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Biomedical subjects

E McDonald

Publications and source records attributed to E McDonald.

At least 19 recordsLinked to original sources
PubMed2006

A fluorescence polarization assay for inhibitors of Hsp90.

Hsp90 encodes a ubiquitous molecular chaperone protein conserved among species which acts on multiple substrates, many of which are important cell-signaling proteins. Inhibition of Hsp90 function has been promoted as a mechanism to degrade client proteins involved in tumorigenesis and disease progression. Several assays to monitor inhibition of Hsp90 function currently exist but are limited in their use for a drug discovery campaign. Using data from the crystal structure of an initial hit compound, we have developed a fluorescence polarization assay to monitor binding of compounds to the ATP-binding site of Hsp90. This assay is very robust (Z' > 0.9) and can detect affinity of compounds with IC50s to 40 nM. We have used this assay in conjunction with cocrystal structures of small molecules to drive a structure-based design program aimed at the discovery and optimization of a novel class of potent Hsp90 inhibitors.

Adenosine Triphosphatases↗
PubMed2006

Minimizing errors of omission: behavioural reenforcement of heparin to avert venous emboli: the BEHAVE study.

OBJECTIVE: To improve patient safety by increasing heparin thromboprophylaxis for medical-surgical intensive care unit patients using a multiple-method approach to evidence-based guideline development and implementation. DESIGN: Prospective longitudinal observational study. SETTING: Medical-surgical intensive care unit. PARTICIPANTS: Multidisciplinary clinicians caring for critically ill patients in a 15-bed medical-surgical closed intensive care unit. INTERVENTIONS: Phase 1 was a 3-month baseline period during which we documented anticoagulation and mechanical thromboprophylaxis. Phase 2 was a 1-yr period in which we implemented a thromboprophylaxis guideline using a) interactive multidisciplinary educational in-services; b) verbal reminders to the intensive care unit team; c) computerized daily nurse recording of thromboprophylaxis; d) weekly graphic feedback to individual intensivists on guideline adherence; and e) publicly displayed graphic feedback on group performance. Phase 3 was a 3-month follow-up period 10 months later, during which we documented thromboprophylaxis. Computerized daily nurse recording of thromboprophylaxis continued in this period. MEASUREMENTS AND MAIN RESULTS: Intensive care unit and hospital mortality rates were similar across phases, although patients in phase 2 had higher Acute Physiology and Chronic Health Evaluation II scores than patients in phases 1 and 3. The proportion (median % [interquartile range]) of intensive care unit patient-days of heparin thromboprophylaxis in phases 1, 2, and 3 was 60.0 (0, 100), 90.9 (50, 100), and 100.0 (60, 100), respectively (p=.01). The proportion (median % [interquartile range]) of days during which heparin thromboprophylaxis was omitted in error in phases 1, 2, and 3 was 20 (0, 53.8), 0 (0, 6.3), and 0 (0, 0), respectively (p<.001). CONCLUSIONS: After development and implementation of an evidence-based thromboprophylaxis guideline, we found significantly more patients receiving heparin thromboprophylaxis. Guideline adherence was maintained 1 yr later. Further research is needed on which are the most effective strategies to implement patient safety initiatives in the intensive care unit.

Aged↗
PubMed2006

Gait and balance impairment in early multiple sclerosis in the absence of clinical disability.

This study evaluated the gait and balance performance of two clinically distinct groups of recently diagnosed and minimally impaired multiple sclerosis (MS) patients (Expanded Disability Status Scale range 0-2.5), compared to control subjects. Ten MS patients with mild pyramidal signs (Pyramidal Functional Systems 1.0), 10 MS patients with no pyramidal signs (Pyramidal Functional Systems 0) and 20 age- and gender-matched control subjects were assessed using laboratory-based gait analysis and clinical balance measures. Both MS groups demonstrated reduced speed and stride length (P < 0.001), and prolonged double limb support (P <0.02), compared to the control group, along with alterations in the timing of ankle muscle activity, and the pattern of ankle motion during walking, which occurred independent of gait speed. The pyramidal MS group walked with reduced speed (P = 0.03) and stride length (P = 0.04), and prolonged double limb support (P =0.01), compared to the non-pyramidal group. Both MS groups demonstrated concomitant balance impairment, performing poorly on the Functional Reach Test compared to the control group (P <0.05). The identification of incipient gait and balance impairment in MS patients with recent disease onset suggests that motor function may begin to deteriorate in the early stages of the disease, even in the absence of clinical signs of pyramidal dysfunction.

Adult↗
PubMed2005

Towards consensus in the long-term management of relapse prevention in schizophrenia.

APPROACH TO DEVELOPING GUIDANCE: When developing guidance for the long-term management of schizophrenia, one approach is to adopt a proactive strategy that sets out clear treatment goals and strategies. This should involve a broad view being taken, embracing overall mental and physical well-being rather than simply the absence of illness. Although relapse prevention is an important goal of any long-term management strategy, there are other aspects that need to be considered, such as reintegration into society, regaining independence and quality of life. CURRENT TREATMENT: To help achieve these goals, a range of interventions can be incorporated into long-term management strategies for schizophrenia, including pharmacological interventions, psychosocial therapies and alliance-building initiatives. The current UK National Institute for Clinical Excellence guidelines already recommend that continuous therapy should be practised using an atypical (second-generation) antipsychotic drug, whenever possible, in preference to older typical drugs. The launch of the first long-acting atypical antipsychotic is an interesting new advance that may benefit many patients with schizophrenia. Psychosocial interventions, particularly family-based therapies, as well as cognitive behavioural and compliance therapies, when used alongside antipsychotics, have been shown to reduce relapse rates dramatically and to assist in social reintegration. In addition, forging collaborative alliances with patients and their carers can help to demystify schizophrenia and empower patients to take responsibility for their illness. CONSENSUS STATEMENT: This article outlines a consensus reached by a panel of leading UK healthcare professionals working with schizophrenia brought together to discuss long-term management strategies.

Antipsychotic Agents↗
PubMed2003

Differential activation on fMRI of monozygotic twins discordant for AD.

This is the first report of fMRI in monozygotic twins discordant for AD. FMRI brain activation patterns were examined during visuospatial and verbal working memory tasks. The affected twin had greater parietal involvement bilaterally during both working memory tasks and reduced left dorsolateral prefrontal cortex activity on the visuospatial memory task. Thus, fMRI may identify additional brain regions recruited in patients with AD to perform a given cognitive task.

Aged↗
PubMed2002

Vitamin K deficiency and D-dimer levels in the intensive care unit: a prospective cohort study.

Patients in the intensive care unit (ICU) are at risk for the development of vitamin K deficiency. We sought to determine the frequency of this deficiency by performing a prospective cohort study in which patients were screened for vitamin K deficiency on ICU admission and every other day thereafter. Vitamin K deficiency was diagnosed by a functional coagulation factor II to Echis factor II ratio < 0.70. Activity of the coagulation cascade was measured by D-dimer. In total, 40 patients were enrolled into the study. Seven of the patients had ratios < 0.70 on the day of admission to the ICU, and three patients developed ratios < 0.70. Thus, 10 of 40 patients (25%; 95% confidence interval, 12-38%) had vitamin K deficiency. Two patients developed coagulopathy, as indicated by an International Normalized Ratio of more than 1.4. D-dimer levels were elevated in 86 of 111 samples. We conclude that vitamin K deficiency is common among critically ill patients, particularly on admission to the ICU. Our findings suggest that additional clinical research is warranted to determine whether vitamin K supplementation on admission to the ICU reduces the risk of ICU-acquired vitamin K deficiency and its attendant complications over the course of the ICU stay.

Aged↗
PubMed2001

Intracellular inhibition of human neutrophil elastase by orally active pyrrolidine-trans-lactams.

Described are the acylation binding of trans-lactam 1 to porcine pancreatic elastase, the selection of the SO2Me activating group for the lactam N which also confers metabolic stability in hamster liver microsomes, the introduction of aqueous solubility through the piperidine salt 9, the in vivo oral activity of 9 and its bioavailability, and the introduction of 9 as an intracellular neutrophil elastase inhibitor.

Acylation↗
PubMed2000

A randomized, controlled trial comparing thoracoscopy and limited thoracotomy for lung biopsy in interstitial lung disease.

BACKGROUND: Lung biopsies are frequently needed to diagnose diffuse interstitial lung diseases. A prospective randomized, controlled trial comparing limited thoracotomy (open lung biopsy) and thoracoscopy for lung biopsy was done. METHODS: Ambulatory patients with a clinical diagnosis of diffuse interstitial lung disease were randomized to thoracoscopy or limited thoracotomy. Data on postoperative pain, narcotic requirements, operating room time, adequacy of biopsy, duration of chest tube drainage, length of hospital stay, spirometry, and complications were collected. RESULTS: A total of 42 randomized patients underwent lung biopsy (thoracoscopy 20, thoracotomy 22). The two study groups were comparable with respect to age, gender, corticosteroid use, and preoperative spirometry. Visual analog scale pain scores were nearly identical in the two groups (p = 0.397). Total morphine dose was 50.8 +/- 27.3 mg in the thoracoscopy group and 52.5 +/- 25.6 mg in the thoracotomy group (p = 0.86). Spirometry (FEV1) values in the two groups were not significantly different on postoperative days 1, 2, 14, and 28 (p = 0.665). Duration of operation was similar in both groups (thoracoscopy 40 +/- 30 minutes, thoracotomy 37 +/- 15 minutes; p = 0.67). The thoracoscopy and thoracotomy groups had equivalent duration of chest tube drainage (thoracoscopy 38 +/- 28 hours, thoracotomy 31 +/- 26 hours; p = 0.47) and length of hospital stay (thoracoscopy 77 +/- 82 hours, thoracotomy 69 +/- 55 hours; p = 0.72). Definitive pathologic diagnoses were made in all patients. CONCLUSIONS: There is no clinical or statistical difference in outcomes for thoracoscopic and thoracotomy approaches. Both thoracoscopy and thoracotomy are acceptable procedures for diagnostic lung biopsy in diffuse interstitial lung disease.

Biopsy↗
PubMed2000

Venous thromboembolic disease: an observational study in medical-surgical intensive care unit patients.

PURPOSE: Acute and chronic illness, immobility, and procedural and pharmacologic interventions may predispose patients in the intensive care unit (ICU) to venous thromboembolic (VTE) disease. The purpose of this study was to observe potential risk factors and diagnostic tests for VTE, and prophylaxis against VTE in medical-surgical ICU patients. MATERIALS AND METHODS: In a prospective observational study, 93 consecutive patients admitted to a mixed medical-surgical ICU were followed. We recorded demographics, admitting diagnoses, APACHE II score, VTE risk factors, antithrombotic, anticoagulant and thrombolytic agents, diagnostic tests for deep venous thrombosis (DVT) and pulmonary embolus (PE), and clinical outcomes. RESULTS: Patients were 65.5 (15.5) years old with an APACHE II score of 21.1 (9.0); 44 (47.3%) were female. Admission diagnoses were medical (58, 67.4%) and surgical (35, 37.6%). The duration of ICU stay was 3 days (interquartile range: 1, 8.5 days) and the ICU mortality rate was 20.4% (19 of 93). We observed 8 VTE events among 5 of 93 patients (incidence 5.4% [0.8 to 10.0]); 2 patients had DVT and PE before admission, 1 had DVT as an admitting diagnosis, 1 had DVT on day 2 and PE on day 3, and 1 had PE on day 2. Over 804 ICU patient-days, 2 of 5 ultrasound examinations diagnosed DVT and 2 of 3 ventilation-perfusion lung scans diagnosed PE. Of 64 patients in whom heparin was not contraindicated and who were not anticoagulated, subcutaneous heparin prophylaxis was prescribed for 40 (62.5%) patients. ICU-acquired VTE risk factors were mechanical ventilation (odds ratio [OR] 1.56), immobility (OR 2.14), femoral venous catheter (OR 2.24), sedatives (OR 1.52), and paralytic drugs (OR 4.81), whereas VTE heparin prophylaxis (OR 0.08), aspirin (OR 0.42), and thromboembolic disease stockings (OR 0.63) were associated with a lower risk. Only warfarin (OR 0.07, P =.01) and intravenous heparin (OR 0.04, P<.01) were associated with a significantly decreased risk of VTE. CONCLUSIONS: Several ICU-acquired risk factors for VTE were documented in this medical-surgical ICU. VTE prophylaxis was underprescribed, and VTE diagnostic tests were infrequent. Further research is required to determine the incidence, predisposing factors, attributable morbidity, mortality, and costs of VTE in medical-surgical ICU patients, the optimal diagnostic test strategies, and the most cost-effective approaches of prophylaxis.

APACHE↗
PubMed1999

Synthetic [5,5] trans-fused indane lactones as inhibitors of thrombin.

Synthesis of trans-fused lactones containing the indane nucleus has resulted in a series of potent acylating inhibitors of thrombin. As an example compound 11e has an apparent second order rate constant of 11 x 10(6) M(-1)sec(-1) for the inhibition of thrombin. The anticoagulant activity of these compounds is discussed.

Anticoagulants↗
PubMed1998

Potent piperazine hydroxyethylamine HIV protease inhibitors containing novel P3 ligands.

The 2-isopropyl thiazolyl group is a highly optimized P3 ligand for C2 symmetry-based HIV protease inhibitors, as exemplified in the drug ritonavir. Here we report that incorporation of this P3 ligand into a piperazine hydroxyethylamine series also yielded novel, highly potent inhibitors. In tissue culture assays, the presence of human serum was less deleterious to the activity of these inhibitors than to that of ritonavir. Furthermore, potent activity against ritonavir resistant HIV was observed.

Animals↗
PubMed1998

Discovery of ritonavir, a potent inhibitor of HIV protease with high oral bioavailability and clinical efficacy.

The structure-activity studies leading to the potent and clinically efficacious HIV protease inhibitor ritonavir are described. Beginning with the moderately potent and orally bioavailable inhibitor A-80987, systematic investigation of peripheral (P3 and P2') heterocyclic groups designed to decrease the rate of hepatic metabolism provided analogues with improved pharmacokinetic properties after oral dosing in rats. Replacement of pyridyl groups with thiazoles provided increased chemical stability toward oxidation while maintaining sufficient aqueous solubility for oral absorption. Optimization of hydrophobic interactions with the HIV protease active site produced ritonavir, with excellent in vitro potency (EC50 = 0.02 microM) and high and sustained plasma concentrations after oral administration in four species. Details of the discovery and preclinical development of ritonavir are described.

Administration, Oral↗
PubMed1998

The role of Project 2000 educated nurses in health promotion within the hospital setting.

This study is concerned with the role of Project 2000-educated nurses in health promotion within the hospital setting. Historically nurses have been viewed as having a role to play in promoting the health of the people for whom they care. More recently, with the advent of the Health For All Movement initiated by the World Health Organization in 1978, the attention has again been focused on what nurses can do towards attainment of this goal, although most of the research has been carried out in relation to community nurses and primary care. Changes in nurse education, specifically that of Project 2000 nurse education, have been hailed as the opportunity to equip nurses with knowledge and skills appropriate to the task, which have been seen as lacking from many nurse educational programmes. Early work on this issue has produced conflicting findings as to the success of these educational changes. This study used an exploratory, qualitative approach to investigate what aspects of health promotion in the hospital setting are being carried out by nurses who have undergone Project 2000 nurse education within a college of nursing and midwifery in Scotland, and whether these nurses feel that they have been adequately prepared for this role during their educational programme. Findings suggest that the nurses interviewed were working with very wide perceptions of health promotion which included the more radical aspects of health promotion such as negotiation, collaboration and empowerment. Health promotion was also seen to include psychosocial factors that influence the health of individuals. The nurses interviewed in general felt that their education had prepared them for a role in health promotion. The value of clinical placements in facilitating the developing the skills for health promotion was established.

Attitude of Health Personnel↗
PubMed1998

ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease.

The valine at position 82 (Val 82) in the active site of the human immunodeficiency virus (HIV) protease mutates in response to therapy with the protease inhibitor ritonavir. By using the X-ray crystal structure of the complex of HIV protease and ritonavir, the potent protease inhibitor ABT-378, which has a diminished interaction with Val 82, was designed. ABT-378 potently inhibited wild-type and mutant HIV protease (Ki = 1.3 to 3.6 pM), blocked the replication of laboratory and clinical strains of HIV type 1 (50% effective concentration [EC50], 0.006 to 0.017 microM), and maintained high potency against mutant HIV selected by ritonavir in vivo (EC50, </=0. 06 microM). The metabolism of ABT-378 was strongly inhibited by ritonavir in vitro. Consequently, following concomitant oral administration of ABT-378 and ritonavir, the concentrations of ABT-378 in rat, dog, and monkey plasma exceeded the in vitro antiviral EC50 in the presence of human serum by >50-fold after 8 h. In healthy human volunteers, coadministration of a single 400-mg dose of ABT-378 with 50 mg of ritonavir enhanced the area under the concentration curve of ABT-378 in plasma by 77-fold over that observed after dosing with ABT-378 alone, and mean concentrations of ABT-378 exceeded the EC50 for >24 h. These results demonstrate the potential utility of ABT-378 as a therapeutic intervention against AIDS.

Animals↗
PubMed1998

Stopping progression to tophaceous gout. When and how to use urate-lowering therapy.

Although the prevalence of tophaceous gout has decreased in the past few years, the disease still exists, and without accurate diagnosis and therapy, it can still result in destructive arthritis. However, use of urate-lowering drugs may reduce plasma urate concentrations enough to allow resorption of tophi and prevent painful tophaceous gout. Some patients may have mechanical problems from tophi, despite adequate control of acute arthritis; in such situations, joint replacement or surgical excision of tophi may be necessary.

Adrenal Cortex Hormones↗
PubMed1997

Determination of ritonavir, a new HIV protease inhibitor, in biological samples using reversed-phase high-performance liquid chromatography.

A simple, accurate and precise high-performance liquid chromatographic method has been developed for measurement of ritonavir concentrations in human plasma. Ritonavir was partitioned from the plasma using liquid-liquid extraction with a mixture of ethyl acetate and hexane at neutral pH, with an average recovery >80%. Following two sequential washings of the reconstituted sample with hexane, chromatographic separation was accomplished on a C18 analytical column with a mobile phase containing acetonitrile, methanol and 0.01 M tetramethylammonium perchlorate in 0.1% aqueous trifluoroacetic acid (40:5:55, v/v) with low wavelength UV detection at 205 nm. Standard curves were linear (r2>0.9998) over the concentration range 0.01-15 microg/ml with both inter- and intra-day coefficients of variation typically less than 5%. The stability of ritonavir in plasma was excellent, with no evidence of degradation after 5 days at room temperature or after 6 months in a freezer. Decontamination procedures for HIV-positive plasma samples showed 5.6 and 10.2% degradation following heating to 60 degrees C for 30 or 60 min, respectively.

Calibration↗