bluuebunny/crossref_metadata_2025 huggingface dataset:
Interruption of the NF-κB pathway by Bay 11-7082 promotes UCN-01-mediated mitochondrial dysfunction and apoptosis in human multiple myeloma cells
Authors: Dai Yun , Pei Xin-Yan , Rahmani Mohamed , Conrad Daniel H. , Dent Paul , Grant Steven
Published: December 2003

Interactions between pharmacologic NF-κB inhibitors (eg, Bay 11-7082, SN-50) and the checkpoint abrogator UCN-01 have been examined in human multiple myeloma (MM) cells. Exposure of U266 cells to Bay 11-7082 (Bay) in combination with UCN-01 resulted in the abrogation of NF-κB/DNA binding activity and the synergistic induction of apoptosis. Comparable synergism was observed in other MM cell lines and patient-derived CD138+ cells and between an inhibitory peptide of NF-κB (SN50) and UCN-01. Bay/UCN-01-mediated lethality involved mitochondrial dysfunction, caspase cleavage, and poly adenosine diphosphate-ribose polymerase (PARP) degradation. Although Bay modestly blocked UCN-01-induced extracellular signal-regulated kinase (ERK) phosphorylation, coadministration activated c-Jun N-terminal kinase (JNK) and cdc2/cdk1 and down-regulated Mcl-1, XIAP, and Bcl-xL. Transfection with a constitutively activated mitogen-activated protein kinase kinase (MEK1)/green fluorescent protein (GFP) construct failed to block apoptosis induced by Bay/UCN-01 but significantly attenuated MEK inhibitor (U0126)/UCN-01-induced lethality. Inhibiting JNK activation with SP600125 or D-JNKI1 peptide markedly reduced Bay/UCN-01-mediated mitochondrial dysfunction and apoptosis and the down-regulation of Mcl-1, XIAP, and Bcl-xL but not of cdc2/cdk1 activation. Stable transfection of cells with dominant-negative caspase-9 dramatically diminished Bay/UCN-01 lethality without altering JNK or cdc2/cdk1 activation. Neither interleukin-6 (IL-6)- nor fibronectin-mediated adherence conferred resistance to Bay/UCN-01-induced apoptosis. Together, these findings suggest that a strategy combining UCN-01 with disruption of the IκB kinase (IKK)/IκB/NF-κB pathway warrants attention in MM. (Blood. 2004;103:2761-2770)
Aeolian-fluvial interactions in dryland environments: examples, concepts and Australia case study
Authors: Bullard Joanna E. , McTainsh Grant H.
Published: December 2003

Over the past 10 to 15 years there has been a rising interest in interactions between aeolian and fluvial processes from geomorphologists and sedimentologists. This reflects recognition of the limitations of a reductionist perspective examining single process systems in understanding landform and landscape development. This paper focuses on the rise of aeolian-fluvial interaction research in dryland environments. We first explore the background to the contemporary situation then review existing research on aeolian-fluvial interactions at global/regional and local scales. From this review it is suggested that landscape sensitivity, or the effectiveness of links between the process systems, spatial environmental transitions and temporal environmental change are the three main driving forces determining the geomorpho-logical significance of aeolian-fluvial interactions. The importance of the first two of these driving forces is explored in more detail using Australia as a case study. We conclude by highlighting some future possible research directions in this field.
Point and interval estimation of the population size using the truncated Poisson regression model
Authors: van der Heijden Peter GM , Bustami Rami , Cruyff Maarten JLF , Engbersen Godfried , van Houwelingen Hans C
Published: December 2003

A method is presented to derive point and interval estimates of the total number of individuals in a heterogenous Poisson population. The method is based on the Horvitz-Thompson approach. The zero-truncated Poisson regression model is fitted and results are used to obtain point and interval estimates for the total number of individuals in the population. The method is assessed by performing a simulation experiment computing coverage probabilities of Horvitz-Thompson confidence intervals for cases with different sample sizes and Poisson parameters. We illustrate our method using capture-recapture data from the police registration system providing information on illegal immigrants in four large cities in the Netherlands.
Generalized log-linear models with random effects, with application to smoothing contingency tables
Authors: Coull Brent A , Agresti Alan
Published: December 2003

We define a class of generalized log-linear models with random effects. For a vector of Poisson or multinomial means m and matrices of constants C and A, the model has the form C log Aμ = Xβ + Zu, where β are fixed effects and u are random effects. The model contains most standard models currently used for categorical data analysis. We suggest some new models that are special cases of this model and are useful for applications such as smoothing large contingency tables and modeling heterogeneity in odds ratios. We present examples of its use for such applications. In many cases, maximum likelihood model fitting can be handled with existing methods and software. We outline extensions of model fitting methods for other cases. We also summarize several challenges for future research, such as fitting the model in its most general form and deriving properties of estimates used in smoothing contingency tables.
Generalized linear mixed models for strawberry inflorescence data
Authors: Cole Diana J , Morgan Byron JT , Ridout Martin S
Published: December 2003

Strawberry inflorescences have a variable branching structure. This paper demonstrates how the inflorescence structure can be modelled concisely using binomial logistic generalized linear mixed models. Many different procedures exist for estimating the parameters of generalized linear mixed models, including penalized likelihood, EM, Bayesian techniques, and simulated maximum likelihood. The main methods are reviewed and compared for fitting binomial logistic generalized linear mixed models to strawberry inflorescence data. Simulations matched to the original data are used to show that a modified EM method due to Steele (1996) is clearly the best, in terms of speed and mean-squared-error performance, for data of this kind.
Longitudinal analysis of repeated binary data using autoregressive and random effect modelling
Authors: Aitkin Murray , Alfò Marco
Published: December 2003

In this paper we extend random coefficient models for binary repeated responses to include serial dependence of Markovian form, with the aim of defining a general association structure among responses recorded on the same individual. We do not adopt a parametric specification for the random coefficients distribution and this allows us to overcome inconsistencies due to misspecification of this component. Model parameters are estimated by means of an EM algorithm for nonparametric maximum likelihood (NPML), which is extended to deal with serial correlation among repeated measures, with an explicit focus on those situations where short individual time series have been observed. The approach is described by presenting a reanalysis of the well-known Muscatine (Iowa) longitudinal study on childhood obesity.
Treating psychological symptoms in sexually abused children
Authors: Ramchandani Paul , Jones David P. H.
Published: December 2003

Background

The experience of having been sexually abused is associated with a wide range of psychiatric symptoms and difficulties, and these problems can persist over years. The psychological treatment of children who have experienced sexual abuse has only recently begun to be systematically investigated. An increasing number of robust studies have been conducted.

Aims

To review systematically the available evidence from randomised controlled trials of psychological treatments for children who have been sexually abused, and to consider the place of these treatments in a multi-disciplinary service.

Method

A systematic search of the available research was undertaken. Included trials were critically appraised and the results considered.

Results

Twelve studies were included in the review. The best evidence of efficacy for improving psychological symptoms in these children was found for cognitive–behavioural therapy, particularly for young children.

Conclusions

Efficacious treatments exist to improve psychological symptoms in children who have experienced sexual abuse. Consideration is given to the place of these treatments within the response of a multi-disciplinary service.
Biochemical terrorism: Too awful to contemplate, too serious to ignore
Authors: Alexander David Alan , Klein Susan
Published: December 2003

Background

It is important not to foster unnecessary public anxiety with regard to the risk of a biochemical terrorist incident, but the authorities need to consider their response strategy, particularly with regard to mental health issues.

Aims

To describe the likely effects of a terrorist incident involving biochemical agents and to identify important response issues.

Method

Literature survey.

Results

Observations following conventional terrorist incidents and other major trauma, including biochemical and nuclear accidents, suggest that a biochemical terrorist incident would have widespread public effects. The mental health services should play a major role in designing an effective multi-disciplinary response, particularly with regard to the reduction of public anxiety, identifying at-risk individuals and collaborating with medical and emergency services, as well as providing care for those who develop post-traumatic psychopathology.

Conclusions

We should not feel helpless in the face of a biochemical threat; there is considerable knowledge and experience to be tapped. Awell-designed, well-coordinated and rehearsed strategy based on empirical evidence will do much to reduce public anxiety and increase professional confidence.
Diet, smoking and cardiovascular risk in people with schizophrenia
Authors: McCreadie R. G. ,   Scottish Schizophrenia Lifestyle Group
Published: December 2003

Background

Physical health of people with schizophrenia is poor and they die early from cardiovascular disease.

Aims

To describe the lifestyle of people with schizophrenia through diet, smoking habits, weight and exercise, and to report risk of coronary heart disease (CHD).

Method

Dietary habits of 102 community-dwelling people with schizophrenia were assessed by the Scottish Health Survey Questionnaire. Also assessed were smoking habits, physical activity biochemical indices of nutrition and future risk of CHD.

Results

Fewer males, compared with the general population, reached acceptable levels for consumption of fruit, vegetables, milk, potatoes and pulses. Fewer females reached the levels for consumption of milk and potatoes. Mean number of fruit and vegetable portions consumed per week was 16 (s.d.=14); 71 (70%) were smokers; 25 (86%) females and 50 (70%) males were overweight or obese; 59 (59%) considered themselves physically active; 46 (53%) had a raised cholesterol: high-density lipoprotein ratio, and 64 (74%) a low α-tocopherol: cholesterol ratio. Mean 10-year risk of CHD in males was 10.5% (s.d.=8) and in females 7% (s.d.=6).

Conclusions

The lifestyle of people with schizophrenia must give cause for concern in relation to CHD Care from secondary care services must address physical as well as mental health.
Mental health services for war-affected children
Authors: Jones Lynne , Rrustemi Alban , Shahini Mimoza , Uka Aferdita
Published: December 2003

Background

In war-affected societies it is assumed that the major mental health problem facing the population will be stress reactions.

Aims

To describe the creation of a child and adolescent mental health service (CAMHS) in Kosovo after the military conflict ended in 1999, and to establish the range of problems and diagnoses that presented.

Method

Data were collected on 559 patients over 2 years, including their referring problems and diagnoses.

Results

Stress-related disorders constituted only a fifth of the case-load in year 1. A substantial number of patients were symptom-free but attended because they had been exposed to atraumatic event, and believed it might make them ill. Non-organic enuresis and learning disability were the most common diagnoses in year 2. Many patients had a complex mix of social and psychological difficulties that did not fit conventional diagnostic categories.

Conclusions

Mental health services that only address traumatic stress may fail to meet the needs of war-affected children. A comprehensive, culturally appropriate CAMHS is needed to address a wide range of problems including learning disability. It should be developed through local actors, and build on existing local infrastructure. Services can also have an educational role in ‘depathologising’ normative responses.
Mental health and quality of life of gay men and lesbians in England and Wales
Authors: King Michael , McKeown Eamonn , Warner James , Ramsay Angus , Johnson Katherine , Cort Clive , Wright Lucie , Blizard Robert , Davidson Oliver
Published: December 2003

Background

Little is known about the mental health of gay men and lesbians living in Europe.

Aims

To compare psychological status, quality of life and use of mental health services by lesbians and gay men with heterosexual people.

Method

Cross-sectional study in England and Wales using ‘snowball’ sampling.

Results

Participants: 656 gay men, 505 heterosexual men, 430 lesbians and 588 heterosexual women. Gay men were more likely than heterosexual men to score above threshold on the Clinical Interview Schedule, indicating greater levels of psychological distress (RR 1.24, 95% Cl 1.07–1.43), as were lesbians compared with heterosexual women (RR 1.30, 95% Cl 1.11-1.52). Gay men and lesbians were more likely than heterosexuals to have consulted a mental health professional in the past, deliberately harmed themselves and used recreational drugs. Lesbians were more likely to have experienced verbal and physical intimidation and to consume more alcohol than heterosexual women.

Conclusions

Awareness of mental health issues for gay men and lesbians should become a standard part of training for mental health professionals, who need to be aware of the potential for substance misuse and self-harm in this group and of the discrimination experienced by many lesbians.
The ‘Catch-22’ of recruitment and retention in
psychiatry
Authors: O'Connor Susan , Vize Christine
Published: December 2003

As the Medical Director and Deputy Medical Director of the Avon and
Wiltshire Mental Health Partnership Trust, we are responsible for the
recruitment and development of a large number of medical staff. We are also
extensively involved in trying to develop new services in line with the two
National Service Frameworks (NSFs), and other central and local directives.
Discussion with colleagues elsewhere suggests that we are not alone in
experiencing a number of problems, including being hampered by the financial
position of our commissioners and the lack of structural protection for
mental health funding. However, the task is also made more difficult by the
conflicting local and central imperatives from the Royal College of
Psychiatrists and the Department of Health. The current problems facing our
Trust are outlined as an illustration of the more generally experienced
difficulties. Some possible solutions are proposed.
Sodium valproate or valproate semisodium: is there a difference
in the treatment of bipolar disorder?
Authors: Fisher Chris , Broderick Wendy
Published: December 2003

The ‘off licence’ use of drugs is common in the UK. One such use is the
treatment of bipolar disorder with sodium valproate. This paper reviews the
evidence for using the licensed alternative, valproate semisodium, under the
headings of licence, efficacy, pharmacokinetics and tolerability.
Combined antipsychotics for ‘difficult-to-manage’ and forensic
patients with schizophrenia: reasons for prescribing and perceived
benefits
Authors: Haw Camilla , Stubbs Jean
Published: December 2003

Aims and Method

We aimed to examine reasons for initiating and continuing the
prescription of combined antipsychotics. A structured interview was
carried out with the responsible medical officers for 40
‘difficult-to-manage’ tertiary referral patients with schizophrenia who
were regularly treated with two or more antipsychotics.

Results

Lack of efficacy of monotherapy was the main reason for initiating and
continuing combined antipsychotics. Other reasons for continuing combined
antipsychotics included not wishing to change medication as the patient
was reasonably well, and safety considerations. Perceived benefits of
combined antipsychotics included fewer positive symptoms and less
disturbed behaviour.

Clinical Implications

‘Difficult-to-manage’ and forensic treatment-resistant patients with
schizophrenia pose a particular therapeutic challenge. Use of combined
antipsychotics, although not evidence-based, is perceived by some
psychiatrists as beneficial when other options have failed.
Ethnic diversity and equality of access to specialist
therapeutic community treatment for severe personality
disorder
Authors: Geraghty Rosalind , Warren Fiona
Published: December 2003

Aims and Method

All mental health services are expected to aim for equality of access to
people from minority ethnic groups. Psychotherapy services typically have
a low proportion of ethnic minority clients. Specialist services such as
therapeutic communities are no exception. It is also possible that ethnic
minority residents are more likely to leave group treatments early if
they are clearly in the minority. The study examined records between
1996–2000 to ascertain whether ethnic minorities show a different pattern
of exit from the process than people from other backgrounds.

Results

Just over 9% of referrals to Henderson Hospital were from ethnic
minorities. Ethnic minority referrals were less likely to be invited to a
selection interview. However, there was no difference in length of stay
in treatment. There was a trend towards ethnic minority referrals having
more severe symptomatology and histories than those from White
backgrounds.

Clinical Implications

Ethnic background should be taken into account when considering referral
for specialist psychotherapy. Routine monitoring of the processing of
ethnic minority referrals should be conducted in all psychotherapy
services.
A standard liaison psychiatry service structure?
Authors: Ruddy Rachel , House Allan
Published: December 2003

Aims and Method

We surveyed all psychiatric services in the six northeast strategic health authorities to determine how the provision of liaison psychiatry services related to College recommendations and the size of the general hospital trusts served.

Results

Thirty-six (100%) services provided usable data, 8% of general hospital trusts had no liaison psychiatry service, 41% of teams were not multidisciplinary with their only staff being nurses, only 38% of services had dedicated consultant psychiatry time and only a quarter met the recommended minimum standard of 0.5 whole-time equivalents. No teams contained clinical psychologists. Disorder-specific out-patient clinic provision was idiosyncratic.

Clinical Implications

There is a lack of rational planning of liaison psychiatry services and as a result, many services are not needs-based and do not comply with College recommendations. One indication of this is the lack of multidisciplinary teams.
An update on mental health services in Iraq
Authors: Abed Riadh T.
Published: December 2003

In the 1970s, Iraq made strides towards building a comprehensive,
well-equipped health system free at the point of delivery. Medical education
in Iraq was originally modelled on the British system and started with
Baghdad Medical School in 1927. Two more medical schools were founded in
Mosul and Basrah, providing Iraq with good numbers of high-calibre medical
graduates. After 1968, several other medical schools were set up in various
parts of Iraq, including three in Iraqi Kurdistan.
Annual General Meeting
Authors: Shooter Mike , Fairbairn Andrew , Subotsky Fiona , Katona Cornelius , Tait David
Published: December 2003

The 32nd Annual Meeting of the College was held at the Edinburgh
International Conference Centre, Edinburgh from 30 June to 3 July 2003.
Effects of the rate and composition of fluid replacement on the pharmacokinetics and pharmacodynamics of intravenous torasemide
Authors: Kim Yu Chul , Lee Myung Gull , Ko Seong-Hee , Kim So Hee
Published: December 2003

The effects of differences in the rate and composition of intravenous fluid replacement for urine loss on the pharmacokinetics and pharmacodynamics of torasemide were evaluated in rabbits. Each rabbit received 2-h constant intravenous infusion of 1 mg kg−1 torasemide with 0% replacement (treatment 1, n = 6), 50% replacement (treatment 2, n = 9), 100% replacement with lactated Ringer's solution (treatment 3, n = 8), and 100% replacement with 5% dextrose in water (treatment 4, n = 6). Total body (4.53, 5.72, 10.0 and 4.45 mL min−1 kg−1 for treatments 1–4, respectively) and renal clearance (1.44, 1.87, 6.78 and 1.72 mL min−1 kg−1) of torasemide, and total amount of unchanged torasemide excreted in 8-h urine (Ae 0–8 h: 694, 780, 1310 and 1040 μg) in treatment 3 were considerably faster and greater compared with treatments 1, 2 and 4. Although the difference in Ae 0–8 h between treatments 1 and 3 was only 88.8%, the diuretic and/or natriuretic effects of torasemide were markedly different among the four treatments. For example, the mean 8-h urine output was 101, 185, 808 and 589 mL for treatments 1–4, respectively, and the corresponding values for sodium excretion were 10.1, 20.6, 89.2 and 29.9 mmol, and for chloride excretion were 14.5, 27.9, 94.0 and 37.2 mmol. Although full fluid replacement was used in both treatments 3 and 4, the 8-h diuretic, natriuretic and chloruretic effects in treatment 3 were significantly greater compared with treatment 4, indicating the importance of the composition of fluid replacement. Both treatments 1 and 4 received no sodium replacement, however, the 8-h diuretic, natriuretic and chloruretic effects were significantly greater in treatment 4 compared with treatment 1, indicating the importance of rate of fluid replacement for the diuretic effects. Therefore, the 8-h diuretic, natriuretic and chloruretic effects were significantly greater in treatment 3 compared with treatments 1, 2 and 4, indicating the importance of full fluid and electrolyte replacement. Some implications for the bioequivalence evaluation of dosage forms of torasemide are discussed.
Ampicillin micronization by supercritical assisted atomization
Authors: Reverchon E , Porta G Della , Spada A
Published: December 2003

The micronization technique called supercritical assisted atomization (SAA) was used to produce ampicillin microparticles with controlled particle size and particle size distribution suitable for aerosol drug delivery. The process is based on the solubilization of supercritical CO2 in a liquid solution. The ternary mixture is then sprayed through a nozzle and, as a consequence of enhanced atomization, solid microparticles are formed. Water and organic solvents were tested with ampicillin to determine the influence of the solvent on the process mechanism. SAA process parameters were studied by testing different supercritical/liquid solvent flow ratios, ampicillin concentrations in the liquid solution and nozzle diameters. The effect of these parameters on morphology, particle size and particle size distribution of microparticles was analysed. Ampicillin particles suitable for aerosol delivery in the size range 1–5 μm were obtained using buffered water. Moreover, by varying the solute concentration, ampicillin particles in a narrower range (1–3 μm) than that usually suggested for aerosol deliverable drugs were obtained. This is an example of particle size tailoring by SAA.
Potential utility of various protease inhibitors for improving the intestinal absorption of insulin in rats
Authors: Liu Hui , Tang Ren , Pan Wei-San , Zhang Yi , Liu Hong
Published: December 2003

The aim of the investigation was to study the effects of protease inhibitors on the absorption of insulin in-situ from closed small and large intestinal loops in rats and to investigate the mechanism of various protease inhibitors in different intestinal loops. The intestinal absorption of insulin was evaluated by its hypoglycaemic effect and serum insulin level in the presence or absence of luminal contents. No marked hypoglycaemic effect was observed after administration of insulin alone in either region in the presence or absence of luminal contents. A significant hypoglycaemic effect of insulin was obtained in the large intestinal loop in the presence or absence of luminal contents when insulin was co-administered with bacitracin (20, 30 mM), sodium glycocholate (20, 40 mM), bestatin (29 mM), leupeptin (21 mM) and cystatin (0.8 mM). In contrast, there was no hypoglycaemic effect in the small intestinal loop in the presence of luminal contents following small intestinal co-administration of insulin with these protease inhibitors. The effectiveness of protease inhibitors was susceptible to their categories, concentrations and activity of proteolytic enzymes in different regions. The degree of improving insulin absorption in intestine was in the order of leupeptin > sodium glycocholate > bacitracin > bestatin > cystatin. At the same time, the percutaneous enhancement effect was observed in the presence of either sodium glycocholate or bacitracin. These results suggest that protease inhibitors could increase the insulin efficacy more effectively in the large intestine than in the small intestine.
The in-vivo effects of sho-saiko-to, a traditional Chinese herbal medicine, on two cytochrome P450 enzymes (1A2 and 3A) and xanthine oxidase in man
Authors: Saruwatari Junji , Nakagawa Kazuko , Shindo Junichi , Nachi Shinobu , Echizen Hirotoshi , Ishizaki Takashi
Published: December 2003

The Chinese herbal medicine sho-saiko-to is a mixture of seven herbal components (Bupleurum root, Pinellia tuber, Scutellaria root, Jujube fruit, Ginseng root, Glycyrrhiza root and Ginger rhizome) that is widely administered to patients with chronic hepatitis in Japan. We assessed the effects of sho-saiko-to on the activity of cytochrome P450 (CYP) 1A2, CYP3A and xanthine oxidase (XO) in man. Twenty-six healthy subjects were studied to evaluate their baseline activity of CYP1A2 and XO by the respective urinary metabolic ratios of an 8-h urine sample after an oral 150-mg dose of caffeine and of CYP3A by a urinary excretion ratio of 6β-hydroxycortisol (6β-HC) to free cortisol (FC). Thereafter, the subjects received a twice-daily 2.5-g dose of sho-saiko-to for five days, and underwent the caffeine test on day 1 and day 5. The mean activity of CYP1A2 decreased by 16% on both day 1 and day 5 compared with the baseline (P = 0.001). The mean activity of XO also significantly decreased by 25% on day 1 and 20% on day 5 (P < 0.0001) compared with the baseline value. The activity of CYP3A tended to be lower on day 5 than the baseline (P = 0.146). It is concluded that sho-saiko-to reduces CYP1A2 and XO activity in man.
Effects of oxygen plasma treatment on the surface wettability and dissolution of furosemide compacts
Authors: Naseem A , Olliff C J , Martini L G , Lloyd A W
Published: December 2003

The plasma irradiation of furosemide (frusemide) was investigated as a possible technique for increasing the dissolution rate of this drug. Oxygen plasma was used to generate oxygen-containing functional groups on the surface of the compact to increase the wettability of the surface and the dissolution rate of the drug. Compacts of furosemide (300 mg) were produced using a stainless steel die and punch assembly, which was placed into a KBr press. The time of the plasma treatment was varied to assess the effect if any upon the dissolution rate and the wettability of the drug. Dissolution experiments of the plasma-treated and untreated compacts were carried out using the paddle apparatus method. Dissolution was carried out at 37°C using 1 L of 0.1 M HCl and phosphate buffer (pH 6). The wettability was assessed by contact angle measurements using the sessile drop technique. Untreated and plasma-treated samples were analysed by scanning electron microscopy at × 5000 magnification. Plasma treatment was found to lower the equilibrium contact angle from approximately 50 to 35° but the dissolution rate was not significantly affected. This was attributed to fusion of the surface by the plasma treatment.
Non-genomic effects of tamoxifen on the activation of membrane-bound guanylate cyclase GC-A
Authors: Chen Zi-Jiang , Vetter Michael , Chang Geen-Dong , Liu Shiguo , Ding Yaxian , Chang Chung-Ho
Published: December 2003

Oestrogen is known to exert both genomic and non-genomic effects on target tissues. Unlike the genomic effects, the identity of receptors mediating the non-genomic effects of oestrogen remains controversial. 17β-Estradiol has been shown to activate membrane-bound guanylate cyclase GC-A in PC12 cells in a non-genomic manner. To examine whether 17β-estradiol exerts a similar effect in other cell types, we measured the effect of 17β-estradiol and tamoxifen, an anti-oestrogen, on guanylate cyclase activity in porcine kidney proximal tubular LLC-PK1 cells. 17β-Estradiol increased cGMP levels in LLC-PK1 cells. Interestingly, addition of tamoxifen also increased cGMP levels in a concentration-dependent manner in LLC-PK1 cells. The effects of both 17β-estradiol and tamoxifen on guanylate cyclase activity were not additive, suggesting that oestrogen and tamoxifen activate the same enzyme. Similar phenomena were also observed in LLC-PK1 cell membrane preparation. LLC-PK1 cells do not express membrane-bound guanylate cyclase GC-B and express low levels of membrane-bound guanylate cyclase GC-C. Tamoxifen inhibited the activation of GC-A by atrial natriuretic factor (ANF). However, it did not affect membrane-bound guanylate cyclase GC-C stimulated by guanylin or Escherichia coli heat-stable toxin STa. These results indicate that 17β-estradiol and tamoxifen activate GC-A in LLC-PK1 cells. Thus, tamoxifen functions as an agonist rather than an antagonist for the membrane oestrogen receptor coupled to the activation of GC-A.
Long-term administration of Salvia miltiorrhiza ameliorates carbon tetrachloride-induced hepatic fibrosis in rats
Authors: Lee Tzung-Yan , Wang Guei-Jane , Chiu Jen-Hwey , Lin Han-Chieh
Published: December 2003

Carbon tetrachloride (CCl4) is metabolized by cytochrome P450 to form a reactive trichloromethyl radical that triggers a chain of lipid peroxidation. These changes lead to cell injury, and chronic liver injury leads to excessive deposition of collagen in liver, resulting in liver fibrosis. The aim of this study was to evaluate the effects of long-term Salvia miltiorrhiza administration in CCl4-induced hepatic injury in rats. Salvia miltiorrhiza (10, 25 or 50 mg kg−1 twice a day) was given for 9 weeks, beginning at the same time as the injections of CCl4. Rats receiving CCl4 alone showed a decreased hepatic glutathione level and an increased glutathione-S-transferase content. The hepatic thiobarbituratic acid-reactive substance levels were increased. CCl4 also caused a prominent collagen deposition in liver histology that was further supported by the increased hepatic mRNA expression of transforming growth factor-β1, tissue inhibitor of metallproteinase-1 and procollagen I. Salvia miltiorrhiza administration led to a dose-dependent increase in hepatic glutathione levels and a decrease in peroxidation products. Additionally, it reduced the mRNA expression of markers for hepatic fibrogenesis. In conclusion, long-term administration of Salvia miltiorrhiza in rats ameliorated the CCl4-induced hepatic injury that probably related to a reduced oxidant stress and degree of hepatic fibrosis.
Evaluation of the bitterness of antibiotics using a taste sensor
Authors: Uchida Takahiro , Tanigake Atsu , Miyanaga Yohko , Matsuyama Kenji , Kunitomo Masaru , Kobayashi Yoshikazu , Ikezaki Hidekazu , Taniguchi Akira
Published: December 2003

The bitterness of nine commercial antibiotics (clarithromycin, erythromycin, cefdinil, doxycycline, vancomycin, tetracycline, minocycline, oxytetracycline and bacampicillin) was evaluated in human gustatory sensation tests with nine volunteers. The bitterness of 0.1–0.3 mM solutions (or suspensions in the case of clarithromycin) of the antibiotics was then measured using an artificial multichannel taste sensor. In the sensor measurements, three variables were used to predict estimated bitterness in single and multiple regression analysis and principal component analysis: sensor output as relative value (R), the change of membrane potential caused by adsorption (C) and C/R. Particularly good correlation was obtained between obtained bitterness scores and predicted scores using C from channel 2 of the sensor (r2 = 0.870, P < 0.005) and C/R values for channels 2 and 3 (r2 = 0.947, P < 0.005). The taste sensor was also successful in assessing the bitterness intensity of clarithromycin powder suspensions of various concentrations. Clarithromycin has a low aqueous solubility but is the most bitter of the nine antibiotics. Sensory data from channel 3 of the sensor predicted the bitterness of clarithromycin powder suspensions and their filtered solutions well. Finally, the bitterness intensity of a commercial clarithromycin dry syrup product (Clarith dry syrup, Taisho Pharmaceutical Co. Ltd, Tokyo, Japan) was evaluated in gustatory sensation tests and using the taste sensor. In Clarith dry syrup the drug is coated with aminoalkyl methacrylate polymer using a spray congealing method. The taste sensor results confirmed that the polymer was successful in almost completely masking the bitter taste of the dry syrup product.
Persistent reversal of P-glycoprotein-mediated daunorubicin resistance by tetrandrine in multidrug-resistant human T lymphoblastoid leukemia MOLT-4 cells
Authors: Liu Zhen-Li , Hirano Toshihiko , Tanaka Sachiko , Onda Kenji , Oka Kitaro
Published: December 2003

Multidrug resistance (MDR) represents a major problem in cancer chemotherapy. P-glycoprotein (P-gp), the drug efflux pump that mediates this resistance, can be inhibited by compounds with a variety of pharmacological functions, thus circumventing the MDR phenotype. The present study was performed to evaluate a unique MDR-reversal feature of a bisbenzylisoquinoline alkaloid tetrandrine (TET) in a P-gp expressing MOLT-4 MDR line (MOLT-4/DNR) established in our laboratory. Cell viability was determined by an MTT assay. P-gp function was characterized by determining the Rh123 accumulation/efflux capacity. P-gp overexpression in resistant MOLT-4/DNR cells was confirmed by flow cytometry analysis after staining with phycoerythrin-conjugated anti-P-gp monoclonal antibody 17F9. Compared to ciclosporin A (CsA), TET exhibited stronger activity to reverse drug resistance to daunorubicin (DNR), vinblastine (VLB) and doxorubicin (DOX) in MOLT-4/DNR cells. TET showed no cytotoxic effects on parental MOLT-4 cells lacking P-gp expression or on the resistant MOLT-4/DNR cells. TET modulated DNR cytotoxicity even after it was washed with the medium for 24 h, while CsA almost completely lost its reversal capability 24 h after washing. TET and CsA similarly increased the accumulation of Rh123 in resistant MOLT-4/DNR cells. However, TET inhibited Rh123 efflux from resistant cells even after washing with the medium, while CsA rapidly lost its ability to inhibit Rh123 efflux after washing. The current study suggests that TET enhances the cytotoxicity of anticancer drugs in the P-gp expressing MDR cell line by modulating P-gp in a different manner to the well-known P-gp inhibitor CsA.
Repetitive administration of Shaoyao-Gancao-tang to rats restores the bioavailability of glycyrrhizin reduced by antibiotic treatment
Authors: He Ju-Xiu , Akao Teruaki , Tani Tadato
Published: December 2003

Shaoyao-Gancao-tang (SGT), a traditional Chinese formulation, is often used together with antibiotics such as amoxicillin and metronidazole (AMPC-MET) for the treatment of peptic ulcers in Japan. However, the bioavailability of glycyrrhizin (GL) in SGT is severely reduced by a single administration of AMPC-MET, and the reducing effect continues for 12 days. GL is one of the major pharmacologically important glycosides in SGT and is transformed into the active metabolite 18β-glycyrrhetic acid (GA) by intestinal bacteria in the gut, followed by absorption of the latter into the blood. In order to reduce the negative effect of AMPC-MET on the bioavailability of GL, the optimum scheduling of the medications was examined. We found that the reduction in the plasma GA concentration and the GL-metabolizing activity in faeces caused by a single dose of AMPC-MET could be sharply attenuated by the repetitive administration of SGT for 4 days. The GA concentration and the GL-metabolizing activity were strongly enhanced by further continuous administration of SGT. These findings suggest that repetitive administration of SGT starting 1 or 2 days after the administration of AMPC-MET speeds the recovery of the bioavailability of GL in SGT. Similar strategies for administering medications may also be useful for combination therapy of antibiotics with other traditional Chinese formulations containing bioactive glycosides.
Magnetic resonance imaging study of the transport phenomena of solvent into the gel layer of hypromellose matrices containing tetracycline hydrochloride
Authors: Tritt-Goc Jadwiga , Kowalczuk Joanna , Pislewski Narcyz
Published: December 2003

Magnetic resonance imaging was used to study the diffusion of a water solution of hydrochloric acid into hypromellose (hydroxypropylmethylcellulose) matrices. Spatially resolved information was obtained about the self-diffusion coefficient and spin–spin relaxation time of solvent protons in the gel layer of hypromellose matrices loaded with different amounts of tetracycline hydrochloride. The data showed the influence of the drug concentration on the diffusion and spin–spin relaxation. Higher drug concentrations in the hypromellose matrix led to greater swelling of the matrix and faster diffusion of the water molecules inside the gel layer of the polymer. The observed differences between the radial and axial diffusion were interpreted in terms of the stresses imposed in the axial direction during the compression of the samples. The spin–spin and diffusion profiles indicated that the diffusion of a water solution of hydrochloric acid into hypromellose, pure and loaded with different amounts of tetracycline hydrochloride, was characterized as a Case II mechanism.
Significance of measured elevation of skin temperature induced by calcitonin gene-related peptide in anaesthetized rats
Authors: Noguchi Masamichi , Ikarashi Yasushi , Yuzurihara Mitsutoshi , Kase Yoshio , Takeda Shuichi , Aburada Masaki
Published: December 2003

To assess whether peripheral changes related to skin temperature rise were induced by ovarian hormone deficiency, we investigated the effects of anaesthesia on calcitonin gene-related peptide (CGRP)- or luteinizing hormone-releasing hormone (LH-RH)-induced elevation of skin temperature in female rats. CGRP was used as an inducer of peripherally-mediated elevation of skin temperature, whereas LH-RH was used as an inducer of centrally-mediated elevation of skin temperature. Intravenous (i.v.) but not intracerebroventricular injection of CGRP (10 μg kg−1) or intracerebroventricular but not intravenous injection of LH-RH (10 μg/rat) elevated the skin temperature of unanaesthetized rats restrained in a Ballman's cage. The elevation with LH-RH was completely inhibited by urethane anaesthesia, whereas the elevation with CGRP was not. These results suggested that changes in skin temperature measured under anaesthesia reflected a peripherally rather than a centrally mediated mechanism. The CGRP (1.0–30 μg kg−1, i.v.)-induced elevation of skin temperature was potentiated in ovariectomized rats and inhibited by pretreatment with a CGRP receptor antagonist CGRP8–37 (1000 μg kg−1, i.v.), suggesting that the potentiation may participate in peripheral factors such as a postsynaptic hypersensitivity to CGRP following ovarian hormone deficiency. Thus, measurement of skin temperature in the anaesthetized rat was a useful procedure to seek the peripheral mechanism of potentiation of skin temperature induced by CGRP, thought to be closely related to menopausal hot flashes.
Inhibitory effect of salmosin, a Korean snake venomderived disintegrin, on the integrin αv-mediated proliferation of SK-Mel-2 human melanoma cells
Authors: Chung Kwang-Hoe , Kim Sung-Hoon , Han Kyu-yeon , Sohn Young-Doug , Chang Soo-Ik , Baek Kwang-Hyun , Jang Yangsoo , Kim Doo-Sik , Kang In-Cheol
Published: December 2003

We have investigated the inhibitory effect of salmosin on integrin-mediated human tumour cell proliferation. SK-Mel-2 human melanoma cell adhesion to denatured collagen or vitronectin was found to be significantly and statistically inhibited by salmosin in a dose-dependent manner (P < 0.05). Moreover, the binding of SK-Mel-2 cells to salmosin-coated plates was specifically disrupted by anti-integrin αv monoclonal antibody at 8αg mL−1, but not by anti-integrin monoclonal antibody. These findings indicated that salmosin inhibited the adhesion of SK-Mel-2 cells to denatured collagen by specifically blocking integrin αv. The proliferation of SK-Mel-2 cells on a denatured collagen-coated plate was statistically and significantly inhibited by salmosin induced apoptosis in a dose-dependent manner (P < 0.05). Anti-integrin αv monoclonal antibody, anti-integrin αvβ3 monoclonal antibody, and synthetic RGD peptide also suppressed SK-Mel-2 cell proliferation. Several lines of experimental evidence strongly suggested that the inhibition of SK-Mel-2 cell proliferation by salmosin was due to the induction of apoptosis via the blocking of integrin αv-mediated cell survival.
Kinetic studies of the degradation of an aminopenicillin antibiotic (amoxicillin trihydrate) in aqueous solution using heat conduction microcalorimetry
Authors: Chadha R , Kashid N , Jain D V S
Published: December 2003

Recent developments in isothermal microcalorimetry allow the direct determination of kinetic and thermodynamic parameters for slow reactions from studies conducted at appropriate temperatures and under designated environmental control. The degradation kinetics of amoxicillin trihydrate has been investigated as a function of pH (1–10) and temperature (303.15–318.15 K) at 0.5 M ionic strength using heat conduction microcalorimetry. Equations were developed incorporating calorimetric accessible data, rate constants and change in enthalpy, which showed that the degradation of amoxicillin trihydrate in aqueous solution followed pseudo-first-order kinetics under our experimental conditions. The enthalpy of degradation reaction was found to be exothermic in nature. The values of the rate constant k for individual steps were determined from the values of the overall rate constants at different pH. Energy of activation of overall reaction as a function of pH and for individual rate constants was determined. The log k-pH profiles indicated specific-acid and specific-base catalysis and there were inflection points near pH 3 and pH 7 corresponding to the pKa1 and pKa2 values. Quantitatively, there was good correlation between calorimetric determined half-life (t1/2) and the literature value in the acidic region determined by other methods at 310.15 K. The presence of a β-lactam ring and of an α-amino group in the C-6 side chain played a critical role in the degradation of amoxicillin trihydrate and the zwitterionic form of the drug was found to be more stable.
Metabolites of orally administered Magnolia officinalis extract in rats and man and its antidepressant-like effects in mice
Authors: Nakazawa Takahiro , Yasuda Takaaki , Ohsawa Keisuke
Published: December 2003

As a part of our search for the active metabolite from the bark of Magnolia officinalis (Magnoliaceae), the aqueous extract was orally administered to rats, and metabolites in the urine were analysed by a high-performance liquid chromatograph equipped with a photodiode array detector. When the extract was given to rats, five metabolites (sinapic acid-4-O-sulfate (1), sinapic acid-4-O-β-glucuronide (2), sinapic acid (3), 3-[2′,6-dihydroxy-5′-(2-propenyl)[1,1′-biphenyl]-3-yl]-(E)-2-propenoic acid (4), and an unchanged form, magnolol (5)) were detected in the urine. It was revealed that metabolites 1–3 and 4 were respectively derived from syringin and magnolol contained in the extract. In a human urine sample, metabolites 3–5 and dihydroxydihydromagnolol (6) were detected. These structures were identified by a combination of spectral methods and/or by comparison with authentic compounds obtained by synthesis. Among these free form metabolites (3–6), acute treatments with magnolol and dihydroxydihydromagnolol (50–100 mg kg−1, i.p.) attenuated the forced swim-induced experimental depression in mice. The results indicated that magnolol and dihydroxydihydromagnolol were the antidepressant constituents of Magnolia officinalis.
Transdermal iontophoresis of insulin. Part 1: A study on the issues associated with the use of platinum electrodes on rat skin
Authors: Pillai Omathanu , Kumar Naresh , Dey Chinmoy Sankar , Borkute Suresh , Nagalingam Sivaprasad , Panchagnula Ramesh
Published: December 2003

We have studied the issues associated with the use of platinum electrodes for transdermal iontophoretic delivery of peptides, using insulin as a model peptide. Insulin permeation was studied using full-thickness rat skin by varying the donor solution pH as a function of electrode polarity. The stability of insulin under the iontophoretic conditions was studied using TLC, SDS-polyacrylamide gel electrophoresis and HPLC. Large pH shifts were observed during anodal iontophoresis (AI), when the donor solution pH was above the isoelectric point of insulin and in cathodal iontophoresis (CI), when the donor solution pH was below the isoelectric point of insulin. The direction and magnitude of electroosmotic flow was influenced by pH of the donor solution and the electrode polarity. On the other hand, the buffer used to maintain the pH governed the contribution of electrorepulsion to the overall transport of insulin. Electrochemical degradation of insulin was significant during Al at pH 7.4. Among the pH investigated, Al of insulin at pH 3.6 and Cl at pH 8.35 were better, as the pH shift was relatively less and electrochemically more stable during iontophoresis as compared with other pH. In summary, the pH shift caused by platinum electrodes had a significant influence on the permeation and stability of insulin.
The potential of chitosan in ocular drug delivery
Authors: Alonso María José , Sánchez Alejandro
Published: December 2003

This paper presents an overview of the potential of chitosan-based systems for improving the retention and biodistribution of drugs applied topically onto the eye. Besides its low toxicity and good ocular tolerance, chitosan exhibits favourable biological behaviour, such as bioadhesion- and permeability-enhancing properties, and also interesting physico-chemical characteristics, which make it a unique material for the design of ocular drug delivery vehicles. The review summarizes the techniques for the production of chitosan gels, chitosan-coated colloidal systems and chitosan nanoparticles, and describes their mechanism of action upon contact with the ocular mucosa. The results reported until now have provided evidence of the potential of chitosan gels for enhancing and prolonging the retention of drugs on the eye surface. On the other hand, chitosan-based colloidal systems were found to work as transmucosal drug carriers, either facilitating the transport of drugs to the inner eye (chitosan-coated colloidal systems containing indometacin) or their accumulation into the corneal/conjunctival epithelia (chitosan nanoparticles containing ciclosporin). Finally, the tolerance, toxicity and biodegradation of the carriers under evaluation were reviewed.