bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimation of energy requirements for mechanically ventilated, critically ill patients using nutritional status
Authors: Kan Mee-Nin , Chang Han-Hsin , Sheu Woei-Fen , Cheng Chien-Hsiang , Lee Bor-Jen , Huang Yi-Chia
Published: August 2003

Background

There is very little information on what is considered an adequate energy intake for mechanically ventilated, critically ill patients. The purpose of the present study was to determine this energy requirement by making use of patients' nutritional status.

Methods

The study was conducted in a multidisciplinary intensive care unit of Taichung Veterans General Hospital, Taiwan. Patients were hemodynamically stable and not comatose, and were requiring at least 7 days of mechanical ventilation. Fifty-four patients successfully completed this study. The resting energy expenditure was measured using indirect calorimetry. The total energy requirement was considered 120% of the measured energy expenditure. The daily nutrient intake was recorded. Nutritional status was assessed using single and multiple parameters, nitrogen balance, and medical records, and was performed within 24 hours of admission and after 7 days in the intensive care unit.

Results

Fifteen patients were being underfed (<90% of total energy requirement), 20 patients were in the appropriate feeding (AF) group (within ± 10% of total energy requirement), and 19 patients received overfeeding (>110% of total energy requirement). Patients in the underfeeding group received only 68.3% of their energy requirement, while the overfeeding group patients received up to 136.5% of their required calories. Only patients in the AF group had a positive nitrogen balance (0.04 ± 5.1) on day 7. AF group patients had a significantly higher Nutritional Risk Index value at day 7 than at day 1.

Conclusion

AF patients had more improvement in nutritional status than patients in the other feeding groups. To provide at least 120% of the resting energy expenditure seemed adequate to meet the caloric energy needs of hemodynamically stable, mechanically ventilated, critically ill patients.
Assessment of six mortality prediction models in patients admitted with severe sepsis and septic shock to the intensive care unit: a prospective cohort study
Authors: Arabi Yaseen , Shirawi Nehad Al , Memish Ziad , Venkatesh Srinivas , Al-Shimemeri Abdullah
Published: August 2003

Introduction

We conducted the present study to assess the validity of mortality prediction systems in patients admitted to the intensive care unit (ICU) with severe sepsis and septic shock. We included Acute Physiology and Health Evaluation (APACHE) II, Simplified Acute Physiology Score (SAPS) II, Mortality Probability Model (MPM) II0 and MPM II24 in our evaluation. In addition, SAPS II and MPM II24 were customized for septic patients in a previous study, and the customized versions were included in this evaluation.

Materials and method

This cohort, prospective, observational study was conducted in a tertiary care medical/surgical ICU. Consecutive patients meeting the diagnostic criteria for severe sepsis and septic shock during the first 24 hours of ICU admission between March 1999 and August 2001 were included. The data necessary for mortality prediction were collected prospectively as part of the ongoing ICU database. Predicted and actual mortality rates, and standardized mortality ratio were calculated. Calibration was assessed using Lemeshow–Hosmer goodness of fit C-statistic. Discrimination was assessed using receiver operating characteristic curves.

Results

The overall mortality prediction was adequate for all six systems because none of the standardized mortality ratios differed significantly from 1. Calibration was inadequate for APACHE II, SAPS II, MPM II0 and MPM II24. However, the customized version of SAPS II exhibited significantly improved calibration (C-statistic for SAPS II 23.6 [P = 0.003] and for customized SAPS II 11.5 [P = 0.18]). Discrimination was best for customized MPM II24 (area under the receiver operating characteristic curve 0.826), followed by MPM II24 and customized SAPS II.

Conclusion

Although general ICU mortality system models had accurate overall mortality prediction, they had poor calibration. Customization of SAPS II and, to a lesser extent, MPM II24 improved calibration. The customized model may be a useful tool when evaluating outcomes in patients with sepsis.
Tissue expression of copines and isolation of copines I and III from the cytosol of human neutrophils
Authors: Cowland Jack B , Carter Daniel , Bjerregaard Malene D , Johnsen Anders H , Borregaard Niels , Lollike Karsten
Published: August 2003

Copines are a recenty identified group of proteins characterized by two Ca2+-binding C2-domains at the N terminus and an A-domain at the C terminus. Although pEST sequences indicate the existence of at least seven copines in man, only copines I, III, and VI have been identified at protein level. Here, we describe the isolation of copines I and III in the cytosol of human neutrophils by use of Ca2+-induced hydrophobic chromatography. This is the first demonstration that copines are coexpressed in the same cell. We found that copine III exists in the cytosol of human neutrophils as a monomer with a blocked N terminus. Copines I and III undergo conformational changes upon Ca2+ binding that lead to exposure of hydrophobic patches. Examination of RNA from 68 human tissues demonstrated that copines I–III are ubiquitously expressed whereas copines IV–VII each has a more restricted and individual expression profile. Expression of copines I–III was also demonstrated in neutrophil precursors from bone marrow. Copine I was uniformly expressed at all stages of neutrophil differentiation, whereas copine II and even more so, copine III were expressed in the more immature neutrophil precursors, which indicates an individual function of these copines.
Cross-talk between regulators of myeloid development: C/EBPα binds and activates the promoter of the PU.1 gene
Authors: Kummalue Tanawan , Friedman Alan D
Published: August 2003

CCAAT/enhancer-binding protein (C/EBP)α and PU.1 are required for myelopoiesis. Examination of the murine PU.1 promoter revealed several potential C/EBP-binding sites. Gel-shift assay demonstrated that C/EBPα expressed in 293T cells bound the site centered at –68 most potently. C/EBPα from 32D cl3 myeloid cell nuclear extracts also bound this site strongly, and endogenous C/EBPβ did so to a lesser extent, whereas these C/EBP isoforms bound the neutrophil elastase promoter with equal affinity. The –68 site in the murine PU.1 promoter is conserved in the human PU.1 promoter. Mutation of the –68 C/EBP-binding site in a −85/+152 promoter segment linked to the luciferase cDNA reduced promoter activity fourfold in 293T cells in the presence of cotransfected C/EBPα and twofold in 32D cl3 myeloid cells. Induction of endogenous PU.1 RNA by C/EBPα-estradiol receptor (ER) in the presence of cycloheximide is obviated by mutation of the C/EBPα DNA-binding domain, and chromosomal immunoprecipitation demonstrated specific interaction of C/EBPα and C/EBPα-ER with the PU.1 promoter. Finally PU.1 RNA is reduced several-fold in immortalized C/EBPα (−/−) compared with (+/−) cells. Together, these findings indicate that C/EBPα binds and activates the endogenous PU.1 gene in myeloid cells. Induction of PU.1 by C/EBPα may account for increased levels of PU.1 in myeloid as compared with B lymphoid cells and in this way, may contribute to the specification of myeloid progenitors.
Expressed emotion across cultures
Authors: Bhugra Dinesh , McKenzie Kwame
Published: August 2003

Expressed emotion has been used as a construct in understanding the interaction between patients and their carers and families. A considerable amount of data from Western cultures suggests that high expressed emotion can lead to relapse in vulnerable individuals, even when they are on medication. However, the data from other cultures are less solid. This paper reviews some of the existing findings and recommends that various components of expressed emotion must be seen in the cultural context and embedded in the normative data of the population before the concept can be considered in association with the pathogenesis of relapse.
The mental health of nurses in the UK
Authors: Nolan Peter , Smojkis Maureen
Published: August 2003

The recruitment and retention crisis in UK nursing puts many reforms outlined in recent health policies at risk. Increasing bureaucratisation of health care, unattractive working conditions, poor pay and the emotionally exhausting nature of the work are associated with high rates of burnout and workplace violence. Some nurses prefer agency work, some leave because they cannot reconcile a caring role with working in the NHS. It seems that health care has become emotionally distant and the profession's longstanding attachment to caring through interpersonal relationships has been overridden by a high-technology, fast-track system of care management. To retain the principles and ethos of nursing at the centre of health developments, attention must be given to the micro-environments in which nurses work.
Substance misuse during pregnancy
Authors: Johnson K. , Gerada C. , Greenough A.
Published: August 2003

The use of illicit substances such as cocaine and heroin during pregnancy is common. Anonymous screening of consecutive urine samples testing positive for pregnancy from a UK inner-city clinic demonstrated that approximately 16% of the women had taken one or more illicit substances (Sherwoodet al, 1999). The prevalence of drug misuse in the USA appears to be even higher: prospective screening of newborns in a high-risk urban population revealed that 44% of 3010 babies tested positive for opiates, cocaine or cannabis (Ostreaet al, 1992). The aim of this editorial is to emphasise the importance of this topic by describing the unfavourable effects illicit substances can have on both pregnancy and infant outcome. In addition, discussion of the evidence base for current management highlights the need for appropriately designed studies to optimise treatment and reduce morbidity.
Effect of 11 September 2001 on suicide and homicide in England and Wales
Authors: Salib Emad
Published: August 2003

Background

The tragic events of 11 September 2001 and televised scenes of the terrorists' homicidal and suicidal acts could have had an impact on the behaviour of some people, who harbour suicidal ideation or homicidal tendencies.

Aims

To assess the effect of 11 September 2001 on the rate of suicide and homicide in England and Wales.

Method

Analysis of the number of suicides (ICD–9 codes: E950–E959), undetermined injury deaths (E980–E989) and homicides (E960–E969) in England and Wales in the 12 weeks before and after 11 September 2001 and during a similar period in the previous two years.

Results

The number of suicides reported in the month of September 2001 was significantly lower than other months in the same year and any September of the previous 22 years in England and Wales. A suicide reduction in men, regardless of age, occurred in the week starting Tuesday 11 September 2001. A reduction in female suicide occurred during the four weeks following the attack. There was no evidence of a similar effect on homicide.

Conclusions

The tragic events of 11 September 2001 appear to have had a brief but significant inverse effect on suicide. The finding of this study supports Durkheim's theory that periods of external threat create group integration within society and lower the suicide rate through the impact on social cohesion.
Prevalence of violent victimisation in severe mental illness
Authors: Walsh Elizabeth , Moran Paul , Scott Charles , McKenzie Kwame , Burns Tom , Creed Francis , Tyrer Peter , Murray Robin M. , Fahy Tom
Published: August 2003

Background

Since de-institutionalisation, much has been written about the risk posed to the community by those with severe mental illness. However, violent victimisation of people with mental illnesses has received little attention.

Aims

To establish the 1-year prevalence of violent victimisation in community-dwelling patients with psychosis and to identify the socio-demographic and clinical correlates of violent victimisation.

Method

A total of 691 subjects with established psychotic disorders were interviewed. The past-year prevalence of violent victimisation was estimated and compared with general population figures. Those who reported being violently victimised were compared with those who did not on a range of social and clinical characteristics.

Results

Sixteen per cent of patients reported being violently victimised. Victims of violence were significantly more likely to report severe psychopathological symptoms, homelessness, substance misuse and previous violent behaviour and were more likely to have a comorbid personality disorder.

Conclusions

Those with psychosis are at considerable risk of violent victimisation in the community. Victimisation experience should be recorded in the standard psychiatric interview.
Unit for Suicide Research, University of Gent, Belgium
Authors: Van Heeringen Kees
Published: August 2003

The Unit for Suicide Research was founded in 1996 with the aims of integrating and stimulating the study of suicidal behaviour, increasing the visibility of the research work, and providing evidence-based information to health policy-makers, the general public and the media. I am Director of the Unit, working alongside Professor Kurt Audenaert, Dr Katrien Bernagie, and psychologists Gwendolyn Portzky (Research Coordinator), Stephanie De Munck, Els Reyserhove and Hannelore Vromman. In this report I will summarise recent and current activities, which are carried out according to three lines of research: the study of the epidemiology of suicidal behaviour; the study of (the association between) biological and psychological characteristics of suicidal behaviour; and the development and evaluation of prevention strategies. Research is carried out in collaboration with other departments of the University of Gent (e.g. the Departments of Nuclear Medicine, Sociology, Radiopharmacy and Veterinary Medicine) and with a large number of other European research centres. The collaboration with Professor Hawton at the Oxford Centre for Suicide Research has been particularly important (Hawton & Van Heeringen, 2000).
A survey of consultants in the psychiatry of learning disability
Authors: Lindsey Mary , Flynn Adrian
Published: August 2003

Aims and Method

All 208 consultant members of the Faculty for the Psychiatry of Learning Disability were contacted and asked to complete a questionnaire to provide qualitative and quantitative information about their work and experiences.

Results

One hundred and thirty-six consultants responded, giving a 64% response rate. They reported a wide range of clinical, academic and management skills, with 72 having registration in other specialities. Insufficient in-patient provision and problems with discharge were cited by 85% of respondents. There was a wide disparity in the provision of mental health services for children and adolescents with learning disabilities and 12 areas reported no services from any source. Although most respondents showed satisfaction with clinical work and professional relationships, there were many concerns about management, commissioning and planning of services.

Clinical Implications

Consultant psychiatrists in the field of learning disability are a broadly skilled group of clinicians with a wide range of responsibilities and areas of expertise, but many are working in services that they see as under-resourced and poorly managed, planned and commissioned. Overall levels of satisfaction are good, particularly in relation to clinical work, peer support and study/academic work.
Seismic Design Aspects of Vertically Irregular Reinforced Concrete Buildings
Authors: Das Satrajit , Nau James M.
Published: August 2003

Seismic building codes such as the Uniform Building Code (UBC) do not allow the equivalent lateral force (ELF) procedure to be used for structures with vertical irregularities. The purpose of this study is to investigate the definition of irregular structures for different vertical irregularities: stiffness, strength, mass, and that due to the presence of nonstructural masonry infills. An ensemble of 78 buildings with various interstory stiffness, strength, and mass ratios is considered for a detailed parametric study. The lateral force-resisting systems (LFRS) considered are special moment-resisting frames (SMRF). These LFRS are designed based on the forces obtained from the ELF procedure. The results from linear and nonlinear dynamic analyses of these engineered buildings exhibit that most structures considered in this study performed well when subjected to the design earthquake. Hence, the restrictions on the applicability of the equivalent lateral force procedure are unnecessarily conservative for certain types of vertical irregularities considered.
Evaluation of Damage Potential of Ground Motions during Great Earthquakes
Authors: Sunasaka Y. , Toki K. , Kiremidjian A. S.
Published: August 2003

In order to select appropriate input ground motions for earthquake-resistant design or estimation of seismic safety of structures, their characteristics should be identified. In this paper, damage potential is defined as a spectrum of strength demand required to maintain a damage index less than or equal to a tolerable damage index value. The damage index proposed by Park and Ang (1985) and a bilinear model are used to calculate the strength demand spectrum. The damage index describes the state of the concrete structure from slight damage to severe damage or collapse. Studies of the damage potential of ground motions during the recent great earthquakes, including the 1995 Hyogoken-Nanbu earthquake in Japan and the 1999 Chi-Chi earthquake in Taiwan, show that damage potential may be greatly affected by the location of the fault, the geological structure of the site, and the fault rupture mechanism. Furthermore, an estimation of damage potential of ground motions over a large area, Kawasaki City in Japan, is described.
A Screen Analysis Procedure for Seismic Slope Stability
Authors: Stewart Jonathan P. , Blake Thomas F. , Hollingsworth Robert A.
Published: August 2003

Site-specific seismic slope stability analyses are required in California by the 1990 California Seismic Hazards Mapping Act for sites located within mapped hazard zones and scheduled for development with more than four single-family dwellings. A screen analysis is performed to distinguish sites for which only small ground deformations are likely from sites for which larger, more damaging landslide movements could occur. No additional analyses are required for sites that pass the screen, whereas relatively detailed analyses are required for sites that fail the screen. We present a screen analysis procedure that is based on a calibrated pseudo-static representation of seismic slope stability. The novel feature of the present screen procedure is that it accounts not only for the effects of ground motion amplitude on slope displacement, but also accounts for duration effects indirectly via the site seismicity. This formulation enables a more site-specific screen analysis than previous formulations that made a priori assumptions of seismicity/duration. This screen procedure has recently been adopted by the Landslide Hazard Implementation Committee for implementation by practicing engineers and engineering geologists in southern California.
Alterations of Plasma Ghrelin Levels in Rats with Lipopolysaccharide-Induced Wasting Syndrome and Effects of Ghrelin Treatment on the Syndrome
Authors: Hataya Yuji , Akamizu Takashi , Hosoda Hiroshi , Kanamoto Naotetsu , Moriyama Kenji , Kangawa Kenji , Takaya Kazuhiko , Nakao Kazuwa
Published: September 2003

Ghrelin not only strongly stimulates GH secretion, but is also involved in energy homeostasis by stimulating food intake and promoting adiposity through a GH-independent mechanism. These effects of ghrelin may play an important role in the pathophysiology of inflammatory wasting syndrome, in which both the somatotropic axis and energy balance are altered. In this study we investigated plasma ghrelin concentrations after lipopolysaccharide (LPS) administration to rats, a model of the wasting syndrome and critical illness. In addition, the therapeutic potential of the antiwasting effects of ghrelin was explored using LPS-injected rats. A single LPS injection suppressed plasma ghrelin levels 6 and 12 h later. Maximal reduction was observed 12 h after LPS injection, in a dose-dependent manner. In contrast, plasma ghrelin levels were elevated after repeated LPS injections on d 2 and 5. Peripheral administration of ghrelin twice daily (10 nmol/rat) for 5 d increased body weight gain in repeated LPS-injected rats. Furthermore, both adipose tissue weight and plasma leptin concentrations were increased after ghrelin administration in these rats. In conclusion, plasma ghrelin levels are altered in LPS-injected rats, and ghrelin treatment may provide a new therapeutic approach to the wasting syndrome and critical illness.
Does Thyrotropin Cleave Its Cognate Receptor?
Authors: Chazenbalk Gregorio D. , Chen Chun-Rong , McLachlan Sandra M. , Rapoport Basil
Published: September 2003

A recent report of major pathophysiological significance, and opposed to present concepts, is that TSH (but not MS-1, a hamster monoclonal thyroid-stimulating antibody), cleaves the single-chain TSH receptor (TSHR) on the cell surface into its two-subunit form. We reassessed the issue using two approaches. First we wished to confirm the flow-cytometric assay previously used to quantitate TSHR cleavage. We used CHO cell lines expressing large (TSHR-10,000 cells) or conventional (TSHR-0 cells) numbers of TSHR. Cells were preincubated (16 h) in either control medium or medium supplemented with TSH (5 × 10−8m) or MS-1 (10 μg/ml). After stringent washing to maximize removal of residual ligand, we performed flow cytometry with two antibodies, one recognizing only the single-chain TSHR, the other recognizing all (cleaved and uncleaved) TSHRs. TSH pretreatment did not appear to increase TSHR cleavage. Instead we observed ligand occupancy of the TSHR (with MS-1) or fewer receptors on the cell surface (down-regulation), particularly with the TSHR-0 cells. Second, we covalently cross-linked [125I]TSH to monolayers of these cells, an unequivocal method to determine directly the proportion of single-chain and two-subunit TSHR forms. Pretreatment of TSHR-10,000 and TSHR-0 cells with TSH had no effect on the degree of TSHR cleavage. MS-1 slightly reduced spontaneous cleavage. In conclusion, in contrast to a recent report, we show that TSH does not alter the subunit structure of its cognate receptor, and we provide insight into the difficulties associated with the flow-cytometric assay for TSHR cleavage.
Identification of a Contact Site for Residue 19 of Parathyroid Hormone (PTH) and PTH-Related Protein Analogs in Transmembrane Domain Two of the Type 1 PTH Receptor
Authors: Gensure Robert C. , Shimizu Naoto , Tsang Janet , Gardella Thomas J.
Published: September 2003

Recent functional studies have suggested that position 19 in PTH interacts with the portion of the PTH-1 receptor (P1R) that contains the extracellular loops and seven transmembrance helices (TMs) (the J domain). We tested this hypothesis using the photoaffinity cross-linking approach. A PTHrP(1–36) analog and a conformationally constrained PTH(1–21) analog, each containing para-benzoyl-l-phenylalanine (Bpa) at position 19, each cross-linked efficiently to the P1R expressed in COS-7 cells, and digestive mapping analysis localized the cross-linked site to the interval (Leu232-Lys240) at the extracellular end of TM2. Point mutation analysis identified Ala234, Val235, and Lys240 as determinants of cross-linking efficiency, and the Lys240→Ala mutation selectively impaired the binding of PTH(1–21) and PTH(1–19) analogs, relative to that of PTH(1–15) analogs. The findings support the hypothesis that residue 19 of the receptor-bound ligand contacts, or is close to, the P1R J domain—specifically, Lys240 at the extracellular end of TM2. The findings also support a molecular model in which the 1–21 region of PTH binds to the extracellular face of the P1R J domain as an α-helix.
S-Nitrosocaptopril: acute in-vivo pulmonary vasodepressor effects in pulmonary hypertensive rats
Authors: Tsui Debbie Y Y , Gambino Agatha , Wanstall Janet C
Published: September 2003

The effects of S-nitrosocaptopril (SNOcap), administered either intravenously or by oral gavage, on pulmonary artery pressure (PAP) were examined in anaesthetised normotensive rats and rats with hypoxic pulmonary hypertension (10% oxygen for 1 week). Mean PAP (MPAP) values in hypoxic and normoxic rats were (mmHg) 26± 1.7 and 15± 1.1, respectively. When given intravenously, 1 mg kg−1 SNOcap reduced MPAP by 28 and 32% in hypoxic and normoxic rats, respectively. The effects of 2 mg kg−1 were no greater than those of 1 mg kg−1. Pulmonary vasodepressor responses reached equilibrium in 1.7$pL0.18 min following intravenous administration. When given orally 30 min before the measurement of PAP, 30 mg kg−1, but not 10 mg kg−1, significantly reduced MPAP in hypoxic rats to 17$pL 1.5 mmHg. These in-vivo data are consistent with previous in-vitro data showing that SNOcap has direct pulmonary vasorelaxant properties in both large and small pulmonary arteries and also show that SNOcap causes pulmonary vasodepression in the setting of pulmonary hypertension. Since SNOcap also inhibits pulmonary vascular angiotensin converting enzyme (ACE) in pulmonary blood vessels (previous study), it would be an interesting drug with which to assess the benefits of direct pulmonary vasodilatation combined with ACE inhibition (which attentuates pulmonary vascular remodelling) in a long-term study in pulmonary hypertension.
The flavonoid quercetin inhibits dimethylnitrosamine-induced liver damage in rats
Authors: Lee Eun-Sil , Lee Hye-Eun , Shin Ji-Young , Yoon Sik , Moon Jeon-Ok
Published: September 2003

Quercetin, one of the most abundant flavonoids in human diet has been reported to exhibit a wide range of pharmacological properties. In this study, we investigated the protective effect of quercetin on hepatic injury induced by dimethylnitrosamine (DMN) in rats. Treatment with DMN caused a significant decrease in body and liver weight. Oral administration of quercetin (10 mg kg−1 daily for 4 weeks) remarkably prevented this DMN-induced loss in body and liver weight and inhibited the elevation of serum alanine transaminase, aspartate transaminase and bilirubin levels. Quercetin also increased serum albumin and hepatic glutathione levels and reduced the hepatic level of malondialdehyde. Furthermore, DMN-induced elevation of hydroxyproline content was reduced in the quercetin treated rats, the result of which was consistent with a reduction in type I collagen mRNA production and histological analysis of liver tissue stained with Sirius red. A reduction in hepatic stellate cell activation, as assessed by α-smooth muscle actin staining, was associated with quercetin treatment as well as a reduction in transforming growth factor-β1 expression. In conclusion, these results demonstrate that quercetin exhibited in-vivo hepatoprotective and anti-fibrogenic effects against DMN-induced liver injury and suggest that quercetin may be useful in the preventing the development of hepatic fibrosis.
Effects of absorption rate on the pre-systemic chiral inversion of ibuprofen in rabbits
Authors: Doki Kosuke , Hayakawa Toru , Lin Wenhui , Yanaguimoto Hitomi , Ding Guohua , Inotsume Nobuo
Published: September 2003

The chiral inversion kinetics of ibuprofen was evaluated after intraduodenal administration of racemic ibuprofen in conventional powder form and sustained-released granules compared with intravenous administration in rabbits. The AUC ratios of the S-(+) and R-(–) enantiomers remained almost constant values with time up to 2 h after administration of sustained-release formulation, while those after administration of the powder increased with time. R-(–) enantiomer to S-(–) enantiomer inversion ratios after intraduodenal administration of the powder form and the sustained-release form, and after intravenous injection were calculated to be 1.63, 1.94 and 1.19, respectively, indicating that pharmacological effects may depend on the absorption rate in rabbits.
Prednisolone 21-sulfate sodium: a colon-specific pro-drug of prednisolone
Authors: Jung Yun Jin , Doh Min Ju , Kim In Ho , Kong Hye Sik , Lee Jeoung Soo , Kim Young Mi
Published: September 2003

Prednisolone 21-sulfate sodium (PDS) was synthesized as a colon-specific pro-drug of prednisolone with the expectation that it would be stable and non-absorbable in the upper intestine and release prednisolone by the action of sulfatase once it was delivered to the colon. In-vitro/in-vivo properties were investigated using rats as test animals. PDS was chemically stable at pH 1.2, 4.5, 6.8 and 8.0, and the apparent partition coefficient was 0.11 in 1-octanol/pH 6.8 buffer solution at 37°C. PDS was stable on incubation with the contents of the stomach or small intestine. When PDS (0.1 mg equiv. of prednisolone) was incubated with the caecal contents (0.05g), prednisolone was produced to a maximum 54% of the dose in 6 h and decreased thereafter, which suggested that reduction of the A ring took place in addition to the hydrolysis by sulfatase. After oral administration of PDS, a small portion of prednisolone was recovered from the cecal contents but not from the small intestine. Neither PDS nor prednisolone was detected in the plasma, suggesting that absorption of PDS is limited. The data demonstrate that the sulfate ester can serve as a novel colon-specific promoiety by limiting the absorption of the pro-drug in the upper intestine and releasing the active compound by the action of microbial sulfatase in the colon.
Selective effect of oleamide, an endogenous sleepinducing lipid amide, on pentylenetetrazole-induced seizures in mice
Authors: Wu Chun-Fu , Li Chun-Li , Song Hong-Rui , Zhang Hua-Feng , Yang Jing-Yu , Wang Yu-Ling
Published: September 2003

The anti-seizure effect of oleamide, an endogenous sleep-inducing fatty acid amide, was studied in mice. Oleamide, in the dose range 43.7–700.0 mg kg−, significantly and dose-dependently inhibited the seizures induced by pentylenetetrazole. However, oleamide showed no inhibitory action on the seizures induced by picrotoxin, strychnine, caffeine or semicarbazide. These results provide the first evidence for the anti-seizure effect of oleamide, and suggest that this effect may be selective to the seizure model induced by pentylenetetrazole.
Inducing a change in the pharmacokinetics and biodistribution of poly-l-lysine in rats by complexation with heparin
Authors: Johnston Thomas P , Kuchimanchi Kamesh R , Alur Hemant , Chittchang Montakarn , Mitra Ashim K
Published: September 2003

The aim of our study was to induce changes in the plasma elimination half-life (t1/2 elim), rate and extent of urinary excretion, and biodistribution of a model macromolecule, poly-l-lysine, in rats following complexation with heparin. Male Sprague-Dawley rats were dosed intravenously with either unfractionated [3H]heparin, FITC-labelled poly-l-lysine, or an [3H]heparin:FITC-labelled poly-l-lysine complex. Serum and blood concentration vs time and urinary excretion profiles were determined as well as the resulting patterns of biodistribution to liver, spleen, kidney, and muscle tissue. While the mean values for the total body clearance of poly-l-lysine and the complex were not significantly different, the volume of distribution and the half-life associated with elimination from the serum were increased greater than 2-fold for the complex compared with free poly-l-lysine. The rate and extent of elimination in the urine followed the relative rank order; heparin >poly-l-lysine> heparin:poly-l-lysine complex. Thirty minutes following intravenous administration, there was significantly more tissue deposition/uptake of the complex in the liver, kidney, and muscle, but not the spleen, when compared with poly-l-lysine administered alone. Complexation of heparin to poly-l-lysine effectively increased the fraction of an administered dose of poly-l-lysine that was deposited in liver, kidney, and muscle tissue. Due to the macromolecular complex being nontoxic and uncharged, potentially it might serve as a suitable carrier for both conventional and peptidic drugs to increase drug distribution to liver, kidney, or muscle tissue.
Influence of single versus multiple actuations on the particle size distribution of beclometasone dipropionate metered-dose inhalers
Authors: Feddah M R , Davies N M
Published: September 2003

The particle size distributions of beclometasone dipropionate delivered from Becotide and Respocort inhalers after single and multiple actuations were investigated using the Andersen Mark II Cascade impactor and the drug was quantified using high performance liquid chromatography. The fine particle mass and the mass median aerodynamic diameter were calculated. An apparent increase in mass median aerodynamic diameter was observed when the number of actuations increased. In addition, the fine particle mass decreased as the number of actuations increased. When performing and analysing cascade impaction study data differences between single versus multiple actuations must be considered. Regulatory guidelines should be amended to stipulate the number of actuations to be loaded into devices used to evaluate the particle size distribution of inhaled aerosol products.
Delivery of an anticancer drug and a chemosensitizer to murine breast sarcoma by intratumoral injection of sulfopropyl dextran microspheres
Authors: Liu Zhi , Ballinger James R , Rauth Andrew M , Bendayan Reina , Wu Xiao Yu
Published: September 2003

Intratumoral injection of controlled-release microsphere formulations of anticancer compounds has the potential to selectively increase tumour exposure to drugs. This work aimed to evaluate the therapeutic effect and toxicity of microsphere formulations containing the anticancer drug, doxorubicin, in a murine tumour model. The effect of co-administration of verapamil, a P-glycoprotein modulator or chemosensitizer, was investigated. Initial in-vitro studies confirmed the ability of verapamil to enhance the accumulation of both doxorubicin and [99mTc]sestamibi, also a P-glycoprotein substrate, in EMT6 murine breast sarcoma cells and a doxorubicin-selected multidrug-resistant variant, EMT6/AR1.0. Ex-vivo studies using confocal microscopy demonstrated release of doxorubicin from microspheres and diffusion of the drug through tissue. For in-vivo studies, EMT6 and EMT6/AR1.0 cells were grown in BALB/c mice. Following intratumoral injection of doxorubicin-loaded microspheres, alone or in combination with verapamil-loaded microspheres, the tumour diameter was measured serially as an indication of therapeutic effect, while the weight, appearance, and behaviour of the mice were monitored as an indication of general toxicity. Intratumoral injections of doxorubicin-loaded microspheres were tolerated much better than systemic administration of equivalent drug concentrations. There was a modest (up to 34%) delay of tumour growth compared with groups receiving no treatment or blank microspheres. Co-injection of verapamil microspheres with doxorubicin microspheres produced a moderate increase in toxicity but no further delay in tumour growth. Controlled-release microsphere formulations of anticancer agents administered intratumorally were an efficient way to deliver high drug doses to the tumour with little systemic toxicity.
Evaluation of the radioprotective effect of Ageratum conyzoides Linn. extract in mice exposed to different doses of gamma radiation
Authors: Jagetia Ganesh Chandra , Shirwaikar Annie , Rao Shaival K , Bhilegaonkar Prasad M
Published: September 2003

The effect of various doses (0, 25, 50, 75, 100, 125, 150, 300, 600 and 900 mg kg−1) of the alcoholic extract of the plant Ageratum conyzoides Linn. (ACE), on the alteration of radiation-induced mortality in mice exposed to 10 Gy of gamma radiation was studied. The acute toxicity studies showed that the drug was non-toxic up to a dose of 3000 mg kg−1, the highest dose that could be tested for acute toxicity. Administration of ACE resulted in a dose-dependent decline in radiation-induced mortality up to a dose of 75 mg kg−1, the dose at which the highest number of survivors (70.83%) was observed. Thereafter, the number of survivors declined with increasing doses of ACE and a nadir was reached at 900 mg kg−1 ACE. Since the number of survivors was highest for 75 mg kg−1 ACE, this was considered the optimum dose for radioprotection and used in further studies in which mice were treated with 75 mg kg−1 ACE before exposure to 6, 7, 8, 9, 10 and 11 Gy of gamma radiation. The treatment of mice with 75 mg kg−1 ACE reduced the severity of symptoms of radiation sickness and mortality at all exposure doses, and a significant increase in survival was observed compared with the non-treated irradiated group. The ACE treatment effectively protected mice against the gastrointestinal as well as bone marrow related death, as revealed by the increased number of survivors at all irradiation doses. The dose reduction factor was found to be 1.3. To understand the mechanism of action, various doses of ACE were evaluated for their in-vitro scavenging action on 1,1-diphenyl-2-picrylhydrazyl (DPPH), a chemically stable free radical. ACE was found to scavenge DPPH radicals in a concentration-dependent manner, indicating that the radioprotection afforded by ACE may be in part due to the scavenging of reactive oxygen species induced by ionizing radiation.
AWD 12–281, a highly selective phosphodiesterase 4 inhibitor, is effective in the prevention and treatment of inflammatory reactions in a model of allergic dermatitis
Authors: Bäumer Wolfgang , Gorr Gilbert , Hoppmann Joachim , Ehinger Andreas M , Rundfeldt Chris , Kietzmann Manfred
Published: September 2003

AWD 12–281 (N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide), a phosphodiesterase 4 inhibitor, which is optimized for topical administration, was tested in a model of allergic dermatitis in mice. To obtain an allergic dermatitis, BALB/c mice were sensitized to toluene-2,4-diisocyanate (TDI). The allergic reaction was challenged by topical administration of TDI onto the mice ears. AWD 12–281 was tested for its anti-inflammatory potential by oral, intraperitoneal and topical administration. The phosphodiesterase 4 inhibitor, cilomilast (SB 207499), and/or the corticosteroid, diflorasone diacetate, were used as reference compounds. Given orally and intraperitoneally 2 h before as well as 5 and 24 h after TDI challenge, AWD 12–281 showed no, or only a transient inhibition of the allergen-induced ear swelling, whereas cilomilast significantly inhibited this ear swelling. Applied topically onto the ears before TDI challenge, AWD 12–281, cilomilast and diflorasone diacetate caused total inhibition of ear swelling 24 h after challenge, confirmed by a decrease of the pro-inflammatory cytokines interleukin-4, interleukin-6 and macrophage inflammatory protein-2. Administered topically after TDI challenge as therapeutic intervention, AWD 12–281 and diflorasone diacetate caused significant inhibition of ear swelling; cilomilast failed to do so. These results indicate that topically administered AWD 12–281 may be potent in the prevention and treatment of allergic/inflammatory skin diseases.
Effects of the aqueous extract from Salvia miltiorrhiza Bge on the pharmacokinetics of diazepam and on liver microsomal cytochrome P450 enzyme activity in rats
Authors: Jinping Qiao , Peiling Hou , Yawei Li , Abliz Zeper
Published: September 2003

The aim of this study was to determine the effects of the aqueous extract of Salvia miltiorrhiza Bge (danshen in Chinese) on the pharmacokinetics of diazepam and on liver microsomal cytochrome P450 enzyme activity in rats. Rats (n = 5) were pretreated with danshen extract (100 mg kg−1 per day, p.o.) for 15 consecutive days. Control rats (n = 5) received saline at the same time. Each rat was then administered a single oral dose of 15 mg kg−1 diazepam. The pharmacokinetic parameters of diazepam were significantly different between the two groups. In the danshen pretreated group, the maximum concentration of diazepam and the area under the plasma concentration–time curve were reduced to about 72.7% and 44.4%, respectively, while the total body clearance was markedly increased by 2-fold. To help explain the results, liver microsomal suspensions were obtained from rats that were randomly divided into the control group (n = 10), and the low- (20 mg kg−1 for 15 days, p.o., n = 10) and high-dose groups (100 mg kg−1 for 15 days, p.o., n = 10) pretreated with danshen extract. Compared with the control rats, the microsomal protein content, cytochrome P450 enzyme level and erythromycin N-demethylase activity of pretreated rats were significantly increased. These results indicate that danshen extract can stimulate the activity of cytochrome P450 isoforms, and changes in the pharmacokinetics of diazepam resulting from danshen extract are related to an increase in metabolic activity of cytochrome P450.
Concept, mechanisms and therapeutics of angiogenesis in cancer and other diseases
Authors: Pralhad Tayade , Madhusudan Saraf , Rajendrakumar Kale
Published: September 2003

Angiogenesis supports normal physiology as well as contributing to the progression of various diseases including cancer. Determination of the key role of angiogenesis in cancer has led to much optimism for the development of targeted drugs without cytotoxic side-effects. Currently, research in angiogenesis therapy is robust, with the discovery of a growing number of pro- and anti-angiogenic molecules. More time, however, is required to be able to elucidate the complex interactions among these molecules, how they affect vasculature and their functions in different environments. As we learn more about the molecular mechanisms of angiogenesis, a number of effective methods to treat cancer and other diseases will be developed.
In-vitro metabolism of the new anxiolytic agent, RWJ-50172, in rat hepatic S9 fraction and microbial transformation in fungi, Cunninghamella sp.
Authors: Wu Wu-Nan , McKown Linda A , Melton John L , Reitz Allen B
Published: September 2003

The in-vitro biotransformation of the anxiolytic agent, RWJ-50172 was studied after incubation with rat hepatic S9 fraction in the presence of an NADPH-generating system, and incubating with Cunninghamella echinulata in soy-bean medium. Unchanged RWJ-50172 (80% of the sample in rat; 86% in fungi) plus 6 metabolites (M1-M6) were profiled, quantified and tentatively identified on the basis of API-MS/MS data. The metabolic pathways for RWJ-50172 are proposed, and the four metabolic pathways are: pyrido-oxidation (pathway A), phenylhydroxylation (B), dehydration (C) and reduction (D). Pathway A formed hydroxy-pyrido-RWJ-50172 (M1, 10% of the sample in both rat and fungi) as the only major metabolite, which further dehydrated to form dehydro-RWJ-50172 in trace quantities in rat. Pathway B produced hydroxyphenyl-RWJ-50172 (M2) in small amounts (4%) in rat, and in conjunction with step A formed dihydroxy-RWJ-50172 as a trace metabolite in rat. Step D produced a minor benzimidazole-reduced metabolite in fungi. RWJ-50172 is substantially metabolized by this rat hepatic S9 fraction and fungi.
Nitric oxide is involved in the expression of neocortical spike-and-wave spindling episodes in DBA/2J mice
Authors: Capasso A , Bianchi A , Loizzo A
Published: September 2003

This study investigated the possible role of nitric oxide (NO) in the development of neocortical spike-and-wave spindling episodes (S&W) of DBA/2J mice. The administration of distilled water did not modify either the number or duration of S&W in DBA/2J mice during the whole recording period (240min). l-NG-nitro arginine methyl ester (L-NAME) (3–300 μg/mouse, i.c.v.) dose-dependently reduced the S&W of DBA/2J mice. This effect appeared 30 min after drug administration and lasted for the duration of the recording period (240min). In addition, L-NAME treatment did not induce significant alterations of stereotyped behaviour such as licking, sniffing, chewing or tremors of the head and body and behavioural excitability, whereas the electroencephalogram desynchronized pattern was also significantly reduced. By contrast d-NG-nitro arginine methyl ester at the same doses did not affect S&W of mice. The inhibitory effect of L-NAME on S&W of mice was dose-dependently reversed by l-arginine (L-ARG, 3–300 μg/mouse, i.c.v.) but not by d-arginine. Finally, glyceryl trinitrate on its own (3–300 μg/mouse, i.c.v.) significantly increased the S&W of mice and it was also able to reverse the inhibition on S&W of mice operated by L-NAME. These results provide evidence that NO may play a significant role in the development of brain excitability.
Binding characteristics of fluoroquinolones to synthetic levodopa melanin
Authors: Ono Chiho , Tanaka Makoto
Published: September 2003

To define the binding characteristics of fluoroquinolones to synthetic levodopa melanin, the binding of various drugs, including levofloxacin and ofloxacin, and positive controls (timolol and chloroquine), was investigated in-vitro. The affinity and capacity of the drug binding were calculated by Langmuir's adsorption isotherm. The affinity constant (K) and the binding capacity (rmax) of levofloxacin were similar to those of timolol and much lower than those of chloroquine. Racemic ofloxacin and its enantiomers showed similar K and rmax, suggesting that the binding lacked stereo-selectivity. The binding experiment with levofloxacin derivatives indicated that the basic nitrogen atom at position 7 of the quinolone ring, but not carboxyl group at position 3, would play a critical role in the interaction of fluoroquinolones with melanin. The melanin–drug complexes of levofloxacin and chloroquine were washed with neutral phosphate buffer, ethanol and 1 m HCl solution to explain the nature of the interaction of melanin with the drugs. Electrostatic forces mainly participate in the formation of the chloroquine–melanin complex, whereas van der Waals' and hydrophobic interactions are involved in the levofloxacin–melanin complex in addition to electrostatic forces. The interactions of various fluoroquinolones such as norfloxacin, enoxacin, sparfloxacin, ciprofloxacin and lomefloxacin with melanin were also studied. The results showed that the relative K value was: chloroquine ≅ ciprofloxacin, sparfloxacin ≥ lomefloxacin > timolol, levofloxacin ≥ enoxacin, norfloxacin, and that the relative rmax value was: norfloxacin, enoxacin ≥ chloroquine, sparfloxacin > levofloxacin, ciprofloxacin, timolol, lomefloxacin. The fluoroquinolones vary in their affinity and capacity to bind with melanin, and ciprofloxacin and sparfloxacin showed a stronger interaction with melanin than the other fluoroquinolones studied.