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Biomedical subjects

D Reilly

Publications and source records attributed to D Reilly.

At least 19 recordsLinked to original sources
PubMed2004

Controlled dermal cell damage as human in vivo model for localised pain and inflammation.

OBJECTIVE AND DESIGN: An unspecific human in vivo model of dermal pain and inflammation was developed by means of limited, localised and controlled cell damage. SUBJECTS: Twelve participants were recruited. TREATMENT: Dermal microdialysis was used to deliver randomised and single blinded aqueous sodium dodecyl sulphate (SDS) at concentrations of 0.01%, 0.1% and 0.5% w/v to the volar forearm. METHODS: Nociceptive responses were recorded on a numerical scale, vasodilatation was assessed by laser Doppler scanning and sampled tissue fluid was analysed for PGE2 by ELISA. RESULTS: Saline control and 0.01% SDS did not differ in their ability to cause vasodilatation, flare reaction or pain. In contrast, SDS (0.1 and 0.5%) evoked a significant increase of blood flow (p<0.005), a widespread reddening (p<0.01), and stinging-burning pain (p<0.005). PGE2 concentration in the dialysate did not change during 0.01% SDS perfusion (p>0.9), but increased significantly following the stimulation with 0.1% and 0.5% SDS (20 to 30-fold). No significant differences of released PGE2 levels were determined between 0.1% and 0.5% SDS stimulation (p>0.05). CONCLUSIONS: We demonstrated that localised intradermal administration of SDS induces a limited pain and inflammatory response in humans. Excitation of nociceptors was accompanied by a massive PGE2 release. Employing this experimental model, the relative contribution of endogenous mediators to induce, maintain or facilitate pain and vasodilatation can be investigated.

Adult↗
PubMed2003

The homeopathic approach to the treatment of symptoms of oestrogen withdrawal in breast cancer patients. A prospective observational study.

This paper reports on an investigation of the homeopathic approach to the management of symptoms of oestrogen withdrawal in women with breast cancer. Forty-five patients entered the study. The most common presenting symptoms were hot flushes (HF) (n=38), mood disturbance (n=23), joint pain (n=12), and fatigue (n=16). Other symptoms included sleeplessness, reduced libido, weight gain, cystitis, vaginal dryness and skin eruptions. The active intervention was an individualised homeopathic medicine. Forty women (89%) completed the study. Significant improvements in mean symptom scores were seen over the study period and for the primary end-point 'the effect on daily living' scores. Symptoms other than HF such as fatigue and mood disturbance appear to be helped. Significant improvements in anxiety, depression and quality of life were demonstrated over the study period. The homeopathic approach appears to be clinically useful in the management of oestrogen withdrawal symptoms in women with breast cancer whether on or off Tamoxifen and improves mood disturbance. A placebo-controlled trial would be the next stage in this line of inquiry.

Adult↗
PubMed2002

Uncoupling of bone turnover following hip replacement.

Studies using total hip replacement surgery as a model for acute hip injury have shown that bone mineral density of the proximal femur decreases 6-18% in the 6 months following surgery. To examine the acute biochemical mechanism associated with bone loss, we measured two indicators of bone formation [serum osteocalcin (OC), serum bone-specific alkaline phosphatase (BSAP)], as well as two markers for bone resorption [urine and serum N-telopeptide cross-linked collagen type 1 (NTx)], in 20 patients (10 men, 10 women, mean age 59.4 years) prior to hip replacement and 1-2 days postsurgery. The average OC value (ng/ml) decreased by 57.3% following surgery (7.5 +/- 4.3 to 3.2 +/- 1.1, P <0.001), and the average BSAP level (U/L) decreased by 27.6% (19.9 +/- 5.6 to 14.4 +/- 3.7, P <0.001). In contrast, levels of urine NTx (nmol BCE/mmol Cr) did not change significantly after the surgery (73.9 +/- 47.2 to 70.1 +/- 29.7). In addition, there was no change in serum NTx (nmol BCE) after surgery (11.8 +/- 2.3 to 11.8 +/- 3.0). Six months after surgery, bone mass had not changed significantly from baseline. These findings suggest that there is an uncoupling of bone turnover following hip replacement surgery which is characterized by significant reductions in bone formation without compensatory decreases in bone resorption, potentially leading to bone loss. Longer periods of follow-up are needed to assess long-term bone mass changes.

Alkaline Phosphatase↗
PubMed2001

Comments on complementary and alternative medicine in Europe.

Despite the advances in Western medicine, up to one in three people in populations served by this medical system are seeking some form of unorthodox care each year, and Europe is no exception. Patients have driven this change, to the point where complementary and alternative medicine (CAM) is the second biggest growth industry in Europe. Often patients have to rely on the growing numbers of CAM practitioners with a variable standard of care that ranges from excellent to dangerous. Many practitioners work without regulation or even work illegally. Many orthodox health care professionals have shared their patients' concerns. Over the last 15 years, these practitioners have moved from silent interest to open enquiry and growing use. For example, approximately one in five of Scotland's general practitioners have received basic training in integrating homeopathy with orthodox practice. The demand for CAM is in part a search for a broader range of therapies, but is also a call for a different approach to care, with less emphasis on drugs, and a more whole-person approach. Mostly, people look to CAM when orthodoxy has failed. But CAM is also increasingly becoming a first-line intervention for some, because of the worry about the side effects of conventional treatments and a perception that orthodoxy has become dehumanized. With some exceptions, research is still in its early stages and lacks infrastructure. Patient satisfaction, empirical clinical outcome, and cost are beginning to be emphasized over mechanism of action or explanatory models. Recent official reports are calling for national and European-level enquiry and response. Future development is likely to emphasize integrative care. The challenge is to create better medical systems, with a whole-person emphasis, calling on a broader range of approaches than is currently orthodox. We seem to need a reunion of the art and science of medicine.

Attitude of Health Personnel↗
PubMed2001

The puzzle of homeopathy.

Homeopathy is a branch of Western medicine that has mostly been rejected by Western orthodoxy for the last 200 years because of conceptual and scientific clashes. Homeopathy uses microdoses of potential toxins to provoke defense and self-regulatory responses, rather than the more orthodox approach of blocking body reactions. This approach hints at its clinical scope: it can help, at times resolve, conditions that are intrinsically reversible rather than mechanical problems, deficiencies, or irreversible breakdowns in body functions where it is only palliative. In recent years, there has been a renaissance of interest. Public demand has soared, and with it professional interest. Approximately 20% of Scotland's general practitioners have completed basic training. This is partly occasioned by public interest in complementary medicine and a sympathy with the more mind-body approach of homeopathy, and partly by recent scientific evidence. Some homeopathic dilutions are so extreme they are dismissed by critics as only placebo. Yet trials and meta-analyses of controlled trials are pointing toward real effects, mechanism of action unknown. Clinical outcome studies suggest useful clinical impact and excellent safety. There seems to be a potential to enhance patient care by integrating the two systems.

Evidence-Based Medicine↗
PubMed2001

Salmeterol plus theophylline combination therapy in the treatment of COPD.

BACKGROUND: Patients with COPD often require multiple therapies to improve lung function and decrease symptoms and exacerbations. Salmeterol and theophylline are indicated for the treatment of COPD, but the use of these agents in combination has not been extensively studied. OBJECTIVES: To compare the efficacy and safety of salmeterol plus theophylline vs either agent alone in COPD. METHODS: Randomized, double-blind, double-dummy, parallel-group trial in 943 patients with COPD. After an open-label theophylline titration period (serum levels, 10 to 20 microg/mL), patients were randomly assigned to receive salmeterol (42 microg bid) plus theophylline, salmeterol (42 microg bid), or theophylline for 12 weeks. Serial pulmonary function tests were completed on day 1 and treatment week 12. Patients kept diary cards and noted their peak flow rates, symptom scores, and albuterol use, and periodically completed quality-of-life and dyspnea questionnaires. RESULTS: All three groups significantly improved compared with baseline. Combination treatment with salmeterol plus theophylline provided significantly (p < or = 0.045) greater improvements in pulmonary function; significantly (p < or = 0.048) greater decreases in symptoms, dyspnea, and albuterol use; and significantly fewer COPD exacerbations (p = 0.023 vs theophylline). In general, treatment with salmeterol provided greater improvement in lung function and satisfaction with treatment compared with theophylline. Salmeterol treatment was also associated with significantly fewer drug-related adverse events (p < or = 0.042) than either treatment that included theophylline. The safety profile (adverse events, vital signs, and ECG findings) of the two treatments that included theophylline were similar. CONCLUSION: Patients with COPD may benefit from combination treatment with salmeterol plus theophylline, without a resulting increase in adverse events or other adverse sequelae.

Adrenergic beta-Agonists↗
PubMed2000

Comparison of powder and aerosol formulations of salmeterol in the treatment of asthma.

BACKGROUND: The efficacy and safety of the aerosol metered-dose inhaler (MDI) formulation of salmeterol for asthma symptoms have been established. Recently, salmeterol has been introduced as a micronized powder formulation administered via a breath-activated multidose powder inhaler (Diskus). OBJECTIVE: A multicenter, randomized, double-blind, double-dummy, parallel-group, placebo-controlled study involving 498 adolescents and adults with mild-to-moderate asthma was conducted to compare the efficacy and safety of salmeterol powder 50 microg twice daily via Diskus, salmeterol aerosol 42 microg twice daily via MDI, and placebo. METHODS: Patients were randomized to one of the three treatment groups for 12 weeks. Efficacy was assessed by serial measurements of forced expiratory volume in one second (FEV1) over 12 hours, daily peak expiratory flow (PEF), self-rated asthma symptom scores, nighttime awakenings, and supplemental albuterol use. Safety of each treatment was evaluated by monitoring vital signs, electrocardiograms, Holter monitoring, and occurrence of adverse events. RESULTS: As compared with placebo, both salmeterol powder and aerosol produced significant improvement in FEV1 and PEF and decreased nighttime awakenings and supplemental albuterol use. There were no significant differences in the efficacy of the two salmeterol formulations. The magnitude of improvement in pulmonary function was undiminished over the 12-week study. Both formulations of salmeterol were well tolerated, with safety profiles not significantly different from placebo. CONCLUSION: Results of this study indicate that salmeterol, administered either as a powder 50 microg twice daily via Diskus or as an aerosol 42 microg twice daily via MDI, produces clinically significant and comparable improvement in pulmonary function and is well tolerated in patients with mild-to-moderate persistent asthma.

Adolescent↗
PubMed1999

Crystal structures of the neurotrophin-binding domain of TrkA, TrkB and TrkC.

The Trk receptors and their neurotrophin ligands control development and maintenance of the nervous system. The crystal structures of the ligand binding domain of TrkA, TrkB, and TrkC were solved and refined to high resolution. The domains adopt an immunoglobulin-like fold, but crystallized in all three instances as dimers with the N-terminal strand of each molecule replaced by the same strand of a symmetry-related mate. Models of the correctly folded domains could be constructed by changing the position of a single residue, and the resulting model of the binding domain of TrkA is essentially identical with the bound structure as observed in a complex with nerve growth factor. An analysis of the existing mutagenesis data for TrkA and TrkC in light of these structures reveals the structural reasons for the specificity among the Trk receptors, and explains the underpinnings of the multi-functional ligands that have been reported. The overall structure of all three domains belongs to the I-set of immunoglobulin-like domains, but shows several unusual features, such as an exposed disulfide bridge linking two neighboring strands in the same beta-sheet. For all three domains, the residues that deviate from the standard fingerprint pattern common to the I-set family fall in the region of the ligand binding site observed in the complex. Therefore, identification of these deviations in the sequences of other immunoglobulin-like domain-containing receptors may help to identify their ligand binding site even in the absence of structural or mutagenesis data.

Amino Acid Sequence↗
PubMed1999

Structure of a CXC chemokine-receptor fragment in complex with interleukin-8.

BACKGROUND: Interactions between CXC chemokines (e.g. interleukin-8, IL-8) and their receptors (e.g. CXCR-1) have a key role in host defense and disease by attracting and upregulating neutrophils to sites of inflammation. The transmembrane nature of the receptor impedes structure-based understanding of ligand interactions. Linear peptides based on the N-terminal, extracellular portion of the receptor CXCR-1 do bind to IL-8, however, and inhibit the binding of IL-8 to the full-length receptor. RESULTS: The NMR solution structure of the complex formed between IL-8 and one such receptor-based peptide indicates that a cleft between a loop and a beta hairpin constitute part of the receptor interaction surface on IL-8. Nine residues from the C terminus of the receptor peptide (corresponding to Pro21-Pro29 of CXCR-1) occupy the cleft in an extended fashion. Intermolecular contacts are mostly hydrophobic and sidechain mediated. CONCLUSIONS: The results offer the first details at an atomic level of the interaction between a chemokine and its receptor. Consideration of other biochemical data allow extrapolation to a model for the interaction of IL-8 with the full-length receptor. In this model, the heparin-binding residues of IL-8 are exposed, thereby allowing presentation of the chemokine from endothelial cell-surface glycosaminoglycans. This first glimpse of how IL-8 binds to its receptor provides a foundation for the structure-based design of chemokine antagonists.

Amino Acid Sequence↗
PubMed1999

Phase I/pharmacokinetic trial of the novel thioxanthone SR233377 (WIN33377) on a 5-day schedule.

PURPOSE: SR233377 (WIN33377) is a novel 4-aminomethyl thioxanthone derivative with promising preclinical activity against solid tumors at doses substantially below the MTD. We performed a phase I trial to determine a suitable phase II dose of SR233377 when administered as a 2-h intravenous infusion for five consecutive days. METHODS: A group of 25 patients with a range of solid tumor diagnoses and good performance status received SR233377 at eight dose levels ranging from 4.8 mg/m2 per day to 74.7 mg/m2 per day. Cycles were repeated every 35 days and patients were evaluated for response following two cycles of treatment. Doses were escalated in cohorts of three using a modified Fibonacci scheme. Pharmacokinetic sampling was performed during the first cycle in all patients. RESULTS: Toxicities of SR233377 on this schedule included neutropenia, fever, nausea, and dyspnea but all were mild and not dose-limiting. Asymptomatic prolongation of the corrected QT (QTc) interval during infusion in all patients monitored at the 74.7 mg/m2 dose level prompted closure of the study. QT lengthening correlated with increasing plasma concentrations of SR233377. SR233377 Cmax values increased linearly with dose, but substantial interpatient variability in SR233377 AUC, clearance, and half-life was noted. There was no evidence of drug accumulation when day 1 and day 5 AUC and Cmax values were compared. Seven patients displayed tumor growth inhibition lasting for 4 months or more. CONCLUSIONS: We conclude that SR233377 administered on a 5-day schedule is associated with tolerable clinical symptoms and some activity against a range of solid tumors but dosing is limited by QTc prolongation, a condition that predisposes to ventricular arrhythmias. Phase II development on this schedule is not recommended based on the occurrence of this concentration-dependent effect. Further investigation of alternative schedules of administration and of SR233377 analogues is warranted.

Adult↗