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Biomedical subjects

G Lockwood

Publications and source records attributed to G Lockwood.

At least 19 recordsLinked to original sources
PubMed2003

Phase II trial of pegylated-liposomal doxorubicin in the treatment of locally advanced unresectable or metastatic transitional cell carcinoma of the urothelial tract.

34 patients with advanced unresectable or metastatic urothelial carcinoma who had not received prior chemotherapy for metastatic disease were treated with pegylated-liposomal doxorubicin (PLD) 50 mg/m(2) by a 1-h intravenous infusion (i.v.) every 4 weeks in a multi-institutional phase II trial. 6 of 30 evaluable patients had a partial response to treatment (20%; 95% Confidence Interval (CI), 8-39%) and seven patients had stable disease. Toxicities were primarily non-haematological, but severe palmar-plantar erythrodysesthesia (PPE), lethargy and anorexia were infrequent. Despite a high proportion of patients with poor prognostic features, PLD had clinically significant activity in urothelial cancer in this study. The activity and unique toxicity profile of this drug make it of interest for further study in advanced urothelial cancers in combination with other active agents.

Aged↗
PubMed2003

Management of recurrent locoregional breast cancer: oncologist survey.

Locoregional recurrence (LRR) after therapy for early breast cancer is common. A questionnaire was used to assess consensus between breast oncologists about the definition, prognosis and management of patients with LRR. The questionnaire was mailed to surgical, radiation and medical oncologists in Canada, the UK and the USA. Of 495 questionnaires, 322 (65%) were returned. Most clinicians sampled agree that disease in the skin of the chest wall, surgical scar, axilla, ipsilateral breast tumor recurrence (IBTR), infraclavicular lymph nodes, supraclavicular fossa lymph nodes and internal mammary lymph nodes constitute sites of LRR. The sites that were felt to be curable by the majority of respondents were: IBTR, surgical scar, axilla or chest wall. It was for these disease sites that local therapy was generally recommended. Irrespective of the site of recurrence, most respondents surveyed recommend initiation of a new systemic therapy at the time of LRR. While the results of this survey show general agreement regarding the definition of sites of LRR, treatment recommendations vary among oncologists. Due to the variation in sites of recurrence, time since initial diagnosis and prior therapy, the exact prognosis and optimal management of LRR remain undefined. In the absence of randomized prospective trial data, recommendations for local and systemic therapy of LRR will continue to mimic those offered at the time of initial presentation of breast cancer.

Biopsy, Needle↗
PubMed2003

Phase I clinical study of infusional 5-fluorouracil with oxaliplatin and gemcitabine (FOG regimen) in patients with solid tumors.

BACKGROUND: The aim of this study was to determine the maximum tolerated dose, recommended phase II dose (RPTD) and toxicities of the FOG regimen (infusional 5-fluorouracil, oxaliplatin, gemcitabine). PATIENTS AND METHODS: Patients with advanced solid tumors were treated in an accelerated titration scheme. 5-Fluorouracil was administered intravenously at 200 mg/m(2)/day for 14 days and repeated every 21 days (one cycle). Gemcitabine was administered on days 1 and 8 over 30 min at 450-650 mg/m(2). Oxaliplatin was administered on day 1 over 2 h at 85-130 mg/m(2). For cycles 1, 3 and beyond, gemcitabine followed oxaliplatin; for cycle 2, gemcitabine preceded oxaliplatin. RESULTS: Forty-five and 39 patients were assessable for toxicity and response, respectively. Cycle 1 dose-limiting toxicities (DLT) included neutropenia, thrombocytopenia and diarrhea. No DLT was observed in cycle 1 at the first four dose levels (DL). At DL-5, two of four (50%) patients experienced DLT in cycle 1. Expanding DL-4, nine of 26 (35%) patients experienced DLT in cycle 1. Because recurrent grade 3 toxicities were observed in three of six (50%) patients at DL-3, DL-2 was considered the RPTD. At the RPTD, three patients had a partial response (response rate 23%). CONCLUSIONS: The RPTD for the 5-fluorouracil-oxaliplatin-gemcitabine combination is 200/100/450 mg/m(2). This novel regimen has demonstrated activity in advanced solid tumors and merits further investigation.

Adult↗
PubMed2002

Expansion of air bubbles in aqueous solutions of nitrous oxide or xenon.

BACKGROUND: Anaesthesia using xenon may be contraindicated in some situations because of its diffusion into intravascular bubbles. The expansion of air bubbles in water equilibrated with either nitrous oxide or xenon was studied. METHODS: Equilibrated water was transferred to a stirred vial, closed except for a long, narrow-bore tube. Injection of an air bubble caused displacement of water along the tube, allowing expansion of the bubble to be charted on a linear scale. RESULTS: At 20 degrees C, bubbles expanded from 10 microliters to a median volume of 23 microliters (range 20-23 microliters) and 30 microliters (range 27-34 microliters) in water equilibrated with xenon and nitrous oxide, respectively. Half of the expansion took place in the first 20 s (15-45 s) for xenon and in the first 5 s (5-10 s) for nitrous oxide. At 37 degrees C the expansion was less with both gases, but the relative differences were maintained between them. CONCLUSION: Xenon anaesthesia may be less likely to aggravate injury from intravascular bubbles than anaesthesia with nitrous oxide.

Air↗
PubMed2000

Is benzodiazepine-induced amnesia due to deactivation of the left prefrontal cortex?

UNLABELLED: The amnesic properties of benzodiazepines result from an impairment in explicit (conscious) acquisition of new material. RATIONALE: Explicit encoding of new material has consistently resulted in an increase in regional cerebral blood flow (rCBF) in the left prefrontal cortex, as measured by positron emission tomography (PET). OBJECTIVE: PET was used to determine whether an amnesic dose of midazolam (0.075 mg/kg) attenuated activation in this area during explicit memory encoding. METHODS: A second condition (condition A) used a task to control for the automatic processing that occurs during explicit learning (condition E). RESULTS: The subjects who received midazolam (n=7) recognised significantly fewer words than those who received placebo (n=8), but were not impaired with regard to automatic processing. rCBF was significantly increased in the left prefrontal cortex during explicit encoding of word lists in all subjects and in the temporal lobe and parieto-occipital regions during automatic processing. rCBF was significantly decreased in the prefrontal, superior temporal and parieto-occipital regions following midazolam. The midazolam-induced deactivation in the prefrontal cortex did not affect rCBF activations induced by the explicit memory condition (E-A). CONCLUSIONS: These results suggest that a specific interaction with prefrontal cortex activation does not underlie the amnesic effect of midazolam. However, it remains possible that a threshold level of prefrontal rCBF is necessary for encoding and that, after midazolam, this was not reached.

Adult↗
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↗
PubMed1998

Safety, tolerability, and pharmacokinetics of SR 49059, a V1a vasopressin receptor antagonist, after repeated oral administration in healthy volunteers.

UNLABELLED: The conventional evaluation of safety and tolerability during Phase I may not be sufficient for new exploratory non-peptide receptor antagonists as selective vasopressin (AVP) receptor antagonists. Previous research and validation of surrogate markers considerably enhance the understanding of phase I, and may even contribute with high accuracy to an early approach of dose finding. SR 49059 is a new potent and selective non peptide AVP-antagonist, with high affinity, selectivity and efficacy towards both animal and human AVP-V1a receptors. The aim of this study was to assess its tolerability and to determine both its pharmacokinetic and pharmacodynamic profiles. The safety and tolerability of SR 49059 was assessed in an ascending repeated dose tolerability trial, double-blind for each dose. 50 healthy subjects non smoker males, divided into 5 groups (doses) of 10 were included, (8 treated/2 placebo per group) and received oral doses of either 1, 10, 100, 300 or 600 mg of SR 49059 o.d. for 7 days. Clinical tolerability and biological safety was excellent for all subjects up to the highest dose of 600 mg SR 49059 appeared to have no action on AVP plasma level, hemostasis parameters, nor on blood pressure, heart rate, ECG, diuresis or plasma/urine osmolality. Two previously validated surrogate markers using exogenous vasopressin were sufficient to provide evidence of the V1a antagonistic effects of SR 49059 after the first single oral administration, and during the 7 days of treatment: Ex-vivo AVP induced platelet aggregation inhibition: SR 49059 has shown potent antagonistic properties in inhibiting AVP-induced human platelet aggregation in vitro (IC50 = 3.7 nM). Using this ex vivo qualitative test, a dose and time proportional activity was observed at doses as low as 10 mg, and an almost complete inhibition was demonstrated from 100 mg and above, from Day 1 with a steady state level of inhibition from Day 4 up to Day 7. AVP induced blanching skin area inhibition: Intradermic administration of AVP 0.1 ml (25 ng) produced a measurable vasoconstriction (computer analysis of blanching area), which was also dose dependently antagonised by the oral administration of SR 49059 with the same profile as for platelet-aggregation inhibition. Steady state SR 49059 levels were achieved on days 4-5 with moderate (1.8-2.4 fold) accumulation (t1/2: 32 hrs). Cmax values were in the range 0.8-30 ng/ml. The IC50 of AVP (50 nM) -induced platelet aggregation and cutaneous blanching effect were 2.1 +/- 0.7 nM (1.3 ng/mL) and 4.6 +/- 2.5 nM (2.8 ng/mL), respectively. CONCLUSIONS: During early phase I, in addition to the conventional safety profile, validated surrogate markers may provide evidence of activity for selective vasopressin receptor antagonists. The results confirmed that SR 49059 is in human a specific V1a-antagonist without activity at V2 receptors, with a good safety profile.

Administration, Oral↗
PubMed1998

Comparison of highly purified FSH (metrodin-high purity) with pergonal for IVF superovulation.

PURPOSE: The use of highly purified follicle-stimulating hormone (Metrodin-HP) was compared with that of a preparation containing follicle-stimulating hormone and luteinizing hormone (Pergonal) for production of superovulation in an IVF program. METHODS: We used the Oxford Fertility Unit database to identify patients undergoing their first cycle of IVF, using either Metrodin-HP or Pergonal. Patients were treated with a standardized drug protocol and were stratified by age and cause of infertility. Ovarian stimulation with either Metrodin-HP (Serono Laboratories) or human menopausal gonadotropin (hMG; Pergonal; Serono Laboratories) after pituitary desensitization commenced in the midluteal phase of the preceding cycle. Monitoring was performed by ultrasound and serum estradiol measurement prior to transvaginal oocyte recovery, followed by IVF and transfer of no more than three embryos. RESULTS: For Metrodin-HP versus Pergonal, the rates of egg retrieval (98 vs 94%), fertilization (89 vs 92%), clinical pregnancy (32.9 vs 23.4%), miscarriage (4.1 vs 4.5%), live birth (26 vs 18.5%), and ovarian hyperstimulation syndrome (5.5% vs 5.9%) were similar in both groups. The apparent increase in clinical pregnancy and live birth with Metrodin-HP did not reach statistical significance. The dosages of gonadotropins used were comparable. Estradiol levels measured on day 8 of stimulation were significantly lower in the Metrodin-HP group than in the Pergonal group, but the difference did not reach statistical significance on the day of hCG administration. Significantly more follicles (greater than 12 mm) were obtained in the Metrodin-HP group, but the numbers of eggs recovered and fertilized were similar in the two groups. CONCLUSIONS: These findings demonstrate that highly purified FSH (Metrodin-HP) is as effective and successful as hMG (Pergonal) for ovarian stimulation in a standard IVF regimen. Exogenous luteinizing hormone (LH) is not required for satisfactory ovarian stimulation in IVF. Measurement of estradiol may be less helpful in the monitoring of Metrodin-HP cycles, but the level reached on the day of hCG administration can still be used to predict, and hence avoid, ovarian hyperstimulation syndrome.

Adult↗
PubMed1997

Effects at two years of a low-fat, high-carbohydrate diet on radiologic features of the breast: results from a randomized trial. Canadian Diet and Breast Cancer Prevention Study Group.

BACKGROUND: The appearance of breast tissue on mammography varies according to its composition. Fat is radiolucent and appears dark on mammography, while stromal and epithelial tissue has greater optical density and appears light. Extensive areas of radiologically dense breast tissue seen on mammography are associated with an increased risk of breast cancer. PURPOSE: The purpose of the present study was to determine whether the adoption of a low-fat, high-carbohydrate diet for 2 years would reduce breast density. METHODS: Women with radiologic densities in more than 50% of the breast area on mammography were recruited and randomly allocated to an intervention group taught to reduce intake of dietary fat (mean, 21% of calories) and increase complex carbohydrate (mean, 61% of calories) or to a control group (mean, 32% of calories from fat and 50% of calories from carbohydrates). Mammographic images from 817 subjects were taken at baseline and compared with those taken 2 years after random allocation by use of a quantitative image analysis system, without knowledge of the dietary group of the subjects or of the sequence in which pairs of images had been taken. The effects of the intervention on the mammographic features of breast area, area of dense tissues in the breast, and the percent of the breast occupied by dense tissue were examined using t tests. Multiple regression was used to examine these effects while accounting for age at trial entry, weight change, and menopausal status. RESULTS: After 2 years, the total area of the breast was reduced by an average of 233.7 mm2 (2.4%) (95% confidence interval [CI] = 106.9-360.6) in the intervention group compared with an average increase of 26.3 mm2 (0.3%) (95% CI = -108.0-160.5) in the control group (P = .01). The area of density was reduced by 374.4 mm2 (6.1%) (95% CI = 235.1-513.8) in the intervention group compared with an average of 127.7 mm2 (2.1%) (95% CI = 8.6-246.7) in the control group (P = .01). Weight loss was associated with a reduction in breast area. The effect of the intervention on breast area was only marginally statistically significant after weight change, menopausal status, and age at trial entry were taken into account (P = .06). Greater weight loss and becoming postmenopausal were associated with statistically significant reductions in the area of density on the mammographic image at 2 years (P = .04 and P<.001, respectively). Age at entry into the trial was marginally significant in the same direction (P = .06). The effect of the intervention on area of density remained statistically significant after controlling for weight loss, age at entry, and menopausal status (P = .03). The change in the percentage of dense tissue in the mammographic image was not significantly different between the two groups (P = .71). CONCLUSIONS AND IMPLICATIONS: These results show that after 2 years, a low-fat, high-carbohydrate diet reduced the area of mammographic density, a radiographic feature of the breast that is a risk factor for breast cancer. Longer observation of a larger number of subjects will be required to determine whether these effects are associated with changes in risk of breast cancer.

Adult↗
PubMed1997

EEG changes during cardiopulmonary bypass surgery and postoperative neuropsychological deficit: the effect of bubble and membrane oxygenators.

OBJECTIVE: Quantitative electroencephalography was used during cardiopulmonary bypass surgery to determine the point in time of most neuronal functional change which may result in postoperative neuropsychological deficit. It was also used to determine any relationship between quantitative electroencephalography changes and type of oxygenator used in surgery. METHODS: We studied 61 coronary artery bypass graft patients. Anaesthesia included thiopental, fentanyl and N2O. Surgery was performed with hypothermic bypass (28 degrees C), arterial pressure of 50-70 mmHg, and alpha-stat, using bubble (Harvey 1700), or membrane (Cobe CML) oxygenators, both with arterial line filters (Pall 40 microns). RESULTS: The main finding was a significant increase in delta power at the end of perfusion (P < 0.01), which showed a positive association with delta power before the start of perfusion. Marked quantitative electroencephalography change at the end of perfusion was not related to systemic hypotension, temperature, type of oxygenator, bypass time, or patient age. Intraoperative quantitative electroencephalography changes found in most patients were transient and could not be related to postoperative cerebral function. However, 16 of the 18 patients who had neuropsychological deficit 2 months after surgery, also had a significant quantitative electroencephalography change at the end of perfusion. CONCLUSIONS: While no difference in anaesthetic technique was found between patients, the variation in quantitative electroencephalography power before perfusion may indicate a difference in individual response to anaesthetic. Usefulness of quantitative electroencephalography to predict postoperative cerebral functional deficit remains doubtful.

Aged↗
PubMed1997

Randomised placebo controlled trial of mefenamic acid for premedication at outpatient hysteroscopy: a pilot study.

An increasing number of diagnostic hysteroscopies are being performed in an outpatient setting. Most women tolerate the examination well, but the single commonest reason for failure is pain. We assessed the efficacy of a nonsteroidal, anti-inflammatory analgesic as premedication before hysteroscopy in a double-blind, placebo controlled trial. Our results showed that 500 mg mefenamic acid given one hour before hysteroscopy had no significant benefit in the discomfort experienced during the procedure but did significantly reduce pain after hysteroscopy. A larger dose or a longer interval between premedication and hysteroscopy may possibly be associated with greater benefits.

Adult↗
PubMed1996

Patient-controlled sedation for cataract surgery using peribulbar block.

Patients undergoing cataract surgery using peribulbar block were allocated randomly to self-administer doses of either midazolam 0.1 mg or propofol 3.3 mg without a lock-out facility; in the control group the syringe was charged with saline, not as a placebo, but to "blind" the surgeon and the nurse observer. For midazolam and propofol, median doses were 2.54 (0.1-6.0) mg and 87.4 (0-145) mg, respectively. Patient-controlled sedation significantly reduced the level of anxiety, with median visual analogue anxiety scores in the midazolam, propofol and saline groups of 5 (0-38) mm, 5 (0-25) mm and 15 (0-92) mm, respectively (P < 0.05). Some patients did not administer the sedative when available while others in the saline group would have benefited from anxiolytic drugs. While both drugs prevented an increase in heart rate, only midazolam prevented an increase in arterial pressure during surgery.

Adult↗
PubMed1996

Mammographic signs of potential relevance to breast cancer risk: the agreement of radiologists' classification.

We have assessed the agreement of radiologists who quantitatively estimated the extent of various mammographic features of the breast. These features are of potential relevance to the estimation of the future risk of developing breast cancer. After preparation, in which various mammographic appearances and their classification were discussed and agreed upon, two radiologists, experienced in mammography, independently estimated the extent of various types of radiological density in 120 sets of mammograms, each comprised of two mediolateral and two craniocaudal views. The results showed a high level of agreement between the two radiologists in the classification of total mammographic densities (r = 0.89). For classification of specific types of density, agreement was best for homogeneous densities (r = 0.79), more intermediate for nodular densities (r = 0.71) and worst for linear densities (r = 0.48). These results show that radiologists can, with suitable preparation, identify total breast density, a mammographic sign relevant to a woman's risk of later developing breast cancer, with a high degree of agreement.

Breast Neoplasms↗
PubMed1996

Symmetry of projection in the quantitative analysis of mammographic images.

Mammographic parenchymal patterns are among the strongest indicators of the risk of developing breast cancer. Risk evaluation through breast patterns may have an important role in studies of the aetiology of breast cancer and for monitoring changes in the breast in evaluating potential risk-modifying interventions. Typically, patterns are assessed by an experienced radiologist according to Wolfe grade, or on a coarse quantitative scale according to percent density. Parenchymal characterization methods, to overcome variability of classification by human observer, are under investigation. These include image segmentation using semi-automatic thresholding and automatic classification through textural and density measures. An important practical question relates to the extent to which information about mammographic pattern is carried by any one of the four views obtained in a typical examination. Specifically, variations of right-left breast symmetry and variations between the two standard views of each breast were tested. The mammograms of 30 premenopausal women, comprising 90 images [30 each of the right cranial-caudal (RCC), left cranial-caudal (LCC) and right medial-lateral oblique (RMLO)] were evaluated. Parameters included both subjective (radiologist classification and interactive image thresholding) and objective (fractal and skewness indices) quantitative measurements of parenchymal pattern. For the parameters tested, a high degree of correlations was observed for measurements on the RCC, LCC and RMLO views. Pearson correlation coefficients between 0.86-0.96 were found for the comparisons of quantitative parameters. The strong correlations suggest that, in the study and application of mammographic density classification, representative information is provided in a single view.

Adult↗
PubMed1995

A column-switching high-performance liquid chromatographic assay for a novel cytotoxic thioxanthone derivative (WIN 33377) in mouse plasma with toxicokinetic results from a mouse LD10 study.

WIN 33377 (I) is a member of a novel class of cytotoxic antitumor agents, 4-aminomethyl thioxanthone derivatives. A simple, rapid and reproducible method has been developed for the assay of I in mouse plasma using a high-performance liquid chromatographic method utilizing a column-switching technique. The method involves direct injection of buffered plasma to the extraction column for sample clean-up followed by switching onto an analytical column for analysis with UV detection at 256 nm. The method has demonstrated accuracy and precision over the range 10-2500 ng/ml using a 100-microliters plasma sample with a minimum quantifiable level at 10 ng/ml. Stability of mouse plasma samples was demonstrated after storage for 4 weeks at -15 to -20 degrees C, as was the ability of samples to be accurately quantified after a maximum of three freeze-thaw cycles. Recovery was greater than 87% for the compound and the internal standard. The assay was accurate and reproducible with measured values lying within the limits of defined acceptance criteria. The utility of the method was demonstrated by analyzing plasma samples obtained from mice dosed with I as part of a pre-clinical safety study intended to assist in the design of a pharmacokinetically guided dose escalation strategy.

Animals↗
PubMed1995

Mammographic densities as a criterion for entry to a clinical trial of breast cancer prevention.

The most convincing evidence that a factor such as dietary fat is causally related to breast cancer would be obtained from a randomised controlled trial in which exposure to dietary fat intake was systematically varied. A limitation of randomised controlled trials of breast cancer prevention, however, is the large sample size required to detect plausible reductions in risk resulting from the intervention. We describe here experience over a period of 9 years with the use of one risk factor for breast cancer as a criterion for entry to a clinical trial of breast cancer prevention. The risk factor used was the presence of extensive densities in the breast tissue on mammography, which has been found by several investigators to be strongly associated with risk of breast cancer. Using this criterion for selection, 1800 subjects of mean age 46 years were enrolled between 1982 and 1986, and again between 1988 and the present. Throughout this period, the point estimate of annual invasive cancer incidence was approximately 6 per 1000 per year. The observed cancer incidence has been consistently 4-5 times the incidence expected from age-specific breast cancer incidence data for women living in Ontario. These data show that the selection of subjects for a clinical trial of breast cancer prevention using the criterion of extensive breast parenchymal densities does identify a group at substantially increased risk of breast cancer. Use of this criterion for the selection of subjects can substantially reduce the sample size required for a clinical trial of a preventive strategy.

Adult↗