bluuebunny/crossref_metadata_2025 huggingface dataset:
Quality of life as a parameter determining therapeutic choices in cancer care in a Greek sample
Authors: Mystakidou Kyriaki , Tsilika Eleni , Befon Sofia , Kululias Vasilios , Vlahos Lambros
Published: May 2003

Health-related quality of life (HRQL) is difficult to define and measure. It is a generic term that includes concepts such as physical health, life satisfaction, psychological well-being and self-integrity. Realizing and appreciating the importance of HRQL is crucial for physicians if they are to be in a position to offer appropriate suggestions in assisting patients and their families in the decision-making process regarding cancer treatment and terminal care. In order to determine whether Greek physicians take into consideration HRQL when assessing different therapeutic options, we conducted a postal survey. A total of 1500 Greek physicians (internists, oncologists and anaesthesiologists) were asked to complete a questionnaire. We received replies from 1280 (85%). In summary, we found that Greek physicians: (1) have already started taking HRQL into consideration when reviewing their therapeutic options; (2) increasingly include HRQL in research studies as an outcome measure; (3) do not yet have thoroughly sufficient training in the holistic care of cancer patients and their families; (4) mostly do not have the opportunity to work in interdisciplinary therapeutic teams where they can exchange ideas and consider different aspects of alternative therapeutic methods.

It is concluded that HRQL has already been introduced as an important determinant of therapeutic choices in cancer care in Greece. However, efforts need to be made to allow HRQL to enjoy its appropriate place in cancer care.
The role of endoscopic biliary stents in palliative care
Authors: Roth L J , Pugh E J
Published: May 2003

This article reviews the role of endoscopic biliary stents in palliative care. In particular it focuses on the indications for stents, and recognition and management of possible complications. These issues are illustrated with three case reports.
Screening for psychiatric illness in the palliative care inpatient setting: a comparison between the Hospital Anxiety and Depression Scale and the General Health Questionnaire-12
Authors: Le Fevre Peter , Devereux Joan , Smith Stephen , Lawrie Stephen M , Cornbleet Michael
Published: May 2003

The objective of this study was to compare the performance of the Hospital Anxiety and Depression Scale (HADS) with the 12-item General Health Questionnaire (GHQ-12) as a screening instrument for the detection of psychiatric disorders in a palliative care inpatient setting. The results from the HADS and GHQ were compared to diagnoses generated from a semistructured psychiatric interview (Revised Clinical Interview Schedule) using standard receiver operating characteristic analysis. The study was conducted at the Marie Curie Centre, Edinburgh, a 37-bedded palliative care inpatient facility. Out of a total of 282 admissions during the study period, 79 took part in the study. The remainder of patients either refused (69) or were too unwell to participate (134).

The HADS was found to be an effective screening tool for identifying depression, with an area under the receiver operating characteristic curve of 0.92. A suggested cut-off of 20 would have a sensitivity of 0.77, a specificity of 0.85 and a positive predictive value (PPV) of 0.48. There was no significant difference between the two subscales in their ability to detect depressive illnesses, although there was a trend for the anxiety subscale to perform better (P < 0.15). The GHQ did not perform as well as the HADS in this type of population. In view of this, it can be concluded that the HADS is a valid screening tool for psychiatric disorders, particularly depression, in a palliative care setting.
Descriptive epidemiological survey on a given day in all palliative care patients hospitalized in a French university hospital
Authors: Morize Véronique , Nguyen Duc Tinh , Lorente Christine , Desfosses Gilbert
Published: May 2003

We conducted a descriptive study on a given day on all inpatients requiring palliative care in a French university hospital. In each department, a collaborative team made up of physicians and nurses identified and described the clinical signs, the treatment protocols, the social and family characteristics and the outcome for each patient using a standardized questionnaire. Study subjects were inpatients in the hospital and presented advanced or terminal-stage life-threatening conditions. Two-hundred-and-forty-five patients were included in the study. These patients represented 13% of the total number of inpatient beds available in the hospital on the day of the survey. Sixty-six per cent of study subjects suffered from physical discomfort and 80% suffered psychologically. Patients still received specific treatment for their condition in 45% of cases.

Social problems were identified principally in medium- or long-term care department inpatientswho made up 36% of the total inpatient population.

A request for transfer to another care structure had been completed for 24% of patients. Assistance from the Palliative Care Unit's support team had been requested in 25% of cases, mainly to provide psychological support for the patient and the health care providers.

These results have led us to reconsider the general organization of palliative care in the health care system.
Improving palliative care services: a pragmatic model for evaluating services and assessing unmet need
Authors: Wiles Rose , Payne Sheila , Jarrett Nicola
Published: May 2003

Evaluating local palliative care services and identifying gaps in services for patients are crucial to the development of services which enable people to die at home in a well-supported environment. A review of the local strategy for providing respite and support services for palliative care patients and their carers was carried out in one area of south-east England. The review comprised four elements: identification of services available; interviews with provider ‘stakeholders’; interviews with patients and carers; questionnaire survey of general practitioners and district nurses. The findings and outcome are described. It is suggested that this approach could be adopted by health authorities to form one part of a comprehensive system of needs assessment. Alternatively, it could be used by groups of providers to evaluate existing services and to identify potential improvements to services. Advantages and disadvantages of the approach for both commissioners of such reviews and those carrying them out are discussed.
A survey of nursing and medical staff views on the use of cardiopulmonary resuscitation in the hospice
Authors: Thorns A R , Ellershaw J E
Published: May 2003

Research evidence suggests that cardiopulmonary resuscitation (CPR) would be indicated in very few hospice patients. However, with the increasing access and expansion of specialist palliative care services the question of CPR is becoming more important. In order to develop a policy in our unit we felt it was important to assess the understanding, attitudes and experience of the health care professionals involved. A semi-structured questionnaire regarding CPR issues, including case scenarios, was distributed to doctors and registered nurses in a palliative care unit. Thirty-seven (80%) of the questionnaires were returned. Ten per cent of respondents identified patients for whom they felt CPR would have been indicated in the event of an unexpected cardiac arrest. Thirty-two per cent could foresee the number of patients in this category increasing in the future. The majority of respondents indicated that CPR should be discussed in certain cases, however 86% had never done so. The success rate of CPR was frequently overestimated. Some respondents felt vulnerable as there was no existing written policy. Factors thought important in making decisions regarding CPR orders included: prognosis; patient's wishes; quality of life; and legal issues. CPR in palliative care units raises many practical and ethical concerns. Our survey shows that staff are aware of the small, but increasing, need for its consideration in certain cases. There was a wide range of views regarding the role of CPR with an overestimation of the chances of success and concerns regarding discussion of the issue with patients. When introducing a CPR policy in a palliative care unit, adequate education and a framework for decision making is required.
Folklore associated with dying in the west of Ireland
Authors: Donnelly Sinead
Published: May 2003

The warm welcome for modern advances in the care of the dying should not exclude the past in which there is much to be learned from the skills of our ancestors.

A bilingual two-year qualitative research project into traditions associated with dying and death was undertaken. Research began in the archives available in the internationally recognized university folklore departments of Ireland and Scotland. This was augmented by 40 indepth personal interviews with Gaelic- and English-speaking residents in rural communities of both countries, recalling local customs and practices in the care of the dying. This paper reports the Irish experience; the collection of data in Scotland continues.

From this study, several main themes emerged. Death was seen and accepted as a natural continuation of life, simply a step into the spirit world. In view of people's oneness with nature and the spiritual world, death was not to be feared. Traditions were unique to each area even down to the precise number of candles used at the sickbed. People understood the signs and symptoms of dying and were skilled in alleviating the distress of both relatives and the dying; and, in this, language was important in capturing and expressing the philosophy of these people. The acceptance of death as the one truism of life was facilitated by the strong faith and prayer of people for whom, in the celebration of death, humour was never far away. In their grief, the community was supported by the loose formality of the wake (torramh), funeral procession, keening (caoineadh) and music. In all these, the men and women of the community and its leaders had distinct and respected roles to play.
How do terminally ill patients at home take their medication?
Authors: Zeppetella Giovambattista
Published: May 2003

Compliance with prescribed medication was assessed in 111 terminally ill patients referred to a community palliative care team using semistructured interviews and pill counting. One-hundred-and-six patients were prescribed a total of 597 drugs; of these patients, 64 (60%) were noncompliant.

Thirty-five patients (33%) took less medication than prescribed, usually due to experiencing, or anxieties about, adverse events; the commonest drugs involved were analgesics. Seventeen patients (16%) took additional medication, usually purchased over the counter in response to inadequate symptom control or to adverse events from other drugs; the most common preparations were vitamins and analgesics. Twelve patients (11%) both took less medication than prescribed and also purchased medication over the counter.

Most patients (90%) had two or more prescribers; patients who saw their general practitioners as their main prescriber were more likely to adhere to their prescribed medication. Patients who omitted and/or reduced their medication were more likely to see the hospital as their main prescriber. Drugs prescribed four times daily were most likely to be omitted and/or reduced.
A comparison of patient and proxy symptom assessments in advanced cancer patients
Authors: Nekolaichuk Cheryl L , Bruera Eduardo , Spachynski Kathy , MacEachern Tara , Hanson John , Maguire Thomas O
Published: May 2003

The purpose of this study was to compare patient and proxy (physician and nurse) assessments of symptoms in advanced cancer patients. The sample consisted of 49 patients with advanced cancer admitted to an acute palliative care unit. Three independent assessments were completed for each patient on two occasions within 11 days of admission. On each occasion, symptoms were rated independently by the patient and two proxies (treating physician and nurse), using the Edmonton Symptom Assessment System (ESAS). The ESAS is a nine-item visual analogue scale (VAS) for assessing pain, activity, nausea, depression, anxiety, drowsiness, appetite, well-being and shortness of breath. Symptom ratings were compared using a repeated-measures ANOVA procedure and correlations. Average physician ratings were generally lower than average patient ratings for both occasions. Average nurse ratings agreed more closely with patient ratings, with a trend towards lower ratings on occasion 1 and higher ratings on occasion 2. There was a significant rater (person rating the effects) effect (P < 0.01) for three of the nine symptoms: physicians rated drowsiness, shortness of breath and pain significantly lower than patients. For drowsiness and shortness of breath, these differences were clinically relevant, representing a difference of more than 12 mm on a 100-mm VAS. The accuracy of assessments amongst those rating the symptoms did not improve over time. Proxy assessments of symptom intensity, particularly by physicians, were significantly lower than patient assessments for three of the nine symptoms. Further research regarding the reliability of patient and proxy assessments is needed to assess and manage symptoms in advanced cancer effectively.
Optimizing hospital-based home care for dying cancer patients: a population-based study
Authors: Rosenquist Anders , Bergman Kristina , Strang Peter
Published: May 2003

In many reports the percentage of home deaths in cancer is based on selected populations. In this population-based study all cancer patients who died within 12 months within a specified area were studied ( n=108). This area is covered by hospital-based home care (HBHC) on a 24-h basis, with doctors available by day and at night. Forty people (37%) out of the total cancer population died in their own homes. Another 11% would theoretically have been ideal candidates for home care at the end of life. Thus, a home death rate of about 50% of the cancer patients is a realistic figure, and much higher than the usual 5–15% reported, provided that an effective HBHC is offered.
A survey of antidepressant prescribing in the terminally ill
Authors: Lloyd-Williams Mari , Friedman Trevor , Rudd Nicky
Published: May 2003

Depression is a symptom in a quarter of patients admitted to a palliative care unit, but little is known of how depression in terminally ill patients is treated. We reviewed 1046 consecutive patient admissions, of whom 106 (10%) were prescribed antidepressant medication while under the care of a palliative care team. Of these patients, 21 were prescribed antidepressants when under the care of the home care team, but 80 patients (76%) were started on medication during the final 2 weeks of life. There was consequently insufficient time for the medication to have any therapeutic effect.

Seventeen patients were discharged home on antidepressant medication. Three patients were referred for a psychiatric assessment. Patients prescribed antidepressants were significantly younger (P = 0.002) than those who were not. There were no prescriptions for psychostimulants. Although the numbers of patients prescribed antidepressant medication were low in all disease groups, it was notable that patients with breast cancer were prescribed antidepressant medication more frequently than any other patient group. We conclude that there appears to be a need for a coordinated approach to both the assessment and the treatment of depression in terminally ill patients.
An evaluation of aromatherapy massage in palliative care
Authors: Wilkinson Susie , Aldridge Judith , Salmon Irene , Cain Elizabeth , Wilson Bernadette
Published: May 2003

The use of complementary therapies, such as massage and aromatherapy massage, is rising in popularity among patients and healthcare professionals. They are increasingly being used to improve the quality of life of patients, but there is little evidence of their efficacy. This study assessed the effects of massage and aromatherapy massage on cancer patients in a palliative care setting. We studied 103 patients, who were randomly allocated to receive massage using a carrier oil (massage) or massage using a carrier oil plus the Roman chamomile essential oil (aromatherapy massage). Outcome measurements included the Rotterdam Symptom Checklist (RSCL), the State–Trait Anxiety Inventory (STAI) and a semi-structured questionnaire, administered 2 weeks postmassage, to explore patients' perceptions of massage.

There was a statistically significant reduction in anxiety after each massage on the STAI (P < 0.001), and improved scores on the RSCL: psychological (P < 0.001), quality of life (P < 0.01), severe physical (P < 0.05), and severe psychological (P < 0.05) subscales for the combined aromatherapy and massage group. The aromatherapy group's scores improved on all RSCL subscales at the 1% level of significance or better, except for severely restricted activities. The massage group's scores improved on four RSCL subscales but these improvements did not reach statistical significance.

Massage with or without essential oils appears to reduce levels of anxiety. The addition of an essential oil seems to enhance the effect of massage and to improve physical and psychological symptoms, as well as overall quality of life.
The role of morphine glucuronides in cancer pain
Authors: Mercadante Sebastiano
Published: May 2003

Morphine metabolites are involved in various ways in determining the complex effects of morphine, both favourable and adverse, and may complicate the clinical use of morphine in the treatment of cancer pain. The production and effects of the principal morphine metabolites, morphine-3-glucuronide and morphine-6-glucuronide, in both normal and pathological states have been reviewed in the current literature. Therapeutic implications are also reviewed on the basis of experimental and clinical reports. The presence of these metabolites should be recognized in the chronic treatment of cancer pain with morphine, especially in the presence of renal impairment, and should be considered to have an important influence on opioid responsiveness, defined as a balance between the achievement of an optimal analgesia and the occurrence of adverse effects.
Documenting War and Forging Reputations: Sir Max Aitken and the Canadian War Records Office in the First World War
Authors: Cook Tim
Published: May 2003

Although the Canadian Corps was one of the finest fighting formations on the Western Front during the First World War and earned a reputation as the shock troops of the British Expeditionary Force, the Corps had an active propaganda campaign that publicized Canadian uniqueness throughout the war.

The organization behind this promotion was the Canadian War Records Office, headed by Sir Max Aitken, who nurtured a relentless campaign extolling the heroic deeds of Canadians in France. With an eye on the future, Aitken ensured that the image constructed of the Canadian soldier was not only based in battlefield accomplishments but also articulated through the legacy of war records and a barrage of media productions.
Development of a pharmacist-coordinated system of chemotherapy protocols in an integrated healthcare delivery organization
Authors: L de Lemos Mário , O’Brien Robin K
Published: May 2003

Objectives. To develop and coordinate protocols for chemotherapy regimens in a large integrated healthcare organization; to disseminate protocols in a timely fashion; to maintain protocols for continuous quality improvement; and to promote utilization of protocol-based chemotherapy.

Methods. Two interdisciplinary groups reviewed the acceptability, accessibility, and appropriateness of the existing protocols, and proposed recommendations to be implemented by the Systemic Therapy Program of the agency.

Results. A standard protocol format and a pharmacist-coordinated protocol system were developed. Protocols were relocated from the Intranet to the network computer directory and Internet website for increased accessibility. To date, 172 protocols are available on the network directory and the website, with 87% (150/172) reviewed by pharmacists and physicians of an interdisciplinary review panel. Preliminary analysis shows increased healthcare professionals’ satisfaction and a protocol use in 77% of patients treated.

Conclusion. A pharmacist-coordinated chemotherapy protocol system improves protocol dissemination, protocol compliance, and chemo-therapy delivery and safety. The project enhances the pharmacist profile and credibility within the organization.
New face for a familiar friend: the deGramont regimen in the treatment of metastatic colorectal cancer given as an outpatient: a feasibility study
Authors: Rowe Michelle , Valle Juan W , Swindell Ric , Fitzsimmons Lesley , James Roger D
Published: May 2003

The use of elastomeric infusional devices to administer chemotherapy is becoming established in a number of malignancies. Historically, hospitals have admitted patients for treatments such as the deGramont regimen, used in advanced colorectal cancer. This consists of intermittent infusional 5-fluorouracil (5-FU) and folinic acid and usually requires two to three inpatient days, every two weeks.

We performed a prospective, single-center, study to assess the feasibility of administering the deGramont regimen on an outpatient basis using elastomeric infusional devices. In addition, we assessed patient acceptability of this mode of administration and the effects on quality of life (using the self-completed EORTC QLQ-C30 questionnaire). Crude cost-benefit analysis was performed and we attempted to define the group of patients for whom this is a viable option.

Twenty-six patients, all receiving the same regimen, were recruited into the study. Two cohorts were (nonrandomly) allocated to receive either standard inpatient (n=13) or novel out-patient (n=13) chemotherapy. Administration of the deGramont regimen using elastomeric infusional devices through an indwelling central venous catheter was found to be both feasible and highly acceptable to patients. Those patients receiving this modality of administration reported marked benefits, improved morale and did not suffer from impaired quality of life. Taking into account the costs of inpatient hospital stay, the outpatient regimen conferred considerable cost savings.

Given the continued use of this popular regimen, either alone or in combination with newer, more active agents such as irinotecan and oxaliplatin, these findings have potential implications for a large number of patients and institutions. It also raises possibility of exploring this approach for other types of ambulatory infusion device chemo-therapy and may hasten the advent of home-based chemotherapy.
Chemotherapy order review and documentation: let’s put the anDROIDs to work!
Authors: Duong Cathy D
Published: May 2003

Objective To develop a process which assists pharmacists in oncology order review, patient assessment, drug therapy monitoring, and documentation and evaluate whether it is useful in practice.

Methods A process called the anDROIDs (Appendix A) is discussed. The acronym represents Antineoplastic Data Collection, Review of Systems, Oncology Target, Identification of drug-related problems, and Documentation System. A tool representing the process was created and introduced to a focus group in an oncology pharmacy workshop. Participants’ responses were measured using pre- and post-workshop assessments.

Results. The focus group had positive responses in the post-workshop assessment compared to pre-workshop data. Participants found the anDROIDs tool to be easy to use and planned to incorporate it into their pharmacy practice.

Conclusion The anDROIDs tool may have potential application in oncology pharmacy and can be modified to other pharmacy practice settings.
Gender and anthropometrics of patients undergoing cisplatin-containing chemotherapy as determinants of acute emesis over repeat courses
Authors: Catalán-Aplandis José Luis , Jiménez-Torres Nicolás Víctor , Calpe-Maravilla Javier , Almenar-Cubells Daniel
Published: May 2003

Objective. To characterize the anthropometric and pharmacotherapeutic variables related to acute emesis over repeat courses of cisplatin-containing regimens (≥50 mg/m survival analysis.2) by means of survival analysis.

Methods. A prospective, cross-sectional non-controlled study was started to analyse acute vomiting in patients treated in a general hospital. The patients received an intravenous combination of drugs based on metoclopramide (two 3 mg/kg doses), diphenhydramine (20 mg) and dexamethasone (20 mg) as first choice antiemetic treatment. An intravenous regimen based on ondansetron (8 mg) and dexamethasone (20 mg) was given as an alternative regimen. Therapeutic failure was defined as the recording of one or more vomiting episodes on a self-evaluation sheet. Other variables included were chemotherapeutic regimen, antiemetic regimen, gender, age, weight and height. The statistical analysis was developed using the Cox proportional hazards model.

Results. Eighty-eight patients were finally included in the study, 16 women (18%) and 72 men (82%). The metoclopramide-based regimen was administered to 74 patients (84%) and the ondansetron-based regimen to 14 patients (15%). The univariate analysis showed that any variable included in the study was significant. The multivariate survival analysis retained three variables: height (hazard ratio 1.22), gender (hazard ratio 2.12) and weight (hazard ratio 1.44) of the patients. It is hypothesized that gender and anthropometrics of patients could represent differences in pharmacokinetic and/or pharmacodynamic behaviour of cisplatin and/or antiemetics. The potential role of these parameters in these drugs is discussed.

Conclusions. Emesis over repeat courses in cisplatin-containing regimens seems a function of the gender and anthropometrics of patients, irrespective of the antiemetic regimen and the emetogenicity of the cytostatics. Dosing individualization of cisplatin and/or antiemetics based on pharmacokinetic and/or pharmacodynamic parameters can be a valid tool to increase the effectiveness and safety of these drugs.
Standardization of body surface area calculations
Authors: T Vu Thanh
Published: May 2003

Purpose. Antineoplastic agents have a narrow therapeutic index and therefore require the greatest degree of dose individualization. In choosing a body surface area (BSA) for‘mula, the challenge remains in obtaining consensus among prescribers. The objective of this review is to assess the various formulae available for calculating BSA and to adopt a standard formula within an institution.

Methods. Retrospective review of medication orders containing the patient’s height and weight as well as BSA calculated by the outpatient clinic staff within the Cross Cancer Institute (CCI) from 7 to 15 July 1998. Four BSA calculating devices, in current use by the clinical staff, were also tested to determine the formula currently utilized by prescribers.

Results. Thirty-three orders sent to the pharmacy containing the patient’s height, weight, and BSA were reviewed. Ninety-four per cent of the BSA calculated by the clinic staff differed from pharmacy’s calculations by 0% to 4%. One BSA calculation differed by 8% and another differed by 14%. With respect to the available BSA calculating devices, all appeared to be based on the Du Bois formula.

Conclusion. Of the various formulae available for estimating BSA, we concluded that the Mosteller equation is the most acceptable based on both BSA calculation accuracy and ease of use. Based on this determination, the CCI approved the adoption of the Mosteller equation as the institutional standard. This equation was later standardized throughout the entire Alberta Cancer Board. Other methods of dose determination are emerging, including therapeutic drug monitoring and PMT dosing. Further investigation is required as to whether these methods will lead to better standardization of dose.
Involvement of inwardly rectifying K+ channels in secretory responses of human ileal mucosa
Authors: Burleigh David E
Published: May 2003

In acute secretory diarrhoea the primary event driving fluid secretion is a transcellular, electrogenic, serosal to mucosal transport of chloride ions. Such transport requires the maintenance of an electrically negative cell membrane voltage, which is achieved through a basolateral outward leakage of potassium ions. The aim of this study was to investigate the nature of K+ channel involvement in facilitating secretory processes in the human ileum. Muscle-stripped mucosal preparations of human ileal mucosa were set up in Ussing chambers for recording short-circuit current and transmucosal conductance. Escherichia coli heat-stable toxin and vasoactive intestinal peptide (VIP) produced concentration-dependent increases in short-circuit current. Responses to the heat- stable toxin were unaffected by basolateral application of 4-aminopyridine (5 mm), glibenclamide (10 μm) or a combination of charybdotoxin (0.3 μ m) plus apamin (0.3 μm). However, basolateral barium (0.2–5 mm) caused a concentration-dependent inhibition. Responses to VIP were similarly affected by barium (0.05–1 mm). These results suggested that electrogenic chloride transport by human ileal mucosa required the presence of basolateral K+ channels. The use of selective K+-channel inhibitors and low concentrations of barium suggested that the channels involved might be of the inwardly rectifying type.
Pharmacological characterization of MP349, a novel 5-HT1A-receptor antagonist with anxiolytic-like activity, in mice and rats
Authors: Wesołowska Anna , Paluchowska Maria H , Gołembiowska Krystyna , Chojnacka-Wójcik Ewa
Published: May 2003

The purpose of this study was to further characterize the pharmacological effects of MP349 (trans-1-(2-methoxyphenyl)-4-(4-succinimidocyclohexyl)piperazine), a new serotonin 5-HT1A postsynaptic receptor antagonist, using several biochemical and behavioural assays. The silent 5-HT1A-receptor antagonist WAY 100635 (N-{2-[4-(2–1-piperazinyl]ethyl)-N-pyridinyl)cyclohexanecarboxamide) was used as a reference compound in in-vivo tests, and diazepam served as standard anxiolytic drug in animal models of anxiety. In this study we showed that MP349 bound with moderate affinity (Ki = 234 nm) for α-adrenoceptors, and with very low affinity (Ki > 2600 nm) for 5-HT2A, dopamine D1, D2 and benzodiazepine receptors. The effects of MP349 on presynaptic 5-HT1A receptors were studied in two models (mice and rats). Like WAY 100635, MP349 antagonized the hypothermia induced by the 5-HT1A-receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin(8-OH-DPAT) in mice. Neither MP349 nor WAY 100635 administered alone induced hypothermia. In a rat microdialysis study, MP349 (like WAY 100635) did not affect 5-HT dialysate level in the prefrontal cortex; however, when given before 8-OH-DPAT, it inhibited the decrease in 5-HT release induced by the 5-HT1A agonist. The data demonstrated that MP349 behaved like a functonal antagonist of presynaptic 5-HT1A receptors. The potential anxiolytic activity of MP349 and reference drugs was examined in a conflict drinking test in rats, a plus-maze test in rats and a four-plate test in mice. MP349 and WAY 100635 produced anxiolytic-like effects, though somewhat weaker than those induced by diazepam, and only in the case of diazepam the anxiolytic-like effects were dose-dependent. Moreover, MP349 administered in doses inducing anxiolytic-like effects did not disturb the locomotor activity (open field test) or locomotor coordination (rota-rod test) of rats. These and earlier results indicated that MP349 was an antagonist of 5-HT1A receptors which exhibited anxiolytic-like activity in an animal model of anxiety.
Pharmaceutical strategies to prevent ventilator-associated pneumonia
Authors: McCrory Roisin , Jones David S , Adair Colin G , Gorman Sean P
Published: May 2003

The increasing incidence of hospital-acquired (nosocomial) infection is a disturbing phenomenon resulting in significant patient mortality and putting considerable strain on healthcare budgets and personnel. One particularly serious aspect of nosocomial infection is that of ventilator-associated pneumonia (VAP). This arises in patients who receive mechanical ventilation within the intensive care unit. The quoted incidence of VAP varies widely (5–67%) and the reported mortality of patients with VAP is in the range of 24–71%. This review will examine the many factors that account for these wide ranges reported, including the patient population under investigation, the causative organism, the method of diagnosis, interventions employed and preventative strategies. The use of bioactive and drug-impregnated biomaterials for endotracheal tube construction is discussed as novel approaches to the prevention of VAP.
Design and validation of a dynamic flow model simulating encrustation of biomaterials in the urinary tract
Authors: Gorman Sean P , Garvin Clare P , Quigley Fergus , Jones David S
Published: May 2003

A number of models exist for assessing encrustation on biomaterials employed as devices in the urinary tract. However, static urine models are suitable only for assessment of biomaterials residing in the bladder and the dynamic models available suffer from a number of disadvantages, notably their complexity and limitation to short-term assessment. The dynamic model described herein is a relatively simple design incorporating the ability to assess a large number of biomaterials in replicate fashion and over long periods of time. The biomaterials tested in the dynamic model conform to the urethral catheter and ureteral stent devices that experience urine flow within the urinary tract. The model was initially validated using Percuflex as a test biomaterial. The mass of calcium and magnesium, representing hydroxyapatite and struvite encrustation, respectively, on Percuflex was detected by atomic absorption spectrometry. No significant differences in encrustation levels were detected either between vessels or between biomaterial positions on any mandrel within the vessels, indicating the suitability of the dynamic model for reproducible determination of biomaterial encrustation. The dynamic model was then used to compare the encrustation of biomaterials commonly employed in urinary-tract devices, namely polyurethane, Percuflex and silicone. Calcium and magnesium levels on polyurethane and Percuflex were shown to be statistically similar, whereas silicone exhibited significantly reduced encrustation. When, subsequently, comparisons were made of biomaterial encrustation between the dynamic model and a static model, calcium and magnesium levels arising from the latter model were significantly higher on each of the biomaterials. However, the same rank order of encrustation resistance was observed for the biomaterials in both models, with silicone performing better than polyurethane or Percuflex. The prediction of in-vivo performance based on in-vitro models of encrustation is often difficult, although the model described provides a more accurate method for assessing the potential of novel and existing biomaterials for use in urinary medical devices requiring flow of urine.
In-vitro and in-vivo antibacterial activity evaluation of a polyurethane matrix
Authors: Lee Sun-Hee , Kim Sung-Ryul , Kim Jung Sun , Bae Hae-Rahn , Lee Chi-Ho , Kim Dae-Duk
Published: May 2003

Various in-vitro and in-vivo methods for evaluation of the duration of antibacterial activity were compared using a controlled-release polyurethane matrix developed for the prevention of surface bacterial adhesion and growth. Cefadroxil was incorporated into this polyurethane matrix by a solvent casting method before the matrix was coated with polyurethane in tetrahydrofuran solution. The release of cefadroxil from the matrix into distilled water at 37 °C was measured by HPLC. The morphological change of matrices before and after release studies was investigated by scanning electron microscopy (SEM). The duration of antimicrobial activity of the matrix against Escherichia coli and Staphylococcus aureus was evaluated by measuring the diameters of the inhibition zone and the optical density of the broth. The matrices were also implanted subcutaneously in rats and the duration of the antibacterial activity was determined by measuring the inhibition zone. The results showed that duration of antibacterial activity of the polyurethane matrix was successfully determined in-vitro by these methods, and the results differed from the conventional in-vitro release study. It was also possible to determine the duration of action of the matrix in-vivo by implanting the matrix in rats, and then measuring the antibacterial activity of the matrix at predetermined time intervals. While a good correlation was observed between the in-vitro and in-vivo methods used in this study to evaluate the duration of the antibacterial activity of the polymeric matrix, the conventional in-vitro release study did not coincide with these results.
Synthesis and hydrolytic behaviour of 2-mercaptoethyl ibuprofenate–polyethylene glycol conjugate as a novel transdermal prodrug
Authors: Davaran Soodabeh , Rashidi Mohammad R , Hashemi Mahdi
Published: May 2003

Thiolated derivatives of ibuprofen and its polyethylene glycol ester were synthesized via condensation of 2-mercaptoethyl ibuprofenate with carboxy-terminated polyethylene glycol. The release of ibuprofen from this polymeric prodrug has been studied under conditions simulating those encountered in the skin. The polymeric prodrug of ibuprofen was found to undergo pH-dependent hydrolysis, ranging from negligible hydrolysis at pH 4 to 23.9% hydrolysis at pH 8.5 (15% at pH 7.4) after 48 h at 37 °C. The polymer–drug conjugate was subjected to enzymatic hydrolysis in human plasma. The polymer showed considerable enzymatic hydrolysis (68% after 48 h). The results showed that the polymeric prodrug model of non-steroidal anti-inflammatory drugs (NSAIDs) described here can be used in topical formulations of NSAIDs. It is expected that the novel thiol derivative will have both enhanced transdermal penetration and stability to oxidation which make it a suitable candidate for transdermal formulations.
Protective effect of Artemisia douglasiana Besser extracts in gastric mucosal injury
Authors: Repetto Marisa , Maria Alejandra , Guzmán Jorge , Giordano Oscar , Llesuy Susana
Published: May 2003

The aim of this work was to evaluate markers of oxidative stress in ethanol-induced gastric ulcers and the protective antioxidant activity in-vivo of Artemisia douglasiana Besser extracts in ethanol-treated rats. Ethanol-induced oxidative damage is believed to be associated with generation of reactive oxygen molecules, which leads to oxidative stress. A. douglasiana is used in folk medicine as a cytoprotective agent against peptic ulcer. Different bioassays were performed: in-vivo stomach chemiluminescence, tert-butyl hydroperoxide initiated chemiluminescence (in-vitro chemiluminescence), total antioxidant capacity (TRAP) and catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity in stomach homogenates. When ethanol (3 g kg−1) was administered, the in-vivo chemiluminescence increased by 107%, in-vitro chemiluminescence by 108%, SOD by 130% (P<0.001), and catalase and TRAP decreased by 43 and 59% (P<0.05 and 0.001, respectively). A. douglasiana (400 mg kg−1) pretreatment decreased in-vivo chemiluminescence by 41% (P<0.05), in-vitro chemiluminescence by 66% (P<0.001) and SOD by 56% (P<0.001) and increased catalase by 14% and TRAP by 168% (P<0.001, respectively) but GPx activity was not significantly different from the ethanol group. These results illustrate the significant antioxidant activity of A. douglasiana extract in-vivo and in-vitro.
Enhancement of polyethylene glycol (PEG)-modified cationic liposome-mediated gene deliveries: effects on serum stability and transfection efficiency
Authors: Kim Jin-Ki , Choi Sung-Hee , Kim Cheong-Ok , Park Jeong-Sook , Ahn Woong-Shick , Kim Chong-Kook
Published: May 2003

In this study, we modified cationic liposomes either by polyethylene glycol (PEG)-grafting or PEG-adding methods, and compared the physical properties of transfection complexes and transfection efficiency in-vitro and prolonged circulation in-vivo. The PEG-grafted transfection complexes were prepared by mixing plasmid DNA with PEG-grafted cationic liposomes, which were composed of DSPE-PEG 2000 and cationic lipids. The PEG-added transfection complexes were prepared by adding DSPE-PEG 2000 to the mixture of cationic liposomes and plasmid DNA. The particle sizes of the PEG-modified transfection complexes (˜200 nm) changed a little over 4 weeks compared with the conventional transfection complexes. In the presence of serum, the transfection efficiency of the conventional transfection complexes was lowered whereas the transfection efficiency of the PEG-modified transfection complexes was maintained. Moreover, the transfection efficiency of the conventional transfection complexes was significantly reduced when they were stored. However, the transfection efficiency was stable for the PEG-modified transfection complexes, even after two weeks of storage. Of the in-vitro transfection efficiencies, there was no difference between PEG-grafted and PEG-added transfection complexes. When the conventional, PEG-grafted, and PEG-added transfection complexes were administered into mice by the tail vein, the PEG-added transfection complexes showed a prolonged circulation of plasmid DNA compared with other transfection complexes. These results suggest that the PEG-added transfection complexes could be a useful non-viral vector because of their simplicity in preparation, enhanced stability and prolonged circulation compared with the conventional transfection complexes.
Thermal gelation of aqueous curdlan suspension: preparation of curdlan jelly
Authors: Hino Tomoaki , Ishimoto Hayato , Shimabayashi Saburo
Published: May 2003

Curdlan jelly was prepared by heating an aqueous curdlan suspension at 70 °C for 5 min. Theophylline, as a model drug, was entrapped in the jelly network. Curdlan jelly had a hardness comparable with that of commercially available jelly for confectionary. Syneresis was observed for 8 days after the preparation and was not detected during the experimental term from the gel prepared from 10% w/v curdlan suspension. Release of theophylline from the jellies was sustained, and was increasingly delayed with an increase in the curdlan concentration. An aqueous curdlan suspension was studied by means of differential scanning calorimetry (DSC) up to 80 °C and down to 25 °C, and subsequent re-heating to 30 °C. Enthalpy increased with the concentration of curdlan, while the temperature at the onset of the endothermic peak decreased with the concentration of curdlan. The enthalpy due to thermal gelation of 1 mg curdlan was 12.2 mJ. An increase in curdlan concentration decreased the enthalpy and lowered the onset temperature of the endothermic peak during the DSC re-heating scan. The results are due to an increase in the amount of non-freezing water and freezing bound water and a decrease in free water. The number of water molecules entrapped in the curdlan jelly as non-freezing water was 8.1 per glucopyranose residue.
Estimation of absorption parameters from the non-steady-state phase in the rat gut perfusion model
Authors: Corrigan Owen I , Gubbins Rachel H , O'Driscoll Caitriona M
Published: May 2003

The aim of the study was to calculate absorption parameters, including permeability coefficients (Papp), from the non-steady-state portion of the outflow to inflow concentration ratio vs time profiles and compare them with those obtained via the more traditionally used steady-state phase. The rat in-situ intestinal perfusion method was used. The compounds studied, diclofenac and macrogol 4000 (polyethylene glycol (PEG) 4000), were perfused at four different flow rates (0.1–2.0 mL min−1). The estimates of Papp from the non-steady-state data were systematically lower for both compounds. The non-steady-state analysis gave estimates of the intestinal radius, r. The internal diameter of the intestine segment increased as the flow rate increased. When this effect was taken into account similar Papp estimates were obtained by the two approaches. Thus the convention of using a constant value of intestinal radius in the steady-state equation leads to an over estimate of the Papp when high flow rates are employed. The different trends observed, between Papp and perfusate flow rate, for the two compounds, macrogol 4000 and diclofenac, may be linked to increased surface area and exposure to membrane pores of larger size. The longitudinal spreading coefficient, De, increased with flow rate and was approximately 1000 times greater than that estimated for molecular diffusion. The high values obtained were consistent with the non-smooth biological surface and peristaltic movement present in-vivo.
The increased intestinal absorption rate is responsible for the reduced hepatic first-pass extraction of propranolol in rats with cisplatin-induced renal dysfunction
Authors: Okabe Hiromi , Mizukami Akiko , Taguchi Masato , Aiba Tetsuya , Yasuhara Masato , Hashimoto Yukiya
Published: May 2003

The mechanisms responsible for the increased bioavailability of propranolol in renal dysfunction were investigated in rats. Experimental acute renal failure (ARF) was induced by intraperitoneal injection of cisplatin (5 mg kg−1). ARF induced a significant increase in blood propranolol concentration after intra-intestinal administration. The extent of bioavailability (F) of propranolol at an intestinal dose of 15 mg kg−1 was 16.4% and 26.9% in control and ARF rats, respectively, and the F value at a 37.5 mg kg−1 dose was 54.7% and 81.4% in control and ARF rats, respectively. In contrast, the blood propranolol concentration following intraportal infusion was not increased significantly in ARF rats. The hepatic first-pass extraction (Eh) was dose-dependent and saturable: Eh of propranolol in control rats was 58.0% and 18.3% at 8 and 20 mg kg−1, respectively, and Eh in ARF rats was 50.8% and 19.9% at 8 and 20 mg kg−1, respectively. The initial absorption rate of propranolol from the intestine in ARF rats was significantly greater compared with control rats. These results indicated that the increased bioavailability of propranolol in rats with cisplatin-induced renal dysfunction was mainly a result of the increased absorption rate in the intestine followed by the partial saturation of hepatic first-pass metabolism.
Evidence that Myc activation depletes the epidermal stem cell compartment by modulating adhesive interactions with the local microenvironment
Authors: Frye Michaela , Gardner Clare , Li Elizabeth R. , Arnold Isabel , Watt Fiona M.
Published: May 2003

Activation of Myc (c-Myc) causes epidermal cells to exit the stem cell compartment and differentiate into sebocytes and interfollicular epidermis at the expense of the hair lineages. To investigate how Myc exerts these effects we analysed the transcription of more than 10,000 genes following Myc activation in the basal layer of mouse epidermis for 1 or 4 days. The major classes of induced genes were involved in synthesis and processing of RNA and proteins, in cell proliferation and in differentiation. More than 40% of the downregulated genes encoded cell adhesion and cytoskeleton proteins. Repression of these genes resulted in profound changes in the adhesive and motile behaviour of keratinocytes. Myc activation inhibited cell motility and wound healing, correlating with decreased expression of a large number of extracellular matrix proteins. Cell adhesion and spreading were also impaired,and this correlated with decreased expression of the α6β4 integrin,decreased formation of hemidesmosomes and decreased assembly of the actomyosin cytoskeleton. We propose that Myc stimulates exit from the stem cell compartment by reducing adhesive interactions with the local microenvironment or niche, and that the failure of hair differentiation reflects an inability of keratinocytes to migrate along the outer root sheath to receive hair inductive stimuli.