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Biomedical subjects

E Doyle

Publications and source records attributed to E Doyle.

At least 19 recordsLinked to original sources
PubMed2006

Net1 and Myeov: computationally identified mediators of gastric cancer.

Gastric adenocarcinoma (GA) is a significant cause of mortality worldwide. The molecular mechanisms of GA remain poorly characterised. Our aim was to characterise the functional activity of the computationally identified genes, NET 1 and MYEOV in GA. Digital Differential Display was used to identify genes altered expression in GA-derived EST libraries. mRNA levels of a subset of genes were quantitated by qPCR in a panel of cell lines and tumour tissue. The effect of pro- and anti-inflammatory stimuli on gene expression was investigated. Cell proliferation and invasion were measured using in an in-vitro GA model following inhibition of expression using siRNA. In all, 23 genes not previously reported in association with GA were identified. Two genes, Net1 and Myeov, were selected for further analysis and increased expression was detected in GA tissue compared to paired normal tissue using quantitative PCR. siRNA-mediated downregulation of Net1 and Myeov resulted in decreased proliferation and invasion of gastric cancer cells in vitro. These functional studies highlight a putative role for NET1 and Myeov in the development and progression of gastric cancer. These genes may provide important targets for intervention in GA, evidenced by their role in promoting invasion and proliferation, key phenotypic hallmarks of cancer cells.

Adenocarcinoma↗
PubMed2006

How effective is macula-off retinal detachment surgery. Might good outcome be predicted?

PURPOSE: To determine factors associated with anatomical and functional outcomes of macula-off retinal detachment surgery in a modern vitreoretinal unit. METHODS: A retrospective casenote review of 185 patients presenting with macula-off retinal detachment was performed. Demographic and ocular characteristics were determined. Logistic regression analysis was used to determine (1) the effect of these factors on visual outcome and (2) their effect on primary and final anatomical success. RESULTS: Primary and ultimate anatomical success were achieved in 76 and 84% of cases. Patients with oil in at final follow-up were considered to be anatomical failures. Statistically significant factors predicting primary anatomical success using a multiple variable model were preoperative logMAR visual acuity, preoperative PVR and number of breaks. Preop logMAR visual acuity and duration of macular detachment were the statistically significant factors predicting ultimate success. In all, 44% of patients regained 6/12 Snellen or better with a median improvement of 0.78 logMAR. For prediction of visual outcome (in patients with no ocular comorbidity) only preoperative logMAR visual acuity achieved statistical significance (P=0.001) at the P=0.05 level. CONCLUSION: In all, 76% of macula-off detachments may be repaired with one operation and 44% of patients regain at least 6/12 Snellen. The median logMAR acuity increment of 0.78 far exceeds that seen in cataract surgery. Preoperative visual acuity is the most important factor predicting primary and final anatomical success as well as visual outcome. Preoperative PVR, number of breaks and duration of detachment also affect outcomes.

Adolescent↗
PubMed2005

Type IV hypersensitivity reactions to upper lid gold weight implants-is patch testing necessary?

AIMS: To report two cases of allergic reaction to upper lid gold weight implants in patients with facial nerve palsy and to identify the use of pre-implantation patch testing in predicting gold hypersensitivity. METHODS: One patient who had a positive family history of gold allergy and had undergone previous gold dental restoration underwent patch testing with gold sodium thiosulphate. The gold weight from the same patient was analysed using scanning electron microscopy and energy dispersive X-ray analysis, which can detect surface impurities. Tissue obtained during surgery to remove the gold weight from the second patient was examined histologically. RESULTS: Patch testing in the first patient gave a positive result. Analysis of the gold weight removed from the same patient confirmed 99.99% purity, and hence sensitivity to the gold itself was considered to be the cause of the inflammatory reaction. Histology of tissue taken from the eyelid of the second patient was consistent with type IV hypersensitivity. CONCLUSION: A personal and family history of gold allergy should be looked for before upper eyelid gold weight implantation. Patch testing should be performed for patients where there is doubt about whether gold has been the specific cause of previous allergic reactions, for patients who have undergone previous dental restoration involving gold, or if there is a positive family history of gold allergy.

Aged↗
PubMed2002

Rapid determination of tafenoquine in small volume human plasma samples by high-performance liquid chromatography-tandem mass spectrometry.

A method was developed for the determination of tafenoquine (I) in human plasma using high-performance liquid chromatography-tandem mass spectrometry. Prior to analysis, the protein in plasma samples was precipitated with methanol containing [2H3(15N)]tafenoquine (II) to act as an internal standard. The supernatant was injected onto a Genesis-C18 column without any further clean-up. The mass spectrometer was operated in the positive ion mode, employing a heat assisted nebulisation, electrospray interface. Ions were detected in multiple reaction monitoring mode. The assay required 50 microl of plasma and was precise and accurate within the range 2 to 500 ng/ml. The average within-run and between-run relative standard deviations were < 7% at 2 ng/ml and greater concentrations. The average accuracy of validation standards was generally within +/- 4% of the nominal concentration. There was no evidence of instability of I in human plasma following three complete freeze-thaw cycles and samples can safely be stored for at least 8 months at approximately -70 degrees C. The method was very robust and has been successfully applied to the analysis of clinical samples from patients and healthy volunteers dosed with I.

Aminoquinolines↗
PubMed2001

A comparison of the respiratory effects of high concentrations of halothane and sevoflurane.

We studied the respiratory effects of the administration of either 5% halothane or 8% sevoflurane in 70% nitrous oxide (N2O) for 5 min in 21 boys aged 1-5 years. A similar degree of ventilatory depression was noted with both agents. Minute volume fell by approximately 50% as a result of a reduction in tidal volume despite an increase in respiratory rate.

Anesthesia, Epidural↗
PubMed2001

In vitro activity of gemifloxacin (SB-265805, LB20304a) against Legionella pneumophila and its pharmacokinetics in guinea pigs with L. pneumophila pneumonia.

The activity of gemifloxacin against intracellular Legionella pneumophila and for the treatment of guinea pigs with L. pneumophila pneumonia was studied. Gemifloxacin, azithromycin, and levofloxacin (1 microg/ml) reduced bacterial counts of two L. pneumophila strains grown in guinea pig alveolar macrophages by 2 to 3 log(10) units. Gemifloxacin and levofloxacin had roughly equivalent intracellular activities. In contrast, erythromycin had static activity only. Therapy studies of gemifloxacin, azithromycin, and levofloxacin were performed in guinea pigs with L. pneumophila pneumonia. When gemifloxacin (10 mg/kg) was given by the intraperitoneal (i.p.) route to infected guinea pigs, mean peak levels in plasma were 1.3 microg/ml at 0.5 h and 1.2 microg/ml at 1 h postinjection. The terminal half-life phase of elimination from plasma was 1.3 h, and the area under the concentration-time curve from 0 to 24 h (AUC(0--24)) was 2.1 microg. h/ml. For the same drug dose, mean levels in lungs were 3.4 microg/g at both 0.5 and 1 h, with a half-life of 1.5 h and an AUC(0--24) of 6.0 microg. h/ml. All 15 L. pneumophila-infected guinea pigs treated with gemifloxacin (10 mg/kg/dose given i.p. once daily) for 2 days survived for 9 days after antimicrobial therapy, as did 13 of 14 guinea pigs treated with the same dose of gemifloxacin given for 5 days. All 12 azithromycin-treated animals (15 mg/kg/dose given i.p. once daily for 2 days) survived, as did 11 of 12 animals treated with levofloxacin (10 mg/kg/dose given i.p. once daily for 5 days). None of 12 animals treated with saline survived. Gemifloxacin is effective against L. pneumophila in infected macrophages and in a guinea pig model of Legionnaires' disease, even with an abbreviated course of therapy. These data support studies of the clinical effectiveness of gemifloxacin for the treatment of Legionnaires' disease.

Animals↗
PubMed2000

Rapid determination of gemifloxacin in human plasma by high-performance liquid chromatography-tandem mass spectrometry.

A method was developed for the determination of gemifloxacin (I) in human plasma using high-performance liquid chromatography-tandem mass spectrometry. Prior to analysis, the protein in plasma samples was precipitated with acetonitrile containing [13C2H3] gemifloxacin (II) to act as an internal standard. The supernatant was injected onto a PLRP-S column without any further clean-up. The mass spectrometer was operated in positive ion mode, employing a heat assisted nebulisation. electrospray interface. Ions were detected in multiple reaction monitoring (MRM) mode. The assay requires 50 microl of plasma and is precise and accurate within the range 10-5,000 ng/ml. The average within-run and between-run coefficients of variation were <11% at 10 ng/ml and greater concentrations. The average accuracy of validation standards was generally within +/-7% of the nominal concentration. There was no evidence of instability of I in human plasma following three complete freeze-thaw cycles and samples can safely be stored for at least 6 months at -20 degrees C. The method proved very robust and was successfully applied to the analysis of clinical samples from patients dosed with gemifloxacin.

Anti-Infective Agents↗
PubMed2000

Pretreatment with ranitidine does not reduce the bioavailability of orally administered topotecan.

PURPOSE: The purpose of this randomized, two-period crossover study was to determine the pharmacokinetics of orally administered topotecan in the presence and absence of oral ranitidine. METHODS: Patients with solid malignant tumors refractory to standard treatment were given topotecan orally on a daily times five schedule repeated every 21 days. Topotecan was given initially at 2.3 mg/m2 per day; dose adjustments were permitted after the first dose of course 2 if necessary. Blood samples for pharmacokinetic assessments were drawn at protocol-specified times for up to 10 h following oral administration of topotecan on day 1 of courses 1 and 2. Patients were randomly assigned to receive a total of nine doses of ranitidine: 150 mg twice daily for 4 days before day 1 of one of the first two courses and 150 mg given 2 h before the first topotecan dose. Plasma samples were assayed for concentrations of active topotecan lactone (TPT-L) and total topotecan (TPT-T, lactone plus open-ring carboxylate form) using high-performance liquid chromatography with fluorescence detection. After completion of courses 1 and 2, patients could continue on therapy for days 1-5 of every 21 days if not withdrawn due to unacceptable toxicity, disease progression, protocol violation, or by request. Patients continued on treatment for a maximum of six courses. RESULTS: No pharmacokinetic parameter for either TPT-L or TPT-T differed significantly during administration of topotecan with ranitidine compared with topotecan alone (n = 13). Geometric mean ratios (95% confidence intervals, CIs) of areas under the curve in the presence and absence of ranitidine were 0.94 (0.80, 1.10) for TPT-L and 0.97 (0.80, 1.16) for TPT-T. Corresponding ratios (CIs) of peak plasma concentrations in the presence and absence of ranitidine were 1.06 (0.78, 1.44) for TPT-L and 1.07 (0.84, 1.38) for TPT-T. The median difference in time to peak plasma concentration was 0.0 h for TPT-L and -0.5 h for TPT-T (i.e. slightly faster in the presence of ranitidine). CONCLUSIONS: Administration of ranitidine prior to oral topotecan resulted in a similar extent of absorption. A slightly faster rate of absorption of topotecan was also observed, which is unlikely to be of clinical significance. Dosage adjustments of orally administered topotecan should not be necessary in patients who are pretreated with ranitidine, an H2 antagonist, or another agent that comparably raises gastric pH.

Administration, Oral↗
PubMed2000

Phase I pharmacologic study of oral topotecan and intravenous cisplatin: sequence-dependent hematologic side effects.

PURPOSE: In in vitro studies, synergism and sequence-dependent effects were reported for the combination of topotecan and cisplatin. Recently, an oral formulation of topotecan became available. This phase I study was performed to assess the feasibility of the combination of oral topotecan and cisplatin, the pharmacokinetic interaction, and sequence-dependent effects. PATIENTS AND METHODS: Topotecan was administered orally (PO) daily for 5 days in escalating doses and cisplatin was given intravenously (IV) at a fixed dose of 75 mg/m(2) either before topotecan administration on day 1 (sequence CT) or after topotecan administration on day 5 (sequence TC) once every 3 weeks. Patients were treated in a randomized cross-over design. RESULTS: Forty-nine patients were entered onto the study; one patient was not eligible. Sequence CT induced significantly more severe myelosuppression than did sequence TC, and the maximum-tolerated dosage of topotecan in sequence CT was 1.25 mg/m(2)/d x 5. In sequence TC, the maximum-tolerated dosage of topotecan was 2.0 mg/m(2)/d x 5. Dose-limiting toxicity consisted of myelosuppression and diarrhea. Pharmacokinetics of topotecan and cisplatin were linear over the dose range studied; no sequence-dependent effects were observed. In addition, topotecan did not influence the protein binding of cisplatin or the platinum-DNA adduct formation in peripheral leukocytes in either sequence. CONCLUSION: The recommended dosages for phase II studies involving patients like the patients in our study are topotecan 1.25 mg/m(2)/d PO x 5 preceded by cisplatin 75 mg/m(2) IV day 1 once every 3 weeks, and topotecan 2.0 mg/m(2)/d PO followed by cisplatin 75 mg/m(2) IV day 5. No pharmacokinetic interaction could be discerned in our study. The antitumor efficacy of both schedules should be evaluated in a randomized phase II study.

Adult↗
PubMed1999

Quantification of topotecan and its metabolite N-desmethyltopotecan in human plasma, urine and faeces by high-performance liquid chromatographic methods.

Sensitive high-performance liquid chromatographic (HPLC) methods have been developed and validated for the simultaneous determination of the antitumor drug topotecan and its metabolite N-desmethyltopotecan in human plasma, urine and faeces. Both compounds are reversibly hydrolysed to their hydroxycarboxylate forms at physiologic pH. Separate HPLC systems have been developed for the determination of lactone and total (lactone plus hydroxycarboxylate forms) concentrations in plasma. The instability of the analytes in plasma requires immediate protein precipitation with ice-cold methanol. The lactone forms of the analytes were stable in the methanol extracts for at least 15 months when stored at -70 degrees C. For the determination of the total levels, the plasma extracts were acidified with 25 mM phosphoric acid to convert the compounds into their lactone forms quantitatively. The sample pretreatment procedure for urine included dilution in methanol while the faecal samples were homogenized in distilled water and then extracted twice with an acetonitrile-ammonium acetate mixture. Separation was achieved on reversed-phase columns (Zorbax SB-C18) and detection was performed fluorimetrically at 380/527 nm. Within-run and between-run precisions were less than 10% and average accuracies were between 90 and 110%. The methods were used in a mass balance study in patients with malignant solid tumors to determine the disposition and routes of elimination of topotecan and N-desmethyltopotecan.

Antineoplastic Agents↗