kinetics of BR14, a novel third-generation ultrasound contrast agent. BACKGROUND: BR14 produces persistent myocardial opacification after the administration of a single intravenous bolus when the left ventricular cavity contrast has considerably diminished. The mechanism of this finding is unknown. METHODS: Nine open-chest dogs with non-critical stenosis of a single coronary artery were given intravenous bolus injections of BR14 during coronary hyperemia. Time versus acoustic intensity (AI) plots were generated from the normal and stenosed beds and myocardial blood flow (MBF) was measured with radiolabeled microspheres. Intravital microscopy was performed on an exteriorized cremaster muscle in 11 wild-type mice to study the microvascular kinetics of the agent. RESULTS: At peak contrast enhancement, the ratio between AI in the stenosed and normal bed was 0.44+/-0.23, which was similar to the radiolabeled microsphere-derived MBF ratio between the two beds (0.45 +/-0.20). At 400 s after injection, the AI ratio between the two beds approximated unity (0.99+/-0.07) despite no changes in MBF, indicating redistribution of the agent. The myocardial kinetics of BR14 was best characterized by a modified lagged normal density function. Only about 3% of administered microbubbles were estimated to be retained in the myocardium. Intravital microscopy showed that most of these bubbles were retained only transiently (2 to 3 s) within capillaries. CONCLUSIONS: BR14 demonstrates redistribution because of transient retention within capillaries. Therefore, similar to (201)Tl, it could potentially be used to detect both coronary stenosis and myocardial viability after a single injection during stress.

Animals↗
PubMed2005

A criticality-based framework for task composition in multi-agent bioinformatics integration systems.

MOTIVATION: During task composition, such as can be found in distributed query processing, workflow systems and AI planning, decisions have to be made by the system and possibly by users with respect to how a given problem should be solved. Although there is often more than one correct way of solving a given problem, these multiple solutions do not necessarily lead to the same result. Some researchers are addressing this problem by providing data provenance information. Others use expert advice encoded in a supporting knowledge-base. In this paper, we propose an approach that assesses the importance of such decisions with respect to the overall result. We present a way of measuring decision criticality and describe its potential use. RESULTS: A multi-agent bioinformatics integration system is used as the basis of a framework that facilitates such functionality. We propose an agent architecture, and a concrete bioinformatics example (prototype) is used to show how certain decisions may not be critical in the context of more complex tasks.

Algorithms↗
PubMed2006

Metastatic breast cancer: sequencing hormonal therapy and positioning of fulvestrant.

Fulvestrant, a novel estrogen receptor (ER) antagonist with no agonist effects, binds, blocks, and degrades the ER, thereby downregulating cellular ER levels, which in turn leads to reduced expression of the progesterone receptor. Due to this specific working mechanism, fulvestrant is an important addition to the armamentarium of endocrine agents in advanced breast cancer (ABC). Fulvestrant has been shown to be equally effective as the third-generation aromatase inhibitor (AI) anastrozole in postmenopausal patients with hormone-sensitive ABC progressing prior to tamoxifen. In another randomized phase III trial, it was shown that fulvestrant had similar efficacy to tamoxifen in the first-line treatment of postmenopausal women with hormone receptor-positive ABC. When comparing the side effects of fulvestrant with tamoxifen and anastrozole, it was shown that fulvestrant is well tolerated compared with these agents and is associated with a lower incidence of joint disorders. Clinical benefit on fulvestrant treatment after AI therapy has been reported in a substantial number of patients (28-46%). On the other hand, it was also shown that sensitivity to further endocrine therapy is retained following progression on first-line or second-line fulvestrant (57% and 46% clinical benefit, respectively). In conclusion, fulvestrant provides us with an additional endocrine treatment option making it possible to prolong the time that patients with ABC can be treated with endocrine therapy.

Antineoplastic Agents, Hormonal↗
PubMed2000

Prefrontal cortical manipulations alter the effects of intra-ventral striatal dopamine antagonists on fixed-interval performance in the rat.

The nature of the functional relationships between areas of prefrontal cortex and ventral striatum remain undefined. This study was designed to examine functional interactions between activity in two areas of prefrontal cortex, the prelimbic (PL) and agranular insular (AI) areas, and ventral striatal (VS) dopamine (DA) function. Interactions were assessed using a Fixed Interval (FI) schedule of reinforcement shown previously in our laboratory to be modulated by VS DA function. The study compared changes in FI performance following intra-VS DA antagonist injections alone (SCH23390 + eticlopride) to those observed when either saline or saline + lidocaine were injected into prefrontal cortex after the intra-VS DA antagonist injections. The intra-VS DA antagonists alone decreased FI response rates and increased postreinforcement pause times at both dose combinations (1/0.1 and 3/0.3 microg of SCH23390/eticlopride per side). Neither saline nor saline + lidocaine injected into the PL area of prefrontal cortex altered the effects of intra-VS DA antagonists on FI performance. Saline administration into the AI area of prefrontal cortex, however, eliminated the FI rate-decreasing effects of intra-VS DA antagonists. The agent or mechanism of this effect, whether it be saline, the act of inserting the cannulae into the cortical tissue, or the act of injecting fluid into this tissue, is not clear. This effect of AI saline was prevented by coadministration of lidocaine with saline into AI. These results, coupled with those from a previous experiment examining lesion effects in PL and AI on FI performance (Evans SB, Cory-Slechta DA. The effects of temporary lesions of the insular and medial prefrontal cortex on fixed-interval schedule-controlled behavior in the rat, Soc Neurosci Abstr 1996;22(1):159) suggest that PL might exert a tonic influence on VS DA function, since FI response rates gradually increase over a 2-week period following lesions of PL. In contrast, AI, although not normally modulating FI performance, can apparently influence VS DA function, possibly when alterations in activity are invoked in AI.

Animals↗
PubMed1982

Inhibitors of the renin-angiotensin system as new antihypertensive agents.

There are several approaches for interfering with the renin-angiotensin system. Antibodies against renin and angiotensins I and II (AI and AII) have not been consistently successful in the past, probably because of nonspecific effects; however, recent purification of renin now makes this approach more promising. Renin inhibitors include pepstatin and analogs, lipids and phospholipids, and renin-substrate analogs. Pepstatin and analogs are the most potent and specific but they are not orally active. The phospholipids are the most effective in vivo but their specificity is yet to be established. Renin-substrate analogs have been developed that have biologically significant effects but are not orally active. Some of the most potent and specific agents available for interfering with the renin-angiotensin system are the AII receptor antagonists. While these compounds effectively prevent the actions of AII, they suffer from several severe deficiencies: partial agonist activity, short duration of action, and lack of oral activity. The recent development of angiotensin-converting enzyme (ACE) inhibitors that are orally active has provided the greatest degree of clinical success for inhibitors of the renin-angiotensin system and, consequently, the impetus to develop still better compounds. Captopril (SQ 14,225) is the prototype ACE inhibitor, being highly potent and specific with no other demonstrated pharmacological activity. Captopril is effective in all forms of human and animal models of hypertension except mineralocorticoid hypertension, which requires concomitant diuretic therapy. Because ACE is the same enzyme as kininase II, the enzyme that degrades kinins, the possibility exists that kinins are involved in the cardiovascular action of captopril, although this prospect is unlikely.

Angiotensinogen↗
PubMed2005

Effects of {2-[(3-carboxy-1-oxoprogy1)amino]-2-deoxy-D-glucose} on human hepatocellular carcinoma cell line.

AIM: To study the effects of {2-[(3-carboxy-1-oxoprogy1)amino]-2-deoxy-D-glucose (COPADG) on cultured human hepatocellular carcinoma cells (HepG2). METHODS: HepG2 cells were cultured in RPMI-1640 medium. Cell proliferation was determined by MTT assay. Apoptosis was determined by fluorescence microscopy, transmission electron microscopy, agarose gel electrophoresis of DNA fragmentation, and flow cytometry. RESULTS: At the concentration ranging between 1-30 micromol/L, COPADG potently inhibited the growth and induced apoptosis of HepG2 cells. CONCLUSION: COPADG could effectively induce apoptosis in human hepatocellular carcinoma cells. More investigations are warranted for the potential use of this compound as a new agent for the non-surgical management of human hepatocellular carcinoma.

Antineoplastic Agents↗
PubMed2003

Human health implications of avian influenza viruses and paramyxoviruses.

Among avian influenza viruses and avian paramyxoviruses are the aetiological agents of two of the most devastating diseases of the animal kingdom: (i). the highly pathogenic form of avian influenza, caused by some viruses of the H5 and H7 subtypes, and (ii). Newcastle disease, caused by virulent strains of APMV type 1. Mortality rates due to these agents can exceed 50% in naïve bird populations, and, for some strains of AI, nearly 100%. These viruses may also be responsible for clinical conditions in humans. The virus responsible for Newcastle disease has been known to cause conjunctivitis in humans since the 1940s. The conjunctivitis is self-limiting and does not have any permanent consequences. Until 1997, reports of human infection with avian influenza viruses were sporadic and frequently associated with conjunctivitis. Recently, however, avian influenza virus infections have been associated with fatalities in human beings. These casualties have highlighted the potential risk that this type of infection poses to public health. In particular, the pathogenetic mechanisms of highly pathogenic avian influenza viruses in birds and the possibility of reassortment between avian and human viruses in the human host represent serious threats to human health. For this reason, any suspected case should be investigated thoroughly.

Animals↗
PubMed2006

Comparative trial of effectiveness of pyrethroid insecticides against peridomestic populations of Triatoma infestans in northwestern Argentina.

The effects of different pyrethroid insecticides, formulations, and doses on peridomestic populations of Triatoma infestans (Klug) were evaluated in 128 houses with 148 identified infested peridomestic sites in northwestern Argentina between October 2003 and March 2005. Four treatments were randomly assigned within each community: two doses of 5% suspension concentrate beta-cypermethrin in water applied with manual compression sprayers, the standard dose (S) at 50 mg and a double dose (2S) at 100 mg active ingredient (AI)/m2; and two emulsifiable concentrates diluted in diesel fuel and applied with power sprayers, 25% cypermethrin (100 mg [AI] /m2) (CF) and 10% permethrin (170 mg [AI]/m2) (DF). Infestation was assessed by timed manual collections with a dislodging agent at baseline, 5, 12, and 17 mo postspraying, and the sites found to be reinfested at 5 mo postspraying were selectively resprayed. Only 2S eliminated T. infestans from all peridomestic sites up to 12 mo postspraying, and it was significantly more effective than all other treatments. At 5 mo postspraying, more sites treated with CF or DF rather than S had bug colonies that probably represented residual foci, which they also failed in eliminating after a second spray. At 17 mo postspraying, the prevalence of reinfested peridomestic sites was 5% for 2S, 29% for S, 43% for CF, and 54% for DF. The application of suspension concentrate pyrethroids in dose twice as large as that currently in use in the attack phase produces a greater initial impact and may eliminate peridomestic populations of T. infestans.

Animals↗
PubMed1988

Antihypertensive and angiotensin converting enzyme inhibitory activities of a novel dihydrobenzofuran analogue.

1. The biochemical and pharmacological profiles of the novel, orally active angiotensin converting enzyme (ACE) inhibitor, N-[N-[[4-(2, 3-dihydro-2-benzofuranyl)-1-(ethoxycarbonyl)]butyl]-(s)-alanyl]- (s)-proline (BRL 36378), have been compared with those of enalapril and captopril. 2. In the conscious sodium deficient spontaneously hypertensive rat, BRL 36378 and enalapril (0.3-10 mg/kg orally) produced comparable falls in blood pressure; at 3 mg/kg orally, captopril was less active than BRL 36378 and enalapril. 3. In the anaesthetised spontaneously hypertensive rat, enalapril was slightly more potent than BRL 36378 as an inhibitor of angiotensin I (AI) pressor responses whilst BRL 36378 was about twice as potent as captopril in this test (i.v. route used). BRL 36378 and enalapril were equipotent as potentiators of bradykinin depressor responses. 4. In the anaesthetised Wistar rat, the maximum inhibition of AI pressor responses by 0.1 microgram/kg i.v. BRL 36378 and captopril was achieved sooner than after the same dose of enalapril. The inhibitory effect of captopril subsided completely by 40-50 min but the maximum effects of BRL 36378 and enalapril persisted for at least 60 min. 5. In the conscious renal hypertensive cat, captopril was slightly more potent than BRL 36378 or enalapril as a blood pressure lowering agent, over 1-10 mg/kg orally. BRL 36378 was more potent than enalapril as an inhibitor of AI induced pressor responses in this model. Captopril possessed similar inhibitory activity to BRL 36378 although minor differences in time course were apparent.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed2005

Adjuvant therapy of breast cancer.

In the past few years the treatment of early stage breast cancer has gone through several important changes. Both chemotherapy and hormonal therapy have been shown by large, randomized trials to offer a survival advantage. The most commonly used chemotherapeutic agents used in the US are doxorubicin and cyclophosphamide (AC). However, 3 studies have suggested that there may be an advantage in the use of taxanes in the adjuvant treatment of breast cancer. Furthermore the use of dose dense chemotherapy, incorporating AC and paclitaxel, has shown very promising results. It is well established that tamoxifen (T), a selective estrogen receptor modulator (SERM), improves overall survival (OS) in women with hormone receptor (HR) positive breast cancer. However, the results from large multicenter, randomized trials, suggest the potential superiority of aromatase inhibitors (AIs), compared to T or an advantage of sequencing T followed by an AI. The role ovarian suppression is still being investigated in patients who have received prior chemotherapy. Newer agents, such as the monoclonal antibody against the her2/neu receptor, trastuzumab, are now being studied as adjuvant therapy in early stage breast cancer. In the next few years, with the completion of several large randomized trials, we will be able to answer several questions, including the optimal way of incorporating AIs into the adjuvant therapy, the long-term sequella of using trastuzumab in the adjuvant treatment of breast cancer and the role of ovarian suppression combined with an AI in premenopausal women with breast cancer.

Breast Neoplasms↗
PubMed1996

Block of pancreatic ATP-sensitive K+ channels and insulinotrophic action by the antiarrhythmic agent, cibenzoline.

1. We investigated the effect of cibenzoline (a class Ia antiarrhythmic drug) on basal insulin secretory activity of rat pancreatic islets and ATP-sensitive K+ channels (KATP) in single pancreatic beta cells of the same species, using radioimmunoassay and patch clamp techniques. 2. Micromolar cibenzoline had a dose-dependent insulinotrophic action with an EC50 of 94.2 +/- 46.4 microM. The compound inhibited the activity of the KATP channel recorded from a single beta-cell in a concentration-dependent manner. The IC50 was 0.4 microM in the inside-out mode and 5.2 microM in the cell-attached mode, at pH 7.4. 3. In the cell-attached mode, alkalinization of extracellular solution increased the inhibitory action of cibenzoline and the IC50 was reduced from 26.8 microM at pH 6.2 to 0.9 microM at pH 8.4. On the other hand, the action of cibenzoline in the excised inside-out mode was acute in onset with a small IC50, indicating that the drug attains its binding site from the cytoplasmic side of the cell membrane. 4. In the inside-out mode, micromolar ADP reactivated the cibenzoline-blocked KATP channels in a manner similar to that by which ADP restored ATP-dependent block of the channel. 5. The binding of [3H]-glibenclamide to pancreatic islets was inhibited by glibenclamide but not by cibenzoline. In contrast, the [3H]-cibenzoline binding was displaced by unlabelled cibenzoline but not by glibenclamide. It is concluded that cibenzoline blocks pancreatic KATP channels via a binding site distinct from the sulphonylurea receptor.

Animals↗
PubMed2006

Modulating beta-lapachone release from polymer millirods through cyclodextrin complexation.

Beta-lapachone (beta-lap) is a novel anticancer agent that kills tumors overexpressing the NADPH: quinone oxidoreductase enzyme. However, poor aqueous solubility and low bioavailability hinder its therapeutic applications. Herein we describe the development of poly(D,L-lactide-co-glycolide) (PLGA) polymer millirods for local delivery of beta-lap. The objective was to investigate the use of beta-lap inclusion complexes with cyclodextrins (CDs) to control beta-lap release kinetics from PLGA millirods. Differential scanning calorimetry was performed to measure drug/polymer interactions, complexation efficiency with different CDs, and complex/polymer interactions. beta-Lap was found to have a solid-state solubility of 13% in PLGA. beta-Lap dissolution in PLGA matrix lowered the glass transition temperature of PLGA from 44 to 31 degrees C, and led to a slow release of beta-lap (8.8+/-1.2% release after 22 days). For beta-lap and CD interactions, increasing complexation efficiency was observed in the order of alpha-CD, gamma-CD, and beta-CD. beta-Lap complexation with hydroxypropyl-beta-cyclodextrin (HPbeta-CD) prevented drug dissolution in PLGA, and led to fast release (79.6+/-2.1% after 2 days). Sustained drug release was achieved when beta-lap was complexed with alpha-CD or gamma-CD. These data demonstrate the ability to tailor beta-lap release kinetics via CD complexation, providing exciting opportunities for the use of beta-lap-millirods for intratumoral drug delivery.

Antineoplastic Agents↗